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Heerfordt syndrome | Heerfordt syndrome is a rare manifestation of sarcoidosis. The symptoms include inflammation of the eye (uveitis), swelling of the parotid gland, chronic fever, and in some cases, palsy of the facial nerves.
Causes
The exact cause of Heerfordt syndrome has not yet been definitively determined. Of those patients who have been diagnosed with Heerfordt syndrome, 15% have a close relative who also has the syndrome. One possible explanation is that the syndrome results from a combination of an environmental agent and a hereditary predisposition. Mycobacterium and Propionibacteria species have both been suggested as the environmental agent, though the evidence for this is inconclusive.
Diagnosis
In patients that have already been diagnosed with sarcoidosis, Heerfordt syndrome can be inferred from the major symptoms of the syndrome, which include parotitis, fever, facial nerve palsy and anterior uveitis. In cases of parotitis, ultrasound-guided biopsy is used to exclude the possibility of lymphoma. There are many possible causes of facial nerve palsy, including Lyme disease, HIV, Melkersson–Rosenthal syndrome, schwannoma, and Bells palsy. Heerfordt syndrome exhibits spontaneous remission.
Treatment
Treatments for sarcoidosis include corticosteroids and immunosuppressive drugs.
Prevalence
In the United States, sarcoidosis has a prevalence of approximately 10 cases per 100,000 whites and 36 cases per 100,000 blacks. Heerfordt syndrome is present in 4.1 to 5.6% of those with sarcoidosis.
History
The condition was first described in 1909 by Danish ophthalmologist Christian Frederick Heerfordt, for whom the syndrome is now named. It was originally attributed to mumps, but after further studies by Swedish doctor Jan G. Waldenström in 1937, it was classified as a distinct manifestation of sarcoidosis.
See also
Darier–Roussy disease
Sarcoidosis
List of cutaneous conditions
Notes
Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
References
== External links == |
Campomelic dysplasia | Campomelic dysplasia (CMD) is a genetic disorder characterized by bowing of the long bones and many other skeletal and extraskeletal features.
It can be lethal in the neonatal period due to respiratory insufficiency, but the severity of the disease is variable, and a significant proportion of patients survive into adulthood.
The name is derived from the Greek roots campo (or campto), meaning bent, and melia, meaning limb. An unusual aspect of the disease is that up to two-thirds of affected 46,XY genotypic males display a range of disorders of sexual development (DSD) and genital ambiguities or may even develop as normal phenotypic females as in complete 46 XY sex reversal. An atypical form of the disease with absence of bowed limbs is called, prosaically, acampomelic campomelic dysplasia (ACD) and is found in about 10% of patients, particularly those surviving the neonatal period.
Signs and symptoms
While the definitive presentation of the disease is a patient having bowed lower limbs and sex reversal in 46,XY males, there are other clinical criteria that can be used, absent these characteristics, to make the diagnosis. Patients may present with shortened and angulated lower limbs, a vertically oriented and narrow pelvis, an enlarged head, an undersized jaw, cleft palate, flat nasal bridge, low set ears, club feet. On radiographs, underdeveloped shoulder blades, dislocated hips, hypoplastic vertebral pedicles in the thoracic region, 11 pairs of ribs instead of 12, or kyphosis of the cervical spine are useful diagnostic clues. Respiratory distress can be caused by an underdeveloped trachea which collapses on inhalation or by insufficient rib cage development.
Genetics
CMD is commonly caused by chromosomal abnormalities in or around the gene SOX9 on the long arm of chromosome 17, specifically at position 17q24, generally spontaneously arising or de novo mutations. Also, numerous single nucleotide variants been identified involving the SOX9 gene that cause some form of CMD.
The SOX9 gene codes for a protein transcription factor which, when expressed at the embryonic stage, plays an important role in determining sexual characteristics and greatly influences skeletal development.
When the SRY gene of the Y chromosome is expressed in human embryos, a cascade of gene interactions controlled by SOX9 begins and ultimately leads to male gender.. Any mutation within the coding region of SOX9 can cause campomelic dysplasia and 75% of the reported mutations lead to sex reversal.
Four major classes of heterozygous SOX9 mutations can cause CMD: amino acid substitutions in the HMG-box, truncations or frameshifts that alter the C-terminal end, mutations at the splice junction, and chromosomal translocations.
Additionally, mutations upstream from SOX9 can also cause CMD. Several researchers have reported cis-acting control elements upstream of SOX9.
Translocation breakpoints scattered over 1Mb proximal to SOX9 indicate the presence of an extended control region.The lack of correlation between specific genetic mutations and observed phenotype, particularly with regard to sex reversal, give clear evidence of the variable expressivity of the disease.
Milder forms of the disease, seen in those who live beyond the neonatal period and those with ACD, may perhaps be attributable to somatic mosaicism—particularly for those with mutations within the SOX9 coding region.
Chromosomal aberrations in the upstream control regions or residual activity of the mutant SOX9 protein could also be responsible for the milder forms of the disease.
Long-term survivors of CMD are significantly more likely to have translocation and inversion mutations upstream of SOX9 rather than mutations in the SOX9 coding region itself.
Diagnosis
In utero sonographic diagnosis is possible when characteristic features such as bilateral bowed femurs and tibia, clubbed feet, prominent curvature of the neck, a bell-shaped chest, pelvic dilation, and/or an undersized jaw are apparent.
Radiographic techniques are generally used only postnatally and also rely on prototypical physical characteristics.
However, bent bones are an unspecific sign and most fetuses with bent bones will have conditions other than campomelic dysplasia
Screening
Genetic screening can be done by comparative genomic hybridization (CGH) studies using DNA microarrays.
and by PCR and sequencing of the entire SOX9 gene. Many different translocation breakpoints and related chromosomal aberrations in patients with CMD have been identified.
Prognosis
In more than half of the cases, death occurs in the neonatal period due to respiratory distress, generally related to small chest size or insufficient development of the trachea and other upper airway structures.Among survivors of CMD, the skeletal malformations change over time to include worsening scoliosis or kyphosis resulting in decreased trunk size relative to the limb length. Neurological damage is also often seen including spinal cord compression and deafness. Even among survivors of the prenatal period, CMD patients have shortened life spans due to lifelong respiratory issues. Those patients with ambiguous genitalia or sex reversal at birth, of course, maintain that state, and are either sterile or have reduced fertility.
Epidemiology
Campomelic dysplasia has a reported incidence of 0.05-0.09 per 10000 live births.
References
External links
GeneReviews/NCBI/NIH/UW entry on Campomelic Dysplasia |
Ovarian remnant syndrome | Ovarian remnant syndrome is a condition that occurs when ovarian tissue is left behind following oophorectomy, causing development of a pelvic mass, pelvic pain, and occasionally dyspareunia. Ovarian remnant syndrome (ORS) is characterized by the presence of residual ovarian tissue after a woman has had surgery to remove one ovary or both ovaries (oophorectomy).
Signs and symptoms
If ovarian hormones are present after the ovaries are removed can be a sign that ovarian tissue still remains. Signs and symptoms may include pelvic pain, a pelvic mass, or the absence of menopause after oophorectomy. Factors may include pelvic adhesions (limiting ability to see the ovary or causing it to adhere to other tissues); anatomic variations; bleeding during surgery; or poor surgical technique. Treatment is indicated for people with symptoms and typically involves surgery to remove the residual tissue. Therapy for those who refuse surgery, cannot have surgery, or do not have a pelvic mass may include hormonal therapy to suppress ovarian function.Some women have symptoms consistent with endometriosis, including difficult or painful intercourse; urinary symptoms; or bowel symptoms. It is likely that some women with ORS dont have any symptoms, but the rate of this is unknown. In most cases, symptoms occur within the first five years of the oophorectomy, although there are reports of ORS presenting 20 years after the initial surgery.
Cause
The cause of ORS is the unintentional retention of ovarian tissue after the procedure to remove the ovaries. If a woman is receiving hormone replacement therapy, distinguishing from other disease process may be difficult. Other confounding conditions contributing to ORS are thick and profuse pelvic adhesions, inflammation, bleeding after surgery (peri-operative bleeding), and ovaries which are retroperitoneal, can all contribute to the unintentional preservation of ovarian fragments.
Risks
The risk of ovarian remnant (ORS) is increased by incomplete removal of the ovary at the time of oophorectomy. Surgical factors that contribute to incomplete removal include those that limit surgical exposure of the ovary, or compromise surgical technique. Factors may include:
adhesions – these can limit visualization of the ovary and may also cause it to adhere to surrounding tissues. Adhesions are often present due to preexisting conditions and/or prior surgeries. In the majority of cases reported since 2007, endometriosis was the most common indication for the initial oophorectomy in patients who subsequently had ORS. Endometriosis increases the risk for functional ovarian tissue being embedded into adjacent structures, making complete excision of tissue challenging.
Anatomic variations - unusual location of ovarian tissue, for example
Intraoperative bleeding
Poor surgical technique – this may include failure to obtain adequate exposure or restore adequate anatomy, or imprecise choice of incision siteOvarian remnant (ORS) may first be considered in women who have undergone oophorectomy and have suggestive symptoms, the presence of a mass, or evidence of persistent ovarian function (by symptoms or laboratory testing). A history of oophorectomy is required, by definition, to make the diagnosis. Notes regarding the indication for the procedure and the procedure itself should be reviewed and may include prior abdominal or pelvic surgery, endometriosis, and/or poor surgical visualization. If ORS is possible, pelvic should be performed to evaluate for a pelvic mass.[1]
Diagnosis
Surgical exploration and confirmation of possible ovarian tissue is required for the definitive diagnosis of ORS, and treatment by excision of the remnant ovarian tissue may be performed during the same procedure. For women who are not candidates for surgery, a clinical diagnosis can be made based on the symptoms and levels (follicle-stimulating hormone and estradiol, after bilateral oophorectomy) and/or findings consistent with the presence of residual ovarian tissue. Laparoscopy and histological assessment can aid in diagnosis.
Treatment
Treatment for ovarian remnant (ORS) is generally indicated for women with suspected ORS who have symptoms (such as pain); have a pelvic mass; or need or desire complete removal of to decrease the risk of ovarian (for example, BRCA ). The mainstay of treatment is surgery to remove the residual ovarian tissue. Women with ORS with a pelvic mass should have appropriate evaluation for malignancy (cancer). Hormonal therapy to suppress ovarian function is an alternative treatment for those who refuse surgery, or those who are not candidates for surgery. Medications may be used to treat ORS and include GnRH agonists, danazol, or progesterone.
Epidemiology
The incidence of ovarian remnant syndrome is difficult to determine. The available data are limited to case reports or to retrospective case series. The best available data are from a study describing the frequency and outcome of laparoscopy in women with chronic pelvic pain and/or a pelvic mass who were found to have ovarian remnants. In 119 women who underwent hysterectomy and oophorectomy by laparoscopy, ovarian remnants were known in 5 and were found during surgery in 21 patients (18%).[2] However, this was a small study and the participants were only symptomatic women. Therefore, it is not known whether the data can be extrapolated to include all women who have undergone oophorectomy.
References
External links
Ovarian remnant syndrome |
Learning disability | Learning disability, learning disorder, or learning difficulty (British English) is a condition in the brain that causes difficulties comprehending or processing information and can be caused by several different factors. Given the "difficulty learning in a typical manner", this does not exclude the ability to learn in a different manner. Therefore, some people can be more accurately described as having a "learning difference", thus avoiding any misconception of being disabled with a lack of ability to learn and possible negative stereotyping. In the United Kingdom, the term "learning disability" generally refers to an intellectual disability, while difficulties such as dyslexia and dyspraxia are usually referred to as "learning difficulties".While learning disability and learning disorder are often used interchangeably, they differ in many ways. Disorder refers to significant learning problems in an academic area. These problems, however, are not enough to warrant an official diagnosis. Learning disability, on the other hand, is an official clinical diagnosis, whereby the individual meets certain criteria, as determined by a professional (such as a psychologist, psychiatrist, speech language pathologist, or pediatrician). The difference is in degree, frequency, and intensity of reported symptoms and problems, and thus the two should not be confused. When the term "learning disorder" is used, it describes a group of disorders characterized by inadequate development of specific academic, language, and speech skills. Types of learning disorders include reading (dyslexia), arithmetic (dyscalculia) and writing (dysgraphia).The unknown factor is the disorder that affects the brains ability to receive and process information. This disorder can make it problematic for a person to learn as quickly or in the same way as someone who is not affected by a learning disability. People with a learning disability have trouble performing specific types of skills or completing tasks if left to figure things out by themselves or if taught in conventional ways.
Individuals with learning disabilities can face unique challenges that are often pervasive throughout the lifespan. Depending on the type and severity of the disability, interventions, and current technologies may be used to help the individual learn strategies that will foster future success. Some interventions can be quite simplistic, while others are intricate and complex. Current technologies may require student training to be effective classroom supports. Teachers, parents, and schools can create plans together that tailor intervention and accommodations to aid the individuals in successfully becoming independent learners. A multi-disciplinary team frequently helps to design the intervention and to coordinate the execution of the intervention with teachers and parents. This team frequently includes school psychologists, special educators, speech therapists (pathologists), occupational therapists, psychologists, ESL teachers, literacy coaches, and/or reading specialists.
Definition
Representatives of organizations committed to the education and welfare of individuals with learning disabilities are known as National Joint Committee on Learning Disabilities (NJCLD). The NJCLD used the term learning disability to indicate a discrepancy between a childs apparent capacity to learn and their level of achievement. Several difficulties existed, however, with the NJCLD standard of defining learning disability. One such difficulty was its belief of central nervous system dysfunction as a basis of understanding and diagnosing learning disability. This conflicted with the fact that many individuals who experienced central nervous system dysfunction, such as those with cerebral palsy, did not experience disabilities in learning. On the other hand, those individuals who experienced multiple handicapping conditions along with learning disability frequently received inappropriate assessment, planning, and instruction. The NJCLD notes that it is possible for learning disability to occur simultaneously with other handicapping conditions, however, the two should not be directly linked together or confused.
In the 1980s, NJCLD, therefore, defined the term learning disability as: a heterogeneous group of disorders manifested by significant difficulties in the acquisition and use of listening, speaking, reading, writing, reasoning or mathematical abilities. These disorders are intrinsic to the individual and presumed to be due to Central Nervous System Dysfunction. Even though a learning disability may occur concomitantly with other handicapping conditions (e.g. sensory impairment, intellectual disability, social and emotional disturbance) or environmental influences (e.g. cultural differences, insufficient/inappropriate instruction, psychogenic factors) it is not the direct result of those conditions or influences.
The 2002 LD Roundtable produced the following definition:Concept of LD: Strong converging evidence supports the validity of the concept of specific learning disabilities (SLD). This evidence is particularly impressive because it converges across different indicators and methodologies. The central concept of SLD involves disorders of learning and cognition that are intrinsic to the individual. SLD are specific in the sense that these disorders each significantly affect a relatively narrow range of academic and performance outcomes. SLD may occur in combination with other disabling conditions, but they are not due primarily to other conditions, such as intellectual disability, behavioral disturbance, lack of opportunities to learn, or primary sensory deficits.The issue of defining learning disabilities has generated significant and ongoing controversy. The term "learning disability" does not exist in DSM-IV, but it has been added to the DSM-5. The DSM-5 does not limit learning disorders to a particular diagnosis such as reading, mathematics, or written expression. Instead, it is a single diagnosis criterion describing drawbacks in general academic skills and includes detailed specifiers for the areas of reading, mathematics, and written expression.
United States and Canada
In the United States and Canada, the terms learning disability and learning disorder (LD) refer to a group of disorders that affect a broad range of academic and functional skills including the ability to speak, listen, read, write, spell, reason, organize information, and do math. People with learning disabilities generally have intelligence that is average or higher.
Legislation in the United States
The Section 504 of the Rehabilitation Act 1973, effective May 1977, guarantees certain rights to people with disabilities, especially in the cases of education and work, such being in schools, colleges and university settings.The Individuals with Disabilities Education Act, formerly known as the Education for All Handicapped Children Act, is a United States federal law that governs how states and public agencies provide early intervention, special education and related services to children with disabilities. It addresses the educational needs of children with disabilities from birth to the age of 21. Considered as a civil rights law, states are not required to participate.
Canada
In Canada, the first association in support of children with learning disabilities was founded in 1962 by a group of concerned parents. Originally called the Association for Children with Learning Disabilities, the Learning Disabilities Association of Canada – LDAC was created to provide awareness and services for individuals with learning disabilities, their families, at work, and the community. Since education is largely the responsibility of each province and territory in Canada, provinces and territories have jurisdiction over the education of individuals with learning disabilities, which allows the development of policies and support programs that reflect the unique multicultural, linguistic, and socioeconomic conditions of its area.
United Kingdom
In the UK, terms such as specific learning difficulty (SpLD), developmental dyslexia, developmental coordination disorder and dyscalculia are used to cover the range of learning difficulties referred to in the United States as "learning disabilities". In the UK, the term "learning disability" refers to a range of developmental disabilities or conditions that are almost invariably associated with more severe generalized cognitive impairment. The Lancet defines learning disability as a "significant general impairment in intellectual functioning acquired during childhood", and states that roughly one in 50 British adults have one.
Japan
In Japan, acknowledgement and support for students with learning disabilities has been a fairly recent development, and has improved drastically in the last decade. The first definition for learning disability was coined in 1999, and in 2001, the Enrichment Project for the Support System for Students with Learning Disabilities was established. Since then, there have been significant efforts to screen children for learning disabilities, provide follow-up support, and provide networking between schools and specialists.
Effects
The effects of having a learning disability or learning difference are not limited to educational outcomes: individuals with learning disabilities may experience social problems as well. Neuropsychological differences can affect the accurate perception of social cues with peers. Researchers argue persons with learning disabilities not only experience negative effects as a result of their learning distinctions, but also as a result of carrying a stigmatizing label. It has generally been difficult to determine the efficacy of special education services because of data and methodological limitations. Emerging research suggests adolescents with learning disabilities experience poorer academic outcomes even compared to peers who began high school with similar levels of achievement and comparable behaviors. It seems their poorer outcomes may be at least partially due to the lower expectations of their teachers; national data show teachers hold expectations for students labeled with learning disabilities that are inconsistent with their academic potential (as evidenced by test scores and learning behaviors). It has been said that there is a strong connection between children with a learning disability and their educational performance.Many studies have been done to assess the correlation between learning disability and self-esteem. These studies have shown that an individuals self-esteem is indeed affected by their own awareness of their learning disability. Students with a positive perception of their academic abilities generally tend to have higher self-esteem than those who do not, regardless of their actual academic achievement. However, studies have also shown that several other factors can influence self-esteem. Skills in non-academic areas, such as athletics and arts, improve self-esteem. Also, a positive perception of ones physical appearance has also been shown to have positive effects of self-esteem. Another important finding is that students with learning disabilities are able to distinguish between academic skill and intellectual capacity. This demonstrates that students who acknowledge their academic limitations but are also aware of their potential to succeed in other intellectual tasks see themselves as intellectually competent individuals, which increases their self-esteem.Research involving individuals with learning disabilities who exhibit challenging behaviors who are subsequently treated with antipsychotic medications provides little evidence that any benefits outweigh the risk.
Causes
The causes for learning disabilities are not well understood, and sometimes there is no apparent cause for a learning disability. However, some causes of neurological impairments include:
Heredity and genetics
Learning disabilities are often linked through genetics and run in the family. Children who have learning disabilities often have parents who have the same struggles. Children of parents who had less than 12 years of school are more likely to have a reading disability. Some children have spontaneous mutations (i.e. not present in either parent) which can cause developmental disorders including learning disabilities. One study estimated that about one in 300 children had such spontaneous mutations, for example a fault in the CDK13 gene which is associated with learning and communication difficulties in the children affected.
Problems during pregnancy and birth
A learning disability can result from anomalies in the developing brain, illness or injury. Risk factors are fetal exposure to alcohol or drugs and low birth weight (3 pounds or less). These children are more likely to develop a disability in math or reading. Children who are born prematurely, late, have a longer labor than usual, or have trouble receiving oxygen are more likely to develop a learning disability.
Accidents after birth
Learning disabilities can also be caused by head injuries, malnutrition, or by toxic exposure (such as heavy metals or pesticides).
Diagnosis
IQ-achievement discrepancy
Learning disabilities can be identified by psychiatrists, speech language pathologists, school psychologists, clinical psychologists, counseling psychologists, neuropsychologists, speech language pathologists, and other learning disability specialists through a combination of intelligence testing, academic achievement testing, classroom performance, and social interaction and aptitude. Other areas of assessment may include perception, cognition, memory, attention, and language abilities. The resulting information is used to determine whether a childs academic performance is commensurate with their cognitive ability. If a childs cognitive ability is much higher than their academic performance, the student is often diagnosed with a learning disability. The DSM-IV and many school systems and government programs diagnose learning disabilities in this way (DSM-IV uses the term "disorder" rather than "disability").
Although the discrepancy model has dominated the school system for many years, there has been substantial criticism of this approach among researchers. Recent research has provided little evidence that a discrepancy between formally measured IQ and achievement is a clear indicator of LD. Furthermore, diagnosing on the basis of a discrepancy does not predict the effectiveness of treatment. Low academic achievers who do not have a discrepancy with IQ (i.e. their IQ scores are also low) appear to benefit from treatment just as much as low academic achievers who do have a discrepancy with IQ (i.e. their IQ scores are higher than their academic performance would suggest).
Since 1998 there have been attempts to create a reference index more useful than IQ to generate predicted scores on achievement tests. For example, for a student whose vocabulary and general knowledge scores matches their reading comprehension score a teacher could assume that reading comprehension can be supported through work in vocabulary and general knowledge. If the reading comprehension score is lower in the appropriate statistical sense it would be necessary to first rule out things like vision problems
Response to intervention
Much current research has focused on a treatment-oriented diagnostic process known as response to intervention (RTI). Researcher recommendations for implementing such a model include early screening for all students, placing those students who are having difficulty into research-based early intervention programs, rather than waiting until they meet diagnostic criteria. Their performance can be closely monitored to determine whether increasingly intense intervention results in adequate progress. Those who respond will not require further intervention. Those who do not respond adequately to regular classroom instruction (often called "Tier 1 instruction") and a more intensive intervention (often called "Tier 2" intervention) are considered "non-responders." These students can then be referred for further assistance through special education, in which case they are often identified with a learning disability. Some models of RTI include a third tier of intervention before a child is identified as having a learning disability.
A primary benefit of such a model is that it would not be necessary to wait for a child to be sufficiently far behind to qualify for assistance. This may enable more children to receive assistance before experiencing significant failure, which may, in turn, result in fewer children who need intensive and expensive special education services. In the United States, the 2004 reauthorization of the Individuals with Disabilities Education Act permitted states and school districts to use RTI as a method of identifying students with learning disabilities. RTI is now the primary means of identification of learning disabilities in Florida.
The process does not take into account childrens individual neuropsychological factors such as phonological awareness and memory, that can inform design instruction. By not taking into account specific cognitive processes, RTI fails to inform educators about a students relative strengths and weaknesses Second, RTI by design takes considerably longer than established techniques, often many months to find an appropriate tier of intervention. Third, it requires a strong intervention program before students can be identified with a learning disability. Lastly, RTI is considered a regular education initiative and consists of members of general education teachers, in conjunction with other qualified professionals. Occupational therapists (OTs) in particular can support students in the educational setting by helping children in academic and non-academic areas of school including the classroom, recess and meal time. They can provide strategies, therapeutic interventions, suggestions for adaptive equipment, and environmental modifications. OTs can work closely with the childs teacher and parents to facilitate educational goals specific to each child under an RTI and/or IEP.
Latino English language learners
Demographers in the United States report that there has been a significant increase in immigrant children in the United States over the past two decades. This information is vital because it has been and will continue to affect both students and how educators approach teaching methods. Various teaching strategies are more successful for students that are linguistic or culturally diverse versus traditional methods of teaching used for students whose first language is English. It is then also true that the proper way to diagnose a learning disability in English language learners (ELL) differs. In the United States, there has been a growing need to develop the knowledge and skills necessary to provide effective school psychological services, specifically for those professionals who work with immigrant populations.Currently, there are no standardized guidelines for the process of diagnosing English language learners (ELL) with specific learning disabilities (SLD). This is a problem since many students will fall through the cracks as educators are unable to clearly assess if a students delay is due to a language barrier or true learning disability. With an unclear diagnosis, many students will suffer because they will not be provided with the tools they need to succeed in the public education school system. For example, in many occasions teachers have suggested retention or have taken no action at all when they lack experience working with English language learners. Students were commonly pushed toward testing, based on an assumption that their poor academic performance or behavioral difficulties indicated a need for special education. Linguistically responsive psychologist understand that second language acquisition is a process and they understand how to support ELLs growth in language and academically.</ref> When ELLs are referred for a psychoeducational assessment, it is difficult to isolate and disentangle what are the effects of the language acquisition process, from poor quality educational services, from what may be academic difficulties that result from processing disorders, attention problems, and learning disabilities. Additionally not having trained staff and faculty becomes more of an issue when staff is unaware of numerous types of psychological factors that immigrant children in the U.S dealing could be potentially dealing with. These factors that include acculturation, fear and/or worry of deportation, separation from social supports such as parents, language barriers, disruptions in learning experiences, stigmatization, economic challenge, and risk factors associated with poverty. In the United States, there are no set policies mandating that all districts employ bilingual school psychologist, nor are schools equipped with specific tools and resources to assist immigrant children and families. Many school districts do not have the proper personnel that is able to communicate with this population.
Spanish-speaking ELL
A well trained bilingual school psychologist will be able to administer and interpret assessment all psychological testing tool. Also, an emphasis is placed on informal assessment measures such as language samples, observations, interviews, and rating scales as well as curriculum-based measurement to complement information gathered from formal assessments. A compilation of these tests is used to assess whether an ELL student has a learning disability or merely is academically delayed because of language barriers or environmental factors. It is very unfortunate that many schools do not have school psychologist with the proper training nor access to appropriate tools. Also, many school districts frown upon taking the appropriate steps to diagnosing ELL students.
Assessment
Many normed assessments can be used in evaluating skills in the primary academic domains: reading, including word recognition, fluency, and comprehension; mathematics, including computation and problem solving; and written expression, including handwriting, spelling and composition.
The most commonly used comprehensive achievement tests include the Woodcock-Johnson IV (WJ IV), Wechsler Individual Achievement Test II (WIAT II), the Wide Range Achievement Test III (WRAT III), and the Stanford Achievement Test–10th edition. These tests include measures of many academic domains that are reliable in identifying areas of difficulty.In the reading domain, there are also specialized tests that can be used to obtain details about specific reading deficits. Assessments that measure multiple domains of reading include Grays Diagnostic Reading Tests–2nd edition (GDRT II) and the Stanford Diagnostic Reading Assessment. Assessments that measure reading subskills include the Gray Oral Reading Test IV – Fourth Edition (GORT IV), Gray Silent Reading Test, Comprehensive Test of Phonological Processing (CTOPP), Tests of Oral Reading and Comprehension Skills (TORCS), Test of Reading Comprehension 3 (TORC-3), Test of Word Reading Efficiency (TOWRE), and the Test of Reading Fluency. A more comprehensive list of reading assessments may be obtained from the Southwest Educational Development Laboratory.The purpose of assessment is to determine what is needed for intervention, which also requires consideration of contextual variables and whether there are comorbid disorders that must also be identified and treated, such as behavioral issues or language delays. These contextual variables are often assessed using parent and teacher questionnaire forms that rate the students behaviors and compares them to standardized norms.
However, caution should be made when suspecting the person with a learning disability may also have dementia, especially as people with Downs syndrome may have the neuroanatomical profile but not the associated clinical signs and symptoms. Examination can be carried out of executive functioning as well as social and cognitive abilities but may need adaptation of standardized tests to take account of special needs.
Types
Learning disabilities can be categorized by either the type of information processing affected by the disability or by the specific difficulties caused by a processing deficit.
By stage of information processing
Learning disabilities fall into broad categories based on the four stages of information processing used in learning: input, integration, storage, and output. Many learning disabilities are a compilation of a few types of abnormalities occurring at the same time, as well as with social difficulties and emotional or behavioral disorders.
Input
This is the information perceived through the senses, such as visual and auditory perception. Difficulties with visual perception can cause problems with recognizing the shape, position, or size of items seen. There can be problems with sequencing, which can relate to deficits with processing time intervals or temporal perception. Difficulties with auditory perception can make it difficult to screen out competing sounds in order to focus on one of them, such as the sound of the teachers voice in a classroom setting. Some children appear to be unable to process tactile input. For example, they may seem insensitive to pain or dislike being touched.
Integration
This is the stage during which perceived input is interpreted, categorized, placed in a sequence, or related to previous learning. Students with problems in these areas may be unable to tell a story in the correct sequence, unable to memorize sequences of information such as the days of the week, able to understand a new concept but be unable to generalize it to other areas of learning, or able to learn facts but be unable to put the facts together to see the "big picture." A poor vocabulary may contribute to problems with comprehension.
Storage
Problems with memory can occur with short-term or working memory, or with long-term memory. Most memory difficulties occur with ones short-term memory, which can make it difficult to learn new material without more repetitions than usual. Difficulties with visual memory can impede learning to spell.
Output
Information comes out of the brain either through words, that is, language output, or through muscle activity, such as gesturing, writing or drawing. Difficulties with language output can create problems with spoken language. Such difficulties include answering a question on demand, in which one must retrieve information from storage, organize our thoughts, and put the thoughts into words before we speak. It can also cause trouble with written language for the same reasons. Difficulties with motor abilities can cause problems with gross and fine motor skills. People with gross motor difficulties may be clumsy, that is, they may be prone to stumbling, falling, or bumping into things. They may also have trouble running, climbing, or learning to ride a bicycle. People with fine motor difficulties may have trouble with handwriting, buttoning shirts, or tying shoelaces.
By function impaired
Deficits in any area of information processing can manifest in a variety of specific learning disabilities. It is possible for an individual to have more than one of these difficulties. This is referred to as comorbidity or co-occurrence of learning disabilities. In the UK, the term dual diagnosis is often used to refer to co-occurrence of learning difficulties.
Reading disorder (ICD-10 and DSM-IV codes: F81.0/315.00)
Reading disorder is the most common learning disability. Of all students with specific learning disabilities, 70–80% have deficits in reading. The term "Developmental Dyslexia" is often used as a synonym for reading disability; however, many researchers assert that there are different types of reading disabilities, of which dyslexia is one. A reading disability can affect any part of the reading process, including difficulty with accurate or fluent word recognition, or both, word decoding, reading rate, prosody (oral reading with expression), and reading comprehension. Before the term "dyslexia" came to prominence, this learning disability used to be known as "word blindness."
Common indicators of reading disability include difficulty with phonemic awareness—the ability to break up words into their component sounds, and difficulty with matching letter combinations to specific sounds (sound-symbol correspondence).
Disorder of written expression (ICD-10 and DSM-IV-TR codes 315.2)
The DSM-IV-TR criteria for a disorder of written expression is writing skills (as measured by a standardized test or functional assessment) that fall substantially below those expected based on the individuals chronological age, measured intelligence, and age-appropriate education, (Criterion A). This difficulty must also cause significant impairment to academic achievement and tasks that require composition of written text (Criterion B), and if a sensory deficit is present, the difficulties with writing skills must exceed those typically associated with the sensory deficit, (Criterion C).Individuals with a diagnosis of a disorder of written expression typically have a combination of difficulties in their abilities with written expression as evidenced by grammatical and punctuation errors within sentences, poor paragraph organization, multiple spelling errors, and excessively poor penmanship. A disorder in spelling or handwriting without other difficulties of written expression do not generally qualify for this diagnosis. If poor handwriting is due to an impairment in the individuals motor coordination, a diagnosis of developmental coordination disorder should be considered.
By a number of organizations, the term "dysgraphia" has been used as an overarching term for all disorders of written expression.
Math disability (ICD-10 and DSM-IV codes F81.2-3/315.1)
Sometimes called dyscalculia, a math disability involves difficulties such as learning math concepts (such as quantity, place value, and time), difficulty memorizing math facts, difficulty organizing numbers, and understanding how problems are organized on the page. Dyscalculics are often referred to as having poor "number sense".
Non ICD-10/DSM
Nonverbal learning disability: Nonverbal learning disabilities often manifest in motor clumsiness, poor visual-spatial skills, problematic social relationships, difficulty with mathematics, and poor organizational skills. These individuals often have specific strengths in the verbal domains, including early speech, large vocabulary, early reading and spelling skills, excellent rote memory and auditory retention, and eloquent self-expression.
Disorders of speaking and listening: Difficulties that often co-occur with learning disabilities include difficulty with memory, social skills and executive functions (such as organizational skills and time management).
Management
Interventions include:
Mastery model:
Learners work at their own level of mastery.
Practice
Gain fundamental skills before moving onto the next level
Note: this approach is most likely to be used with adult learners or outside the mainstream school system.
Direct instruction:Emphasizes carefully planned lessons for small learning increments
Scripted lesson plans
Rapid-paced interaction between teacher and students
Correcting mistakes immediately
Achievement-based grouping
Frequent progress assessments
Classroom adjustments:
Special seating assignments
Alternative or modified assignments
Modified testing procedures
Quiet environment
Special equipment:
Word processors with spell checkers and dictionaries
Text-to-speech and speech-to-text programs
Talking calculators
Books on tape
Computer-based activities
Classroom assistants:
Note-takers
Readers
Proofreaders
Scribes
Special education:
Prescribed hours in a resource room
Placement in a resource room
Enrollment in a special school or a separate classroom in a regular school for learning disabled students
Individual education plan (IEP)
Educational therapySternberg has argued that early remediation can greatly reduce the number of children meeting diagnostic criteria for learning disabilities. He has also suggested that the focus on learning disabilities and the provision of accommodations in school fails to acknowledge that people have a range of strengths and weaknesses, and places undue emphasis on academic success by insisting that people should receive additional support in this arena but not in music or sports. Other research has pinpointed the use of resource rooms as an important—yet often politicized component of educating students with learning disabilities.
Society and culture
School laws
Schools in the United States have a legal obligation to new arrivals to the country, including undocumented students. The landmark Supreme Court ruling Plyler v. Doe (1982) grants all children, no matter their legal status, the right to a free education. This ruling suggests that as a country we acknowledge that we have a population of students with specific needs that differ from those of native speakers. Additionally specifically in regards to ELLs the supreme court ruling Lau v. Nichols (1974) stated that equal treatment in school did not mean equal educational opportunity. Thus if a school teaches a lesson in a language that students do not understand then they are effectively worthless. This ruling is also supported by English language development services provided in schools, but these rulings do not require the individuals that teach and provide services to have any specific training nor is licensing different from a typical teacher or services provider.
Critique of the medical model
Learning disability theory is founded in the medical model of disability, in that disability is perceived as an individual deficit that is biological in origin. Researchers working within a social model of disability assert that there |
Learning disability | are social or structural causes of disability or the assignation of the label of disability, and even that disability is entirely socially constructed. Since the turn of the 19th century, education in the United States has been geared toward producing citizens who can effectively contribute to a capitalistic society, with a cultural premium on efficiency and science. More agrarian cultures, for example, do not even use learning ability as a measure of adult adequacy, whereas the diagnosis of learning disabilities is prevalent in Western capitalistic societies because of the high value placed on speed, literacy, and numeracy in both the labor force and school system.
Culture
There are three patterns that are well known in regards to mainstream students and minority labels in the United States:
"A higher percentage of minority children than of white children are assigned to special education";
"within special education, white children are assigned to less restrictive programs than are their minority counterparts";
"the data — driven by inconsistent methods of diagnosis, treatment, and funding — make the overall system difficult to describe or change".In the present day, it has been reported that white districts have more children from minority backgrounds enrolled in special education than they do majority students. "It was also suggested that districts with a higher percentage of minority faculty had fewer minority students placed in special education suggesting that minority students are treated differently in predominantly white districts than in predominantly minority districts".Educators have only recently started to look into the effects of culture on learning disabilities. If a teacher ignores a students culturally diverse background, the student will suffer in the class. "The cultural repertoires of students from cultural learning disorder backgrounds have an impact on their learning, school progress, and behavior in the classroom". These students may then act out and not excel in the classroom and will, therefore, be misdiagnosed: "Overall, the data indicates that there is a persistent concern regarding the misdiagnosis and inappropriate placement of students from diverse backgrounds in special education classes since the 1975".
Social roots of learning disabilities in the U.S.
Learning disabilities have a disproportionate identification of racial and ethnic minorities and students who have low socioeconomic status (SES). While some attribute the disproportionate identification of racial/ethnic minorities to racist practices or cultural misunderstanding, others have argued that racial/ethnic minorities are overidentified because of their lower status. Similarities were noted between the behaviors of "brain-injured" and lower class students as early as the 1960s. The distinction between race/ethnicity and SES is important to the extent that these considerations contribute to the provision of services to children in need.
While many studies have considered only one characteristic of the student at a time, or used district- or school-level data to examine this issue, more recent studies have used large national student-level datasets and sophisticated methodology to find that the disproportionate identification of African American students with learning disabilities can be attributed to their average lower SES, while the disproportionate identification of Latino youth seems to be attributable to difficulties in distinguishing between linguistic proficiency and learning ability. Although the contributing factors are complicated and interrelated, it is possible to discern which factors really drive disproportionate identification by considering a multitude of student characteristics simultaneously. For instance, if high SES minorities have rates of identification that are similar to the rates among high SES Whites, and low SES minorities have rates of identification that are similar to the rates among low SES Whites, we can know that the seemingly higher rates of identification among minorities result from their greater likelihood to have low SES. Summarily, because the risk of identification for White students who have low SES is similar to that of Black students who have low SES, future research and policy reform should focus on identifying the shared qualities or experiences of low SES youth that lead to their disproportionate identification, rather than focusing exclusively on racial/ethnic minorities. It remains to be determined why lower SES youth are at higher risk of incidence, or possibly just of identification, with learning disabilities.
Learning disabilities in adulthood
A common misconception about those with learning disabilities is that they outgrow it as they enter adulthood. This is often not the case and most adults with learning disabilities still require resources and care to help manage their disability. One resource available is the Adult Basic Education (ABE) programs, at the state level. ABE programs are allotted certain amounts of funds per state in order to provide resources for adults with learning disabilities. This includes resources to help them learn basic life skills in order to provide for themselves. ABE programs also provide help for adults who lack a high school diploma or an equivalent. These programs teach skills to help adults get into the workforce or into a further level of education. There is a certain pathway that these adults and instructors should follow in order to ensure these adults have the abilities needed to succeed in life. Some ABE programs offer GED preparation programs to support adults through the process to get a GED. It is important to note that ABE programs do not always have the expected outcome on things like employment. Participants in ABE programs are given tools to help them succeed and get a job but, employment is dependent on more than just a guarantee of a job post-ABE. Employment varies based on the level of growth a participant experiences in an ABE program, the personality and behavior of the participant, and the job market they are entering into following completion of an ABE program.Another program to assist adults with disabilities are federal programs called "home and community based services" (HCBS). Medicaid funds these programs for many people through a fee waiver system, however, there are still lots of people on a stand-by list. These programs are primarily used for adults with Autism Spectrum Disorders. HCBS programs offer service more dedicated to caring for the adult, not so much providing resources for them to transition into the workforce. Some services provided are: therapy, social skills training, support groups, and counseling.
Contrast with other conditions
People with an IQ lower than 70 are usually characterized as having an intellectual disability and are not included under most definitions of learning disabilities because their difficulty in learning are considered to be related directly to their overall low intelligence.
Attention-deficit hyperactivity disorder (ADHD) is often studied in connection with learning disabilities, but it is not actually included in the standard definitions of learning disabilities. Individuals with ADHD may struggle with learning, but can often learn adequately once successfully treated for the ADHD. A person can have ADHD but not learning disabilities or have learning disabilities without having ADHD. The conditions can co-occur.People diagnosed with ADHD sometimes have impaired learning. Some of the struggles people with ADHD have might include lack of motivation, high levels of anxiety, and the inability to process information. There are studies that suggest people with ADHD generally have a positive attitude toward academics and, with medication and developed study skills, can perform just as well as individuals without learning disabilities. Also, using alternate sources of gathering information, such as websites, study groups and learning centers, can help a person with ADHD be academically successful.Before the discovery of ADHD, it was technically included in the definition of LDs since it has a very pronounced effect on the "executive functions" required for learning. Thus historically, ADHD was not clearly distinguished from other disabilities related to learning. Therefore, when a person presents with difficulties in learning, ADHD should be considered as well. Scientific research continues to explore the traits, struggles, effective learning styles and comorbid LDs of those with ADHD.
References
Further reading
Barr, S.; Eslami, Z.; Joshi, R.M. (2012). "Core strategies to support English language learners". The Educational Forum. 76: 105–117. doi:10.1080/00131725.2011.628196. S2CID 143509969.
Garcia-Joslin, J.J.; Carrillo, G.L.; Guzman, V.; Vega, D.; Plotts, C.A.; Lasser, J. (2016). "Latino immigration: Preparing school psychologists to meet students needs". School Psychology Quarterly. 31 (2): 256–269. doi:10.1037/spq0000136. PMID 26551253.
Helman, A. L.; Calhoon, M.B.; Kern, L. (2015). "Improving science vocabulary of high school English language learners with reading disabilities". Learning Disability Quarterly. 38 (1): 40–52. doi:10.1177/0731948714539769. S2CID 145520140.
Keller-Margulis, M.; Payan, A.; Jaspers, K.E.; Brewton, C. (2016). "Validity and diagnostic accuracy of written expression curriculum-based measurement for students with diverse language backgrounds". Reading & Writing Quarterly: Overcoming Learning Difficulties. 32 (2): 174–198. doi:10.1080/10573569.2014.964352. S2CID 146790684.
Rodríguez, James L.; Cadiero-Kaplan, Karen (2008). "Bilingualism & Biliteracy: Issues of Equity, Access, & Social Justice for English Language Learners: Introduction to This Special Issue". Equity & Excellence in Education. 41 (3): 275–278. doi:10.1080/10665680802179139. S2CID 143725571.
Hay I, Elias G, Fielding-Barnsley R, Homel R, Freiberg K (2007). "Language delays, reading delays, and learning difficulties: interactive elements requiring multidimensional programming". Journal of Learning Disabilities. 40 (5): 400–9. doi:10.1177/00222194070400050301. PMID 17915494. S2CID 21854907
OBryon, E.C.; Rogers, M.R. (2010). "Bilingual school psychologists assessment practices with English language learners". Psychology in the Schools. Wiley-Blackwell. 47 (10): 1018–1034. doi:10.1002/pits.20521. eISSN 1520-6807. ISSN 0033-3085. LCCN 64009353. OCLC 1763062.
Rodríguez Silva, L.H.; Roehr-Brackin, K. (2016). "Perceived learning difficulty and actual performance: Explicit and implicit knowledge of L2 English grammar points among instructed adult learners" (PDF). Studies in Second Language Acquisition. 38 (2): 317–340. doi:10.1017/S0272263115000340. eISSN 1470-1545. ISSN 0272-2631. LCCN 81642978. OCLC 4536243. S2CID 6451728.
Wagner, R.K.; Francis, D.J.; Morris, R.D. (2005). "Identifying English Language Learners with Learning Disabilities: Key Challenges and Possible Approaches". Learning Disabilities Research & Practice. Council for Exceptional Children. Division of Learning Disabilities. 20 (1): 6–15. doi:10.1111/j.1540-5826.2005.00115.x. ISSN 1540-5826. OCLC 884084718.
Rodis, P., Garrod, A., & Boscardin, M. L. (Eds.). (2001). Learning Disabilities & Life Stories. Boston, USA: Allyn & Bacon. ISBN 9780205320103 OCLC 888129572
"Learning Difficulties Australia" (PDF). Vol. 40, no. 2. June 2008. Archived from the original (PDF) on 2021-01-21. Retrieved 2019-07-20. {{cite magazine}}: Cite magazine requires |magazine= (help)
"Learning Disabilities Mortality Review (LeDeR) Programme" (Annual report). National Health Service. UK. December 2017. Retrieved 3 July 2022.
"Learning Disabilities: Prevalence". Social Work, Alcohol & Drugs. University of Bedfordshire. Archived from the original on 2014-10-26. Retrieved 2014-10-18.
"Special Educational Needs and Disability: A. Cognition and Learning Needs". teachernet. Archived from the original on 2010-05-01. Retrieved 2010-12-08.
Vickerman, Philip (2009-07-08). "Severe Learning Difficulties". Teacher Training Resource Bank. UK. Archived from the original on 2014-10-26. Retrieved 2014-10-19. Extensive further references.
External links
Learning Disabilities at Curlie |
Caput succedaneum | Caput succedaneum is a neonatal condition involving a serosanguinous, subcutaneous, extraperiosteal fluid collection with poorly defined margins caused by the pressure of the presenting part of the scalp against the dilating cervix (tourniquet effect of the cervix) during delivery.It involves bleeding below the scalp and above the periosteum.
See also
Cephalohematoma
Cephalic
Chignon (medical term)
Hematoma
Subgaleal hemorrhage
References
== External links == |
Necrotizing bronchiolitis | Necrotizing bronchiolitis is an acute inflammatory lesion of the lower airway, a potential complication of mechanical ventilation.
== References == |
Decapitation | Decapitation or beheading is the total separation of the head from the body. Such an injury is invariably fatal to humans and most other animals, since it deprives the brain of oxygenated blood, while all other organs are deprived of the involuntary functions that are needed for the body to function.
The term beheading refers to the act of deliberately decapitating a person, either as a means of murder or as an execution; it may be performed with an axe, sword, knife, machete or by mechanical means such as a guillotine or chainsaw. An executioner who carries out executions by beheading is sometimes called a headsman. Accidental decapitation can be the result of an explosion, a car or industrial accident, improperly administered execution by hanging or other violent injury. Suicide by decapitation is rare but not unknown. The national laws of Saudi Arabia, Yemen, and Qatar permit beheading; however, in practice, Saudi Arabia is the only country that continues to behead its offenders regularly as a punishment for capital crime.Less commonly, decapitation can also refer to the removal of the head from a body that is already dead. This might be done to take the head as a trophy, for public display, to make the deceased more difficult to identify, for cryonics, or for other, more esoteric reasons.
Etymology
The word decapitation has its roots in the Late Latin word decapitare. The meaning of the word decapitare can be discerned from its morphemes de- (down, from) + capit- (head). The past participle of decapitare is decapitatus which was used to create decapitationem, the noun form of decapitatus in Medieval Latin. From the Medieval Latin form, decapitationem, the French word décapitation was produced.
History
Humans have practiced capital punishment by beheading for millennia. The Narmer Palette (c. 3000 BCE) shows the first known depiction of decapitated corpses. The terms "capital offence", "capital crime", "capital punishment", derive from the Latin caput, "head", referring to the punishment for serious offences involving the forfeiture of the head; i.e. death by beheading.Some cultures, such as ancient Rome and Greece regarded decapitation as the most honorable form of death. In the Middle Ages, many European nations continued to reserve the method only for nobles and royalty. In France, the French Revolution made it the only legal method of execution for all criminals regardless of class, one of the periods many symbolic changes.Others have regarded beheading as dishonorable and contemptuous, such as the Japanese troops who beheaded prisoners during World War II. In recent times, it has become associated with terrorism.
Physiological aspects
Pain
If the headsmans axe or sword was sharp and his aim was precise, decapitation was quick and is presumed to be a relatively painless form of death. If the instrument was blunt or the executioner was clumsy, repeated strokes might be required to sever the head, resulting in a prolonged and more painful death. The person to be executed was therefore advised to give a gold coin to the headsman to ensure that he did his job with care. Robert Devereux, 2nd Earl of Essex, and Mary, Queen of Scots required three strikes at their respective executions. The same could be said for the execution of Johann Friedrich Struensee, favorite of the Danish queen Caroline Matilda of Great Britain. Margaret Pole, 8th Countess of Salisbury, is said to have required up to 10 strokes before decapitation was achieved. This particular story may, however, be apocryphal (since highly divergent accounts exist). Historian and philosopher David Hume, for example, relates the following about her death:She refused to lay her head on the block, or submit to a sentence where she had received no trial. She told the executioner, that if he would have her head, he must win it the best way he could: and thus, shaking her venerable grey locks, she ran about the scaffold; and the executioner followed her with his axe, aiming many fruitless blows at her neck before he was able to give the fatal stroke.
To ensure that the blow would be fatal, executioners swords usually were blade-heavy two-handed swords. Likewise, if an axe was used, it almost invariably was wielded with both hands. In England a bearded axe was used for beheading, with the blades edge extending downwards from the tip of the shaft.Finlands official beheading axe resides today at the Museum of Crime in Vantaa. It is a broad-bladed two-handed axe. It was last used when murderer Tahvo Putkonen was executed in 1825, the last execution in peacetime in Finland.
Physiology of death by decapitation
Decapitation is quickly fatal to humans and most animals. Unconsciousness occurs within 10 seconds without circulating oxygenated blood (brain ischemia). Cell death and irreversible brain damage occurs after 3–6 minutes with no oxygen, due to excitotoxicity. Some anecdotes suggest more extended persistence of human consciousness after decapitation, but most doctors consider this unlikely and consider such accounts to be misapprehensions of reflexive twitching rather than deliberate movement, since deprivation of oxygen must cause nearly immediate coma and death ("[Consciousness is] probably lost within 2–3 seconds, due to a rapid fall of intracranial perfusion of blood").A laboratory study testing for humane methods of euthanasia in awake animals used EEG monitoring to measure the time duration following decapitation for rats to become fully unconscious, unable to perceive distress and pain. It was estimated that this point was reached within 3–4 seconds, correlating closely with results found in other studies on rodents (2.7 seconds, and 3–6 seconds). The same study also suggested that the massive wave which can be recorded by EEG monitoring approximately one minute after decapitation ultimately reflects brain death. Other studies indicate that electrical activity in the brain has been demonstrated to persist for 13 to 14 seconds following decapitation (although it is disputed as to whether such activity implies that pain is perceived), and a 2010 study reported that decapitation of rats generated responses in EEG indices over a period of 10 seconds that have been linked to nociception across a number of different species of animals, including rats.Some animals (such as cockroaches) can survive decapitation, and die not because of the loss of the head directly, but rather because of starvation. A number of other animals, including snakes, and turtles, have also been known to survive for some time after being decapitated, as they have a slower metabolism, and their nervous systems can continue to function at some capacity for a limited time even after connection to the brain is lost, responding to any nearby stimulus. In addition, the bodies of chickens and turtles may continue to move temporarily after decapitation.Although head transplantation by the reattachment of blood vessels has seen some very limited success in animals, a fully functional reattachment of a severed human head (including repair of the spinal cord, muscles, and other critically important tissues) has not yet been achieved.
Technology
Guillotine
Early versions of the guillotine included the Halifax Gibbet, which was used in Halifax, England, from 1286 until the 17th century, and the "Maiden", employed in Edinburgh from the 16th through the 18th centuries.
The modern form of the guillotine was invented shortly before the French Revolution with the aim of creating a quick and painless method of execution requiring little skill on the part of the operator. Decapitation by guillotine became a common mechanically assisted form of execution.
The French observed a strict code of etiquette surrounding such executions. For example, a man named Legros, one of the assistants at the execution of Charlotte Corday, was imprisoned for three months and dismissed for slapping the face of the victim after the blade had fallen in order to see whether any flicker of life remained. The guillotine was used in France during the French Revolution and remained the normal judicial method in both peacetime and wartime into the 1970s, although the firing squad was used in certain cases. France abolished the death penalty in 1981.
The guillotine was also used in Algeria before the French relinquished control of it, as shown in Gillo Pontecorvos film The Battle of Algiers.
Another guillotine existed in Vatican City until recent years. It had been brought in by Napoleons forces during the early 19th century; and, as of 1870, the pope still claimed the authority to use it. The Holy See has since abolished capital punishment within its own jurisdiction, and recent popes have condemned capital punishment wherever it is still practised.
German Fallbeil
Many German states had used a guillotine-like device known as a Fallbeil ("falling axe") since the 17th and 18th centuries, and decapitation by guillotine was the usual means of execution in Germany until the abolition of the death penalty in West Germany in 1949. It was last used in communist East Germany in 1966.
In Nazi Germany, the Fallbeil was reserved for common criminals and people convicted of political crimes, including treason. Members of the White Rose resistance movement, a group of students in Munich that included siblings Sophie and Hans Scholl, were executed by decapitation.
Contrary to popular myth, executions were generally not conducted face up, and chief executioner Johann Reichhart was insistent on maintaining "professional" protocol throughout the era, having administered the death penalty during the earlier Weimar Republic. Nonetheless, it is estimated that some 16,500 persons were guillotined in Germany and Austria between 1933 and 1945, a number that includes resistance fighters both within Germany itself and in countries occupied by Nazi forces. As these resistance fighters were not part of any regular army, they were considered common criminals and were in many cases transported to Germany for execution. Decapitation was considered a "dishonorable" death, in contrast to execution by firing squad.
Historical practices by nation
Africa
Congo
In the Democratic Republic of Congo, the conflict and ethnic massacre between local army and Kamuina Nsapu rebels has caused several deaths and atrocities such as rape and mutilation. One of them is decapitation, both a fearsome way to intimidate victims as well as an act that may include ritualistic elements. According to an UN report from Congolese refugees, they believed the Bana Mura and Kamuina Nsapu militias have "magical powers" as a result of drinking the blood of decapitated victims, making them invincible. According to some reports, they indeed feed the blood from their victims heads to younger members as an initiation rite, then they often burn the remains or sometimes consume these, committing cannibalism.Besides the massive decapitations (like the beheading of 40 members of the State Police), a globally notorious case happened in March 2017 to Swedish politician Zaida Catalán and American UN expert Michael Sharp, who were kidnapped and executed during a mission near the village of Ngombe in Kasaï Province. The UN was reportedly horrified when video footage of the executions surfaced in April that same year, where some grisly details led to assume ritual components of the beheading: the perpetrators first cut the hair of both victims, and then one of them beheaded Catalán only, because it would "increase his power", which may be linked to the fact that Congolese militias are particularly brutal in their acts of violence toward women and children.In the trial that followed investigations after the bodies were discovered, and according to a testimony of a primary school teacher from Bunkonde, near the village of Moyo Musuila where the executions took place, he witnessed a teenage militant carrying the young womans head, but despite the efforts of the investigation, the head was never found. According to a report published on 29 May 2019, the Monusco peacekeeping military mission led by Colonel Luis Mangini, in the search for the missing remains, arrived to a ritual place in Moyo Musila where "parts of bodies, hands and heads" were cut and used for rituals, where they lost track of the victims head.
Asia
Azerbaijan
During the 2016 Armenian–Azerbaijani clashes, reports emerged that Yazidi-Armenian serviceman, Kyaram Sloyan, was decapitated by the Azerbaijani servicemen. Azerbaijan denied this.Several reports of decapitation, along with other types of mutilation of the Armenian POWs by Azerbaijani soldiers emerged during the 2020 Nagorno-Karabakh war.
China
In traditional China, decapitation was considered a more severe form of punishment than strangulation, although strangulation caused more prolonged suffering. This was because in Confucian tradition, bodies were gifts from their parents, and so it was therefore disrespectful to their ancestors to return their bodies to the grave dismembered. The Chinese however had other punishments, such as dismembering the body into multiple pieces (similar to the English quartering). In addition, there was also a practice of cutting the body at the waist, which was a common method of execution before being abolished in the early Qing dynasty due to the lingering death it caused. In some tales, people did not die immediately after decapitation.
India
The British officer John Masters recorded in his autobiography that Pathans in British India during the Anglo-Afghan Wars would behead enemy soldiers who were captured, such as British and Sikh soldiers.
Japan
In Japan, decapitation was a common punishment, sometimes for minor offences. Samurai were often allowed to decapitate soldiers who had fled from battle, as it was considered cowardly. Decapitation was historically performed as the second step in seppuku (ritual suicide by disembowelment). After the victim had sliced his own abdomen open, another warrior would strike his head off from behind with a katana to hasten death and to reduce the suffering. The blow was expected to be precise enough to leave intact a small strip of skin at the front of the neck—to spare invited and honored guests the indelicacy of witnessing a severed head rolling about, or towards them; such an occurrence would have been considered inelegant and in bad taste. The sword was expected to be used upon the slightest sign that the practitioner might yield to pain and cry out—avoiding dishonor to him and to all partaking in the privilege of observing an honorable demise. As skill was involved, only the most trusted warrior was honored by taking part. In the late Sengoku period, decapitation was performed as soon as the person chosen to carry out seppuku had made the slightest wound to his abdomen.
Decapitation (without seppuku) was also considered a very severe and degrading form of punishment. One of the most brutal decapitations was that of Sugitani Zenjubō (杉谷善住坊), who attempted to assassinate Oda Nobunaga, a prominent daimyō, in 1570. After being caught, Zenjubō was buried alive in the ground with only his head out, and the head was slowly sawn off with a bamboo saw by passers-by for several days (punishment by sawing; nokogiribiki (鋸挽き). These unusual punishments were abolished in the early Meiji era. A similar scene is described in the last page of James Clavells book Shōgun.
Korea
Historically, decapitation had been the most common method of execution in Korea, until it was replaced by hanging in 1896. Professional executioners were called mangnani (망나니) and they were volunteered from death-rows.
Pakistan
Pakistans government employs death by hanging for capital punishment. Since 2007, militants from Tehrek-e-Taliban Pakistan have used beheadings as a form of punishment for opponents, criminals and spies in the north west region of Pakistan. Severed heads of opponents or government officials in Swat Valley were left on popular street corners in order to terrorize local population. The beheadings have stopped in Swat since the military incursion and sweep-up that began in May 2009 and ended in June 2009. Three Sikhs were beheaded by the Taliban in Pakistan in 2010. Daniel Pearl was beheaded by his captors in the city of Karachi.
Despite official condemnation from the state itself, such beheading continues to flourish in the Taliban strongholds of Baluchistan and Khyber-Pakhtunkhwa.
Thailand
Historically, decapitation had been the main method of execution in Thailand, until it was replaced by shooting in 1934.
Europe
Bosnia and Herzegovina
During the war in Bosnia and Herzegovina (1992–1995) there were a number of ritual beheadings of Serbs and Croats who were taken as prisoners of war by mujahedin members of the Bosnian Army. At least one case is documented and proven in court by the ICTY where mujahedin, members of 3rd Corps of Army BiH, beheaded Bosnian Serb Dragan Popović.
Britain
In British history, beheading was typically used for noblemen, while commoners would be hanged; eventually, hanging was adopted as the standard means of non-military executions. The last actual execution by beheading was of Simon Fraser, 11th Lord Lovat on 9 April 1747, while a number of convicts (typically traitors were sentenced to be hanged, drawn and quartered, a method which had already been discontinued) were beheaded posthumously up to the early 19th century. Beheading was degraded to a secondary means of execution, including for treason, with the abolition of drawing and quartering in 1870 and finally abolished by the Statute Law (Repeals) Act 1973. One of the most notable executions by decapitation in Britain was that of King Charles I of England, who was beheaded outside the Banqueting House in Whitehall in 1649, after being captured by parliamentarians during the English Civil War.
Celts
The Celts of western Europe long pursued a "cult of the severed head", as evidenced by both Classical literary descriptions and archaeological contexts. This cult played a central role in their temples and religious practices and earned them a reputation as head hunters among the Mediterranean peoples. Diodorus Siculus, in his 1st-century Historical Library (5.29.4) wrote the following about Celtic head-hunting:
They cut off the heads of enemies slain in battle and attach them to the necks of their horses. The blood-stained spoils they hand over to their attendants and striking up a paean and singing a song of victory; and they nail up these first fruits upon their houses, just as do those who lay low wild animals in certain kinds of hunting. They embalm in cedar oil the heads of the most distinguished enemies, and preserve them carefully in a chest, and display them with pride to strangers, saying that for this head one of their ancestors, or his father, or the man himself, refused the offer of a large sum of money. They say that some of them boast that they refused the weight of the head in gold.
Both the Greeks and Romans found the Celtic decapitation practices shocking and the latter put an end to them when Celtic regions came under their control. However, Greeks and Romans both employed decapitation and other horrific tortures, highlighting a tendency to view practices as more shocking when carried out by an outside group, even if the practices are essentially similar.According to Paul Jacobsthal, "Amongst the Celts the human head was venerated above all else, since the head was to the Celt the soul, centre of the emotions as well as of life itself, a symbol of divinity and of the powers of the other-world." Arguments for a Celtic cult of the severed head include the many sculptured representations of severed heads in La Tène carvings, and the surviving Celtic mythology, which is full of stories of the severed heads of heroes and the saints who carry their own severed heads, right down to Sir Gawain and the Green Knight, where the Green Knight picks up his own severed head after Gawain has struck it off in a beheading game, just as Saint Denis carried his head to the top of Montmartre.A further example of this regeneration after beheading lies in the tales of Connemaras Saint Féchín, who after being beheaded by Vikings carried his head to the Holy Well on Omey Island and on dipping it into the well placed it back upon his neck and was restored to full health.
Classical antiquity
The ancient Greeks and Romans regarded decapitation as a comparatively honorable form of execution for criminals. The traditional procedure, however, included first being tied to a stake and whipped with rods. Axes were used by the Romans, and later swords, which were considered a more honorable instrument of death. Those who could verify that they were Roman citizens were to be beheaded, rather than undergoing the much more horrific experience of crucifixion. In the Roman Republic of the early 1st century BC, it became the tradition for the severed heads of public enemies—such as the political opponents of Marius and Sulla, for example—to be publicly displayed on the Rostra in the Forum Romanum after execution. Perhaps the most famous such victim was Cicero who, on instructions from Mark Antony, had his hands (which had penned the Philippicae against Antony) and his head cut off and nailed up for display in this manner.
France
In France, until the abolition of capital punishment in 1981, the main method of execution had been by beheading by means of the guillotine. Other than a small number of military cases in which a firing squad was used (including that of Jean Bastien-Thiry), the guillotine was the only legal method of execution from 1791, when it was introduced by the Legislative Assembly during the last days of the kingdom French Revolution, until 1981. Before the revolution, beheading had typically been reserved for noblemen and carried out manually. In 1981, President François Mitterrand abolished capital punishment and issued commutations for those whose sentences had not been carried out.
The first person executed by the guillotine in France was highwayman Nicolas Jacques Pelletier in April 1792. The last execution was of murderer Hamida Djandoubi, in Marseilles, in 1977. Throughout its extensive overseas colonies and dependencies, the device was also used, including on St Pierre in 1889 and on Martinique as late as 1965.
Germany
Fritz Haarmann, a serial killer from Hannover who was sentenced to death for killing 27 young men, was decapitated in April 1925. He was nicknamed "The Butcher from Hannover" and was rumored to have sold his victims flesh to his neighbors restaurant.
In July 1931, notorious serial killer Peter Kürten, known as "The Vampire of Düsseldorf", was executed on the guillotine in Cologne.
On 1 August 1933, in Altona, Bruno Tesch and three others were beheaded. These were the first executions in Nazi Germany. The executions concerned the Altona Bloody Sunday (Altonaer Blutsonntag) riot, an SA march on 17 July 1932 that turned violent and led to 18 people being shot dead.
Marinus van der Lubbe by guillotine in 1934 after a show trial in which he was found guilty of starting the Reichstag fire.
In February 1935 Benita von Falkenhayn and Renate von Natzmer were beheaded with the axe and block in Berlin for espionage for Poland. Axe beheading was the only method of execution in Berlin until 1938, when it was decreed that all civil executions would henceforth be carried out by guillotine. However, the practice was continued in rare cases such as that of Olga Bancic and Werner Seelenbinder in 1944. Beheading by guillotine survived in West Germany until 1949 and in East Germany until 1966.
A group of three Catholic clergymen, Johannes Prassek, Eduard Müller and Hermann Lange, and an Evangelical Lutheran pastor, Karl Friedrich Stellbrink, were arrested following the bombing of Lübeck, tried by the Peoples Court in 1943 and sentenced to death by decapitation; all were beheaded on 10 November 1943, in the Hamburg prison at Holstenglacis. Stellbrink had explained the raid next morning in his Palm Sunday sermon as a "trial by ordeal", which the Nazi authorities interpreted to be an attack on their system of government and as such undermined morale and aided the enemy.
In October 1944, Werner Seelenbinder was executed by manual beheading, the last legal use of the method (other than by guillotine) in both Europe and the rest of the Western world. Earlier the same year, Olga Bancic had been executed by the same means.
In February 1943, American academic Mildred Harnack and the university students Hans Scholl, Sophie Scholl, and Christoph Probst of the White Rose protest movement, were all beheaded by the Nazi State. Four other members of the White Rose, an anti-Nazi group, were also executed by the Peoples Court later that same year. The anti-Nazi Helmuth Hübener was also decapitated by Peoples Court order.
In 1966, former Auschwitz doctor Horst Fischer was executed by the German Democratic Republic by guillotine, the last executed by this method outside France. Beheading was subsequently replaced by shooting in the neck.
Nordic countries
In Nordic countries, decapitation was the usual means of carrying out capital punishment. Noblemen were beheaded with a sword, and commoners with an axe. The last executions by decapitation in Finland in 1825, Norway in 1876, Faroe Islands in 1609, and in Iceland in 1830 were carried out with axes. The same was the case in Denmark in 1892. Sweden continued the practice for a few decades, executing its second to last criminal—mass murderer Johan Filip Nordlund—by axe in 1900. It was replaced by the guillotine, which was used for the first and only time on Johan Alfred Ander in 1910.
The official beheading axe of Finland resides today in the Museum of Crime, Vantaa.
Spain
In Spain executions were carried out by various methods including strangulation by the garrotte. In the 16th and 17th centuries, noblemen were sometimes executed by means of beheading. Examples include Anthony van Stralen, Lord of Merksem, Lamoral, Count of Egmont and Philip de Montmorency, Count of Horn. They were tied to a chair on a scaffold. The executioner used a knife to cut the head from the body. It was considered to be a more honourable death if the executioner started with cutting the throat.
Middle East
Iran
Iran, since the 1979 Islamic Revolution, has alleged it uses beheading as one of the methods of punishment.
Iraq
Though not officially sanctioned, legal beheadings were carried out against at least 50 prostitutes and pimps under Saddam Hussein as late as 2000.Beheadings have emerged as another terror tactic especially in Iraq since 2003. Civilians have borne the brunt of the beheadings, although U.S. and Iraqi military personnel have also been targeted. After kidnapping the victim, the kidnappers typically make some sort of demand of the government of the hostages nation and give a time limit for the demand to be carried out, often 72 hours. Beheading is often threatened if the government fails to heed the wishes of the hostage takers. Sometimes, the beheadings are videotaped and made available on the Internet. One of the most publicized of such executions was that of Nick Berg.Judicial execution is practiced in Iraq, but is generally carried out by hanging.
Saudi Arabia
Saudi Arabia has a criminal justice system based on Shariah law reflecting a particular state-sanctioned interpretation of Islam. Crimes such as rape, murder, apostasy, and sorcery are punishable by beheading. It is usually carried out publicly by beheading with a sword.
A public beheading will typically take place around 9am. The convicted person is walked into the square and kneels in front of the executioner. The executioner uses a sword |
Decapitation | to remove the condemned persons head from his or her body at the neck with a single strike. After the convicted person is pronounced dead, a police official announces the crimes committed by the beheaded alleged criminal and the process is complete. The official might announce the same before the actual execution. This is the most common method of execution in Saudi Arabia.According to Amnesty International, at least 79 people were executed in Saudi Arabia in 2013. Foreigners are not exempt, accounting for "almost half" of executions in 2013.
Syria
The Syrian government employs hanging as its method of capital punishment. However, the terrorist organisation known as the Islamic State, which controlled territory in much of eastern Syria, had regularly carried out beheadings of people. Syrian rebels attempting to overthrow the Syrian government have been implicated in beheadings too.
North America
Mexico
Miguel Hidalgo y Costilla, Ignacio Allende, José Mariano Jiménez and Juan Aldama were tried for treason, executed by firing squad and beheaded during the Mexican independence in 1811. Their heads were on display on the four corners of the Alhóndiga de Granaditas, in Guanajuato.
During the Mexican Drug War, some Mexican drug cartels turned to decapitation and beheading of rival cartel members as a method of intimidation.
This trend of beheading and publicly displaying the decapitated bodies was started by the Los Zetas, a criminal group composed by former Mexican special forces operators, trained in the infamous US Army School of the Americas, in torture techniques and psychological warfare.
United States
The United States government has never employed beheading as a legal method of execution. However, beheading has sometimes been used in mutilations of the dead, particularly of black people like Nat Turner, who led a rebellion against slavery. When caught, he was publicly hanged, flayed, and beheaded. This was a technique used by many enslavers to discourage the "frequent bloody uprisings" that were carried out by "kidnapped Africans". While bodily dismemberment of various kinds was employed to instill terror, Dr. Erasmus D. Fenner noted postmortem decapitation was particularly effective.US soldiers have committed decapitations in various invasions and/or conquests, including of the Native Americans, the Philippines, Korea, and Vietnam.Regarding Vietnam, correspondent Michael Herr notes "thousands" of photo-albums made by US soldiers "all seemed to contain the same pictures": "the severed head shot, the head often resting on the chest of the dead man or being held up by a smiling Marine, or a lot of the heads, arranged in a row, with a burning cigarette in each of the mouths, the eyes open". Some of the victims were "very young".
General George Patton IV, son of the famous WWII general George S. Patton, was known for keeping "macabre souvenirs", such as "a Vietnamese skull that sat on his desk." Other Americans "hacked the heads off Vietnamese to keep, trade, or exchange for prizes offered by commanders."As a terror tactic, "some American troops hacked the heads off... dead [Vietnamese] and mounted them on pikes or poles".Although the Utah Territory permitted a person sentenced to death to choose beheading as a means of execution, no person chose that option, and it was dropped when Utah became a state.
Notable people who have been beheaded
See also
Atlanto-occipital dislocation, where the skull is dislodged from the spine; a generally, but not always, fatal injury.
Beheading in Islam
Beheading video
Blood atonement
Blood squirt, a result from a decapitation.
Cephalophore, a martyred saint who supposedly carries his/her severed head.
Chhinnamasta, a Hindu goddess who supposedly decapitates herself and holds her head in her hand.
Cleveland Torso Murderer, a serial killer who decapitated some of his victims.
Dismemberment
François-Jean de la Barre
Headhunting
List of methods of capital punishment
Mike the Headless Chicken
Notes
References
This article incorporates text from a publication now in the public domain: Chambers, Ephraim, ed. (1728). Cyclopædia, or an Universal Dictionary of Arts and Sciences (1st ed.). James and John Knapton, et al. {{cite encyclopedia}}: Missing or empty |title= (help)
External links
Media related to Decapitation at Wikimedia Commons
Crime Library
CapitalPunishmentUK.org |
Postpartum psychosis | Early in the history of medicine, it was recognized that severe mental illness sometimes started abruptly in the days after childbirth, later known as postpartum psychosis or puerperal psychosis. Gradually, it became clear that this was not a single and unique phenomenon, but a group of at least twenty distinct disorders.Psychosis implies the presence of manic symptoms, stupor or catatonia, perplexity, confusion, disorders of the will and self, delusions and/or hallucinations. Psychiatric disorders that lack these symptoms are excluded; depression, however severe, is not included, unless there are psychotic features.
Of this group of psychoses, postpartum bipolar disorder is overwhelmingly the most common in high-income nations.
Postpartum bipolar disorder
Signs and symptoms
Almost every symptom known to psychiatry occurs in these mothers – every kind of delusion including the rare delusional parasitosis, delusional misidentification syndrome, Cotard delusion, erotomania, the changeling delusion, denial of pregnancy or birth, command hallucinations, disorders of the will and self, catalepsy and other symptoms of catatonia, self-mutilation and all the severe disturbances of mood. In addition, literature from the 18th century also describes symptoms not generally recognized, such as rhyming speech, enhanced intellect, and enhanced perception.As for collections of symptoms (syndromes), about 40% have puerperal mania, with increased vitality and sociability, reduced need for sleep, rapid thinking and pressured speech, euphoria and irritability, loss of inhibition, violence, recklessness and grandiosity (including religious and expansive delusions); puerperal mania is considered to be particularly severe, with highly disorganized speech, extreme excitement and eroticism.Another 25% have an acute polymorphic (cycloid) syndrome. This is a changing clinical state, with transient delusions, fragments of other syndromes, extreme fear or ecstasy, perplexity, confusion, and motility disturbances. In the past, some experts regarded this as pathognomonic (specific) for puerperal psychosis, but this syndrome is found in other settings, not just the reproductive process, and in men. These psychoses are placed in the World Health Organizations ICD-10 under the rubric of acute and transient psychotic disorders. In general psychiatry, manic and cycloid syndromes are regarded as distinct, but, studied long-term among childbearing women, the bipolar and cycloid variants are intermingled in a bewildering variety of combinations, and, in this context, it seems best to regard them as members of the same bipolar/cycloid group. Together, the manic and cycloid variants make up about two thirds of childbearing psychoses.
Diagnosis
Postpartum bipolar disorders must be distinguished from a long list of organic psychoses that can present in the puerperium, and from other non-organic psychoses; both of these groups are described below. It is also necessary to distinguish them from other psychiatric disorders associated with childbirth, such as anxiety disorders, depression, post-traumatic stress disorder, complaining disorders and bonding disorders (emotional rejection of the infant), which occasionally cause diagnostic difficulties.
Clinical assessment requires obtaining the history from the mother herself and, because she is often severely ill, lacking in insight and unable to give a clear account of events, from at least one close relative. A social work report and, in mothers admitted to hospital, nursing observations are information sources of great value. A physical examination and laboratory investigations may disclose somatic illness complicating the obstetric events, which sometimes provokes psychosis. It is important to obtain the case records of previous episodes of mental illness, and, in patients with multiple episodes, to construct a summary of the whole course of her psychiatric history in relation to her life.
In the 10th edition of the International Classification of Diseases, published in 1992, the recommendation is to classify these cases by the form of the illness, without highlighting the postpartum state. There is, however, a category F53.1, entitled severe mental and behavioural disorders associated with the puerperium, which can be used when it is not possible to diagnose some variety of affective disorder or schizophrenia. The American Psychiatric Associations Diagnostic and Statistical Manual, whose 5th edition was published in May 2013, allows the use of a peripartum onset specifier in episodes of mania, hypomania or major depression if the symptoms occur during pregnancy or the first four weeks of the puerperium. The failure to recognize postpartum psychosis, and its complexity, is unhelpful to clinicians, epidemiologists, and other researchers.
Onset groups
Postpartum bipolar disease belongs to the bipolar spectrum, whose disorders exist in two contrasting forms – mania and depression. They are highly heritable, and affected individuals (less than 1% of the population ) have a lifelong tendency (diathesis) to develop psychotic episodes in certain circumstances. The triggers include a number of pharmaceutical agents, surgical operations, adrenal corticosteroids, seasonal changes, menstruation and childbearing. Research into puerperal mania is, therefore, not the study of a disease-in-its-own right, but an investigation into the childbearing triggers of bipolar disorder.
Psychoses triggered in the first two weeks after the birth – between the first postpartum day (or even during parturition until about the 15th day – complicate approximately 1/1,000 pregnancies. The impression is sometimes given that this is the only trigger associated with childbearing. But there is evidence of four other triggers – late postpartum, prepartum, post-abortion and weaning. Marcé, widely considered an authority on puerperal psychoses, claimed that they could be divided into early and late forms; the late form begins about six weeks after childbirth, associated with the return of the menses. His view is supported by the large number of cases in the literature with onset 4–13 weeks after the birth, mothers with serial 4-13 week onsets and some survey evidence. The evidence for a trigger acting in pregnancy is also based on the large number of reported cases, and particularly on the frequency of mothers experiencing two or more prepartum episodes. There is evidence, especially from surveys, of bipolar episodes triggered by abortion (miscarriage or termination). The evidence for a weaning trigger rests on 32 cases in the literature, of which 14 were recurrent. The relative frequency of these five triggers is given by the number of cases in the literature – just over half early postpartum onset, 20% each late postpartum and prepartum onset, and the rest post-abortion and weaning onset.
In addition, episodes starting after childbirth may be triggered by adrenal corticosteroids, surgical operations (such as Caesarean section) or bromocriptine as an alternative to, or in addition to, the postpartum trigger.
Course of the illness
With modern treatment, a full recovery can be expected within 6–10 weeks. After recovery from the psychosis, some mothers have depression, which can last for weeks or months. About one third have a relapse, with a return of psychotic symptoms a few weeks after recovery; these relapses are not due to a failure to comply with medication, because they were often described before pharmaceutical treatment was discovered. A minority have a series of periodic relapses related to the menstrual cycle. Complete recovery, with a resumption of normal life and a normal mother-infant relationship is the rule.Many of these mothers experience other bipolar episodes, on the average about one every six years. Although suicide is almost unknown in an acute puerperal manic or cycloid episode, depressive episodes later in life carry an increased risk, and it is wise for mothers to maintain contact with psychiatric services in the long term.
In the event of a further pregnancy, the recurrence rate is high – in the largest series, about three quarters had a recurrence, but not always in the early puerperium; the recurrence could occur during pregnancy, or later in the postpartum period. This suggests a link between early onset and other onset groups.
Management, treatment and prevention
Pre-conception counselling
It is known that women with a personal or family history of puerperal psychosis or bipolar disorder are at risk of a puerperal episode. The highest risk of all (82%) is a combination of a previous postpartum episode and at least one earlier non-puerperal episode. There is a need to counsel women at high risk before they embark on pregnancy, especially those on prophylactic treatment. The issues include the teratogenic risk, the frequency of recurrence and the risks and benefit of various treatments during pregnancy and breast-feeding; a personal analysis should be made for each individual, and is best shared with close family members. The teratogenic risks of antipsychotic agents are small, but are higher with lithium and anti-convulsant agents. Carbamazepine, when taken in early pregnancy, has some teratogenic effects, but valproate is associated with spina bifida and other major malformations, and a foetal valproate syndrome; it is contra-indicated in women who may become pregnant. Given late in pregnancy, antipsychotic agents and lithium can have adverse effects on the infant. Stopping mood-stabilisers has a high risk of recurrence during pregnancy.
Pre-birth planning
If a woman at high risk becomes pregnant, it is essential to convene a planning meeting. This is urgent because the diagnosis of pregnancy may be late, and the birth may be premature. The meeting should be attended by primary care, obstetric and psychiatric staff, together (if possible) with the expectant mother and her family and (if appropriate) a social worker. There are many issues – pharmaceutical treatment, antenatal care, early signs of a recurrence, the management of the puerperium, and the care and safety of the infant. It is important that the psychiatric team is notified as soon as the infant is born.
Home treatment and hospitalization
It has been recognized since the 19th century that it is optimal for a woman with puerperal psychosis to be treated at home, where she can maintain her role as homemaker and mother to her other children, and develop her relationship with the new-born. But there are many risks, and it is essential that she is monitored by a competent adult round the clock, and visited frequently by professional staff. Home treatment is a counsel of perfection and most women will be admitted to a psychiatric hospital, many as an emergency, and usually without their babies. In a few countries, especially Australia, Belgium, France, India, the Netherlands, Switzerland and the United Kingdom, special units allow the admission of both woman and infant. Conjoint admission has many advantages, but the risks to the infant of admission to a ward full of severely ill mothers should not be understated, and the high ratio of nursing staff, required to safeguard the infants, make these among the most expensive psychiatric units.
Treatment of the acute episode
These mothers require sedation with anti-psychotic (neuroleptic) agents, but are liable to extrapyramidal symptoms, including the neuroleptic malignant syndrome. Since the link with bipolar disorder was recognized (about 1970), treatment with mood-stabilizing agents, such as lithium and anti-convulsant drugs, has been employed with success. Electroconvulsive therapy has the reputation of efficacy in this disorder, and it can be given during pregnancy (avoiding the risk of pharmaceutical treatment), with due precautions. But there have been no trials, and Dutch experience has shown that almost all mothers recover quickly without it. After recovery the mother may need antidepressant treatment and/or prophylactic mood stabilizers; she will need counselling about the risk of recurrence and will often appreciate psychotherapeutic support.
Prevention
There is much evidence that lithium can at least partly prevent episodes in mothers at high risk. It is dangerous during parturition, when pressure in the pelvis can obstruct the ureters and raise blood levels. Started after the birth its adverse effects are minimal, even in breast-fed infants.
Causes
The cause of postpartum bipolar disorder breaks down into two parts – the nature of the brain anomalies that predispose to manic and depressive symptoms, and the triggers that provoke these symptoms in those with the bipolar diathesis. The genetic, anatomical and neurochemical basis of bipolar disorder is at present unknown, and is one of the most important projects in psychiatry; but is not the main concern here. The challenge and opportunity presented by the childbearing psychoses is to identify the triggers of early postpartum onset and other onset groups.
Considering that these psychoses have been known for centuries, little effort has so far been made to understand the underlying biology. Research has lagged far behind other areas of medicine and psychiatry. There is a dearth of knowledge and of theories. There is a much evidence of heritability, both from family studies and molecular genetics. Early onset cases occur more frequently in first time mothers, but this is not true of late postpartum or pregnancy onset. There are not many other predictors. Sleep deprivation has been suggested. Inhibition of steroid sulphatase caused behavioural abnormalities in mice. A recent hypothesis, supported by collateral studies, invokes the re-awakening of auto-immunity after its suppression during pregnancy, on the model of multiple sclerosis or autoimmune thyroiditis; a related hypothesis has proposed that abnormal immune system processes (regulatory T cell biology) and consequent changes in myelinogenesis may increase postpartum psychosis risk. Aberrant steroid hormone–dependent regulation of neuronal calcium influx via extracellular matrix proteins and membrane receptors involved in responding to the cells microenvironment might be important in conferring biological risk. Another promising lead is based on the similarity of bipolar-cycloid puerperal and menstrual psychosis; many women have had both. Late-onset puerperal psychoses, and relapses may be linked to menstruation. Since almost all reproductive onsets occur when the menstrual cycle is released from a long period of inhibition, this may be a common factor, but it can hardly explain episodes starting in the 2nd and 3rd trimesters of pregnancy.
History
Between the 16th and 18th centuries about 50 brief reports were published; among them is the observation that these psychoses could recur, and that they occur both in breast-feeding and non-lactating women. In 1797, Osiander, an obstetrician from Tübingen, reported two cases at length – masterly descriptions which are among the treasures of medical literature. In 1819, Esquirol conducted a survey of cases admitted to the Salpêtrière, and pioneered long-term studies. From that time, puerperal psychosis became widely known to the medical profession. In the next 200 years over 2,500 theses, articles and books were published. Among the outstanding contributions were Delays unique investigation using serial curettage and Kendells record-linkage study comparing 8 trimesters before and 8 trimesters after the birth. In the last few years, two monographs reviewed over 2,400 works, with more than 4,000 cases of childbearing psychoses from the literature and a personal series of more than 320 cases.
Research directions
The lack of a formal diagnosis in the DSM and ICD has hindered research. Research is needed to improve the care and treatment of affected mothers, but it is of paramount importance to investigate the causes, because this can lead to long term control and elimination of the disease. The opportunities come under the heading of clinical observation, the study of the acute episode, long-term studies, epidemiology, genetics and neuroscience. In a disorder with a strong genetic element and links to the reproductive process, costly imaging, molecular-genetic and neuroendocrinological investigations will be decisive. These depend on expert laboratory methods. It is important that the clinical study is also state-of-the-art– that scientists understand the complexity of these psychoses, and the need for multiple and reliable information sources to establish the diagnosis.
Other non-organic postpartum psychoses
It is much less common to encounter other acute psychoses in the puerperium.
Psychogenic psychosis
This is the name given to a psychosis whose theme, onset and course are all related to an extremely stressful event. The psychotic symptom is usually a delusion. Over 50 cases have been described, but usually in unusual circumstances, such as abortion or adoption, or in fathers at the time of the birth of one of their children. They are occasionally seen after normal childbirth.
Paranoid and schizophrenic psychoses
These are so uncommon in the puerperium that it seems reasonable to regard them as sporadic events, not puerperal complications.
Early postpartum stupor
Brief states of stupor have rarely been described in the first few hours or days after the birth. They are similar to parturient delirium and stupor, which are among the psychiatric disorders of childbirth.
Organic postpartum psychoses
There are at least a dozen organic (neuropsychiatric) psychoses that can present in pregnancy or soon after childbirth. The clinical picture is usually delirium – a global disturbance of cognition, affecting consciousness, attention, comprehension, perception and memory – but amnesic syndromes and a mania-like state also occur. The two most recent were described in 1980 and 2010, and it is quite likely that others will be described. Organic psychoses, especially those due to infection, may be more common in nations with high parturient morbidity.
Infective delirium
The most common organic postpartum psychosis is infective delirium. This was mentioned by Hippocrates: there are 8 cases of puerperal or post-abortion sepsis among the 17 women in the 1st and 3rd books of epidemics, all complicated by delirium. In Europe and North America the foundation of the metropolitan maternity hospitals, together with instrumental deliveries and the practice of attending necropsies, led to epidemics of streptococcal puerperal fever, resulting in maternal mortality rates up to 10%. The peak was about 1870, after which antisepsis and asepsis gradually brought them under control. These severe infections were often complicated by delirium, but it was not until the nosological advances of Chaslin and Bonhöffer that they could be distinguished from other causes of postpartum psychosis. Infective delirium hardly ever starts during pregnancy, and usually begins in the first postpartum week. The onset of sepsis and delirium are closely related, and the course parallels the infection, although about 20% of patients continue to have chronic confusional states after recovery from the infection. Recurrences after another pregnancy are rare. Their frequency began to decline at the end of the 19th century, and fell steeply after the discovery of the sulphonamides. Puerperal sepsis is still common in Bangladesh, Nigeria and Zambia. Even in the United Kingdom, cases are still occasionally seen. It would be a mistake to forget this cause of puerperal psychosis.
Eclamptic and Donkin psychoses
Eclampsia is the sudden eruption of convulsions in a pregnant woman, usually around the time of delivery. It is the late complication of pre-eclamptic toxaemia (gestosis). Although its frequency in nations with excellent obstetric services has fallen below 1/500 pregnancies, it is still common in many other countries. The primary pathology is in the placenta, which secretes an anti-angiogenic factor in response to ischaemia, leading to endothelial dysfunction. In fatal cases, there are arterial lesions in many organs including the brain. This is the second most frequent organic psychosis, and the second to be described. Psychoses occur in about 5% of cases, and about 240 detailed cases have been reported. It particularly affects first time mothers. Seizures may begin before, during or after labour, but the onset of psychosis is almost always postpartum. These mothers usually experience delirium but some have manic features. The duration is remarkably short, with a median duration of 8 days. This, together with the absence of a family history and of recurrences, contrasts with puerperal bipolar/cycloid psychoses. After recovery, amnesia and sometimes retrograde memory loss may occur, as well as other permanent cerebral lesions such as dysphasia, hemiplegia or blindness.
A variant was described by Donkin. He had been trained by Simpson (one of those who first recognized the importance of albuminuria) in Edinburgh, and recognized that some cases of eclamptic psychosis occurred without seizures; this explains the interval between seizures (or coma) and psychosis, a gap that has occasionally exceeded 4 days: seizures and psychosis are two different consequences of severe gestosis. Donkin psychosis may not be rare: a British series included 13 possible cases; but clarifying its distinction from postpartum bipolar disorder requires prospective investigations in collaboration with obstetricians.
Wernicke-Korsakoff psychosis
This was described by Wernicke and Korsakoff. The pathology is damage to the core of the brain including the thalamus and mamillary bodies. Its most striking clinical feature is loss of memory, which can be permanent. It is usually found in severe alcoholics, but can also result from pernicious vomiting of pregnancy (hyperemesis gravidarum), because the requirement for thiamine is much increased in pregnancy; nearly 200 cases have been reported. The cause is vitamin B1 (thiamine) deficiency. This has been available for treatment and prevention since 1936, so the occurrence of this syndrome in pregnancy should be extinct. But these cases continue to be reported – more than 50 in this century – from all over the world, including some from countries with advanced medical services; most are due to rehydration without vitamin supplements. A pregnant woman who presents in a dehydrated state due to pernicious vomiting urgently needs thiamine, as well as intravenous fluids.
Vascular disorders
Various vascular disorders occasionally cause psychosis, especially cerebral venous thrombosis. Puerperal women are liable to thrombosis, especially thrombophlebitis of the leg and pelvic veins; aseptic thrombi can also form in the dural venous sinuses and the cerebral veins draining into them. Most patients present with headache, vomiting, seizures and focal signs such as hemiplegia or dysphasia, but a minority of cases have a psychiatric presentation. The incidence is about 1 in 1,000 births in Europe and North America, but much higher in India, where large series have been collected. Psychosis is occasionally associated with other arterial or venous lesions: epidural anaesthesia can, if the dura is punctured, lead to leakage of cerebrospinal fluid and subdural haematoma. Arterial occlusion may be due to thrombi, amniotic fragments or air embolism. Postpartum cerebral angiopathy is a transitory arterial spasm of medium caliber cerebral arteries; it was first described in cocaine and amphetamine addicts, but can also complicate ergot and bromocriptine prescribed to inhibit lactation. Subarachnoid haemorrhage can occur after miscarriage or childbirth. All these usually present with neurological symptoms, and occasionally with delirium.
Epilepsy
Women with a lifelong epileptic history are liable to psychoses during pregnancy, labour and the puerperium. Women occasionally develop epilepsy for the first time in relation to their first pregnancy, and psychotic episodes have been described. There are over 30 cases in the literature.
Hypopituitarism
Pituitary necrosis following postpartum haemorrhage (Sheehans syndrome) leads to failure and atrophy of the gonads, adrenal and thyroid. Chronic psychoses can supervene many years later, based on myxoedema, hypoglycaemia or Addisonian crisis. But these patients can also develop acute and recurrent psychoses, even as early as the puerperium.
Water intoxication
Hyponatraemia (which leads to delirium) can complicate oxytocin treatment, usually when given to induce an abortion. By 1975, 29 cases had been reported, of which three were severe or fatal.
Urea cycle disorders
Inborn errors of the Krebs-Henseleit urea cycle lead to hyperammonaemia. In carriers and heterozygotes, encephalopathy can develop in pregnancy or the puerperium. Cases have been described in carbamoyl phosphate synthetase 1, argino-succinate synthetase and ornithine carbamoyltransferase deficiency.
Anti-NMDA receptor encephalitis
The most recent form of organic childbearing psychosis to be described is encephalitis associated with antibodies to the NMDA receptor; these women often have ovarian teratomas. A Japanese review found ten reported during pregnancy and five after delivery.
Other organic psychoses with a specific link to childbearing
Sydenhams chorea, of which chorea gravidarum is a severe variant, has a number of psychiatric complications, which include psychosis. This usually develops during pregnancy, and occasionally after the birth or abortion. Its symptoms include severe hypnagogic hallucinations (hypnagogia), possibly the result of the extreme sleep disorder. This form of chorea was caused by streptococcal infections, which at present respond to antibiotics; it still occurs as a result of systemic lupus or anti-phospholipid syndromes. Only about 50 chorea psychoses have been reported, and only one this century; but it could return if the streptococcus escapes control. Alcohol withdrawal states (delirium tremens) occur in addicts whose intake has been interrupted by trauma or surgery; this can happen after childbirth. Postpartum confusional states have also been reported during withdrawal from opium and barbiturates. One would expect acquired immunodeficiency syndrome (HIV/AIDS) encephalitis to present in pregnancy or the puerperium, because it is a venereal disease that can progress rapidly; one case of AIDS encephalitis, presenting in the 28th week of gestation, has been reported from Haiti, and there may be others in countries where AIDS is rife. Anaemia is common in pregnancy and the puerperium, and folate deficiency has been linked to psychosis.
Incidental organic psychoses
The psychoses, mentioned above, all had a recognized connection with childbearing. But medical disorders with no specific link have presented with psychotic symptoms in the puerperium; in them the association seems to be fortuitous. They include neurosyphilis, encephalitis including von Economos, meningitis, cerebral tumours, thyroid disease and ischaemic heart disease.
Society and culture
Support
In the UK, a series of workshops called "Unravelling Eve" were held in 2011, where women who had experienced postpartum depression shared their stories.
Notable cases in history and fiction
Harriet Sarah, Lady Mordaunt (1848–1906), formerly Harriet Moncreiffe, was the Scottish wife of an English baronet and Member of Parliament, Sir Charles Mordaunt. She was the defendant in a sensational divorce case in which the Prince of Wales (later King Edward VII) was embroiled; after a controversial trial lasting seven days, the jury determined that Lady Mordaunt had "puerperal mania" and her husbands petition for divorce was dismissed, while Lady Mordaunt was committed to an asylum.Andrea Yates had depression and, four months after the birth of her fifth child, relapsed, with psychotic features. Several weeks later she drowned all five children. Under the law in Texas, she was sentenced to life imprisonment, but, after a retrial, was committed to a mental hospital.
Guy de Maupassant, in his novel Mont-Oriol (1887) described a brief postpartum psychotic episode.
Charlotte Perkins Gilman, in her short story The Yellow Wallpaper (1892) described severe depression with psychotic features starting after childbirth, perhaps similar to that experienced by the author herself.
Stacey Slater, a fictional character in the long-running BBC soap-opera EastEnders had postpartum psychosis in 2016, and was one of the shows biggest storylines that year.
Legal status
Postpartum psychosis, especially when there is a marked component of depression, has a small risk of filicide |
Postpartum psychosis | . In acute manic or cycloid cases, this risk is about 1%. Most of these incidents have occurred before the mother came under treatment, and some have been accidental. Several nations including Canada, United Kingdom, Australia, and Italy recognize postpartum mental illness as a mitigating factor in cases where mothers kill their children. In the United States, such a legal distinction was not made as of 2009, and an insanity defense is not available in all states.The United Kingdom has had the Infanticide Act since 1922.
Books written about postpartum psychosis and postpartum bipolar disorder
Apart from the two monographs mentioned in the text (references 1 and 86), the following books have been published about these psychoses:
Ripping, Dr (1877) Die Geistesstörungen der Schwangeren, Wöchnerinnen und Säugenden. Stuttgart, Enke.
Knauer O (1897) Über Puerperale Psychose für practische Ärzte. Berlin, Karger.
Twomey T (2009) Understanding Postpartum Psychosis: A Temporary Madness. Westport, Praeger.
Harwood D (2017) Birth of a New Brain - Healing from Postpartum Bipolar Disorder. Brentwood, Post Hill Press.
References
== External links == |
Müllerian agenesis | Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome), also known as Müllerian agenesis, Müllerian aplasia, or vaginal agenesis is a congenital malformation characterized by a failure of the Müllerian duct to develop, resulting in a missing uterus and variable degrees of vaginal hypoplasia of its upper portion. Müllerian agenesis (including absence of the uterus, cervix and/or vagina) is the cause in 15% of cases of primary amenorrhoea. Because most of the vagina does not develop from the Müllerian duct, instead developing from the urogenital sinus, along with the bladder and urethra, it is present even when the Müllerian duct is completely absent. Because ovaries do not develop from the Müllerian ducts, affected people might have normal secondary sexual characteristics but are infertile due to the lack of a functional uterus. However, parenthood is possible through use of gestational surrogates.
Mayer–Rokitansky–Küster–Hauser syndrome is hypothesized to be a result of autosomal dominant inheritance with incomplete penetrance and variable expressivity, which contributes to the complexity involved in identifying of the underlying mechanisms causing the condition. Because of the variance in inheritance, penetrance and expressivity patterns, MRKH is subdivided into two types: type 1, in which only the structures developing from the Müllerian duct are affected (the upper vagina, cervix, and uterus), and type 2, where the same structures are affected, but is characterized by the additional malformations of other body systems most often including the renal and skeletal systems. MRKH type 2 includes MURCS (Müllerian Renal Cervical Somite).
The majority of MRKH syndrome cases are characterized as sporadic, but familial cases have provided evidence that, at least for some patients, MRKH is an inherited disorder. The underlying causes of MRKH syndrome is still being investigated, but several causative genes have been studied for their possible association with the syndrome. Most of these studies have served to rule-out genes as causative factors in MRKH, but thus far, only WNT4 has been associated with MRKH with hyperandrogenism.Reports of MRKH syndrome can be traced back to Hippocrates (460 B.C.–377 B.C.). The medical eponym honors August Franz Josef Karl Mayer (1787–1865), Carl Freiherr von Rokitansky (1804–1878), Hermann Küster (1879–1964) and Georges Andre Hauser (1921–2009).
Signs and symptoms
A female with this condition is hormonally normal; that is, the woman will enter puberty with development of secondary sexual characteristics including thelarche and pubarche (pubic hair). The womans karyotype will be 46,XX. At least one ovary is intact, if not both, and ovulation usually occurs. Typically, the vagina is shortened and intercourse may, in some cases, be difficult and painful. Medical examination supported by gynecologic ultrasonography demonstrates a complete or partial absence of the cervix, uterus, and vagina.If there is no uterus, a woman with MRKH cannot carry a pregnancy without intervention. It is possible for the woman to have genetic offspring by in vitro fertilization (IVF) and surrogacy. Successful uterine transplant has been performed in limited numbers of patients, resulting in several live births, but the technique is not widespread or accessible to many women.A woman with MRKH typically discovers the condition when, during puberty years, the menstrual cycle does not start (primary amenorrhoea). Some find out earlier through surgeries for other conditions, such as a hernia.
Causes
The etiology of MRKH syndrome in many cases remains elusive. However, mutations in a variety of different genes have been implicated in causing MRKH syndrome. The typical and atypical forms of the disorder are presumably caused by mutations in different genes.WNT4 (found on the short arm (p) of chromosome 1) has been clearly implicated in the atypical version of this disorder. A genetic mutation causes a leucine to proline residue substitution at amino acid position 12. This occurrence reduces the intranuclear levels of β catenin. In addition, it removes the inhibition of steroidogenic enzymes like 3β-hydroxysteriod dehydrogenase and 17α-hydroxylase. Patients therefore have androgen excess. Furthermore, without WNT4, the Müllerian duct is either deformed or absent. Female reproductive organs, such as the cervix, fallopian tubes, and much of the vagina, are hence affected.An association with 17q12 microdeletion syndrome, a deletion mutation in the long arm (q) of chromosome 17, has been reported. The gene LHX1 is located in this region and may be the cause of a number of these cases.
Diagnosis
Classification
Typical MRKH – Isolated uterovaginal aplasia/hypoplasia
Prevalence – 64%
Atypical MRKH – Uterovaginal aplasia/hypoplasia with renal malformation or uterovaginal aplasia/hypoplasia with ovarian dysfunction
Prevalence – 24%
MURCS syndrome – Uterovaginal aplasia/hypoplasia with renal malformation, skeletal malformation, and cardiac malformation
Prevalence – 12%
Treatment
A number of treatments have become available to create a functioning vagina, the first successful uterus transplantation has been done in 2021, giving fertility to the transplant recipient. Standard approaches use vaginal dilators and/or surgery to develop a functioning vagina to allow for penetrative sexual intercourse. A number of surgical approaches have been used. In the McIndoe procedure, a skin graft is applied to form an artificial vagina. After the surgery, dilators are still necessary to prevent vaginal stenosis. The Vecchietti procedure has been shown to result in a vagina that is comparable to a normal vagina in patients. In the Vecchietti procedure, a small plastic “olive” is threaded against the vaginal area, and the threads are drawn through the vaginal skin, up through the abdomen and through the navel using laparoscopic surgery. There the threads are attached to a traction device. The operation takes about 45 minutes. The traction device is then tightened daily so the olive is pulled inwards and stretches the vagina by approximately 1 cm per day, creating a vagina approximately 7 cm deep in 7 days, although it can be more than this. Another approach is the use of an autotransplant of a resected sigmoid colon using laparoscopic surgery; results are reported to be very good with the transplant becoming a functional vagina.Uterine transplantation has been performed in a number of people with MRKH, but the surgery is still in the experimental stage. Since ovaries are present, people with this condition can have genetic children through IVF with embryo transfer to a gestational carrier. Some also choose to adopt. In October 2014, it was reported that a month earlier a 36-year-old Swedish woman became the first woman with a transplanted uterus to give birth to a healthy baby. She was born without a uterus, but had functioning ovaries. She and the father went through IVF to produce 11 embryos, which were then frozen. Doctors at the University of Gothenburg then performed the uterus transplant, the donor being a 61-year-old family friend. One of the frozen embryos was implanted a year after the transplant, and the baby boy was born prematurely at 31 weeks after the mother developed pre-eclampsia.Promising research include the use of laboratory-grown structures, which are less subject to the complications of non-vaginal tissue, and may be grown using the womans own cells as a culture source. The recent development of engineered vaginas using the patients own cells has resulted in fully functioning vaginas capable of menstruation and orgasm in a number of patients showing promise of fully correcting this condition.
Epidemiology
The prevalence remains sparsely investigated. To date, two population-based nationwide studies have been conducted both estimating a prevalence about 1 in 5,000 live female births. According to some reports, Queen Amalia of Greece may have had the syndrome, but a 2011 review of the historical evidence concludes that it is not possible to determine the inability of her and her husband to have a child. Their inability to conceive an heir contributed to the overthrow of the king King Otto.
People with MRKH
Ben Barres, transgender male scientist
Esther Morris Leidolf, medical sociologist and intersex activist
Stephanie Lum, Australian intersex activist
Shon Klose, Australian intersex activist and musician
Jaclyn Schultz, Miss Michigan
Suspected cases
Eva Braun
Amalia of Oldenburg
See also
MURCS association
Cervical agenesis
WNT4 deficiency
SERKAL syndrome
Regenerative medicine
MRKH AUSTRIA
References
Further reading
External links
Online Mendelian Inheritance in Man (OMIM): 277000
American College of Obstetricians and Gynecologists, Müllerian Agenesis: Resource Overview |
X-linked dystonia parkinsonism | X-linked dystonia parkinsonism (XDP), also known as Lubag Syndrome or X-linked Dystonia of Panay, is a rare x-linked progressive movement disorder with high penetrance found almost exclusively in males from Panay, Philippines. It is characterized by dystonic movements first typically occurring in the 3rd and 4th decade of life. The dystonic movements often either coexist or develop into parkinsonism within 10 years of disease onset.
Symptoms and signs
Symptoms typically present in the 3rd or 4th decade of life, but have been seen as early as the age of 14. It presents with torsion dystonia, particularly when presenting at a younger age, which then progresses to parkinsonism with or without ongoing dystonia. Often the two symptoms coexist. The parkinsonian features of x-linked dystonia parkinsonism include festinating gait, bradykinesia, blepharospasm, and postural instability. It often lacks a resting tremor, helping to differentiate it from Parkinsons disease.
Genetics
X-linked dystonia parkinsonism is thought to result from a mutation of the TAF1 (TATA-binding protein-associated factor 1) gene at Xq13.1. It has an X-linked, recessive pattern of inheritance. Genetic analysis suggests that the responsible mutation was introduced into the ethnic groups of Panay (especially to the Hiligaynon people) over two millennia ago.
Diagnosis
Treatment
There is no cure for XDP and medical treatment offers only temporary relief. Some authors have reported benzodiazepines and anticholinergic agents in the early stages of the disease. Botulinum toxin injections have been used to relieve focal dystonia. Deep brain stimulation has shown promise in the few cases treated surgically.
Epidemiology
Although all early reported cases occurred in the Philippines, X-linked dystonia parkinsonism has been diagnosed in Japan, US, Canada, and Germany in people of Filipino descent. The prevalence in the Philippines has been estimated at 1/322,000 and as high as 1/4,000 in the province of Capizs male population. As an x-linked recessive disease, the majority of those affected are males with females generally being asymptomatic carriers. In the largest described series, the mean age of onset was 39.7 years, the mean duration of illness was 16 years, and the mean age of death was 55.6 years.
History
The high concentration of XDP in the Philippines was first documented in the 1970s after the Philippine General Hospital received 5 neurology referrals labelled as "dystonia musculorum deformans". This sparked an epidemiological survey which was published in 1976. Lee et al. described a series of 28 men, 23 of whom were from Panay Island. She found six families that each had more than one male member affected with XDP and found that there was no male to male transmission. There was also a family history of parkinsonism in some of the patients.
The name Lubag is based on the term used by Ilongo speaking Filipinos. It describes any movements with torsion.
References
== External links == |
Postpartum thyroiditis | Postpartum thyroiditis refers to thyroid dysfunction occurring in the first 12 months after pregnancy and may involve hyperthyroidism, hypothyroidism or the two sequentially. According to the National Institute of Health, postpartum thyroiditis affects about 8% of pregnancies. There are, however, different rates reported globally. This is likely due to the differing amounts of average postpartum follow times around the world, and due to humans own innate differences. For example, in Bangkok, Thailand the rate is 1.1%, but in Brazil it is 13.3%. The first phase is typically hyperthyroidism. Then, the thyroid either returns to normal or a woman develops hypothyroidism. Of those women who experience hypothyroidism associated with postpartum thyroiditis, one in five will develop permanent hypothyroidism requiring lifelong treatment.
Postpartum thyroiditis is believed to result from the modifications to the immune system necessary in pregnancy, and histologically is a subacute lymphocytic thyroiditis. The process is normally self-limiting, but when conventional antibodies are found there is a high chance of this proceeding to permanent hypothyroidism. Postpartum thyroiditis is a member of the group of thyroiditis conditions known as resolving thyroiditis.
Signs and symptoms
The initial phase of hyperthyroid symptoms occurs transiently about two to six months postpartum. Typical symptoms include irritability, nervousness, palpitations, and heat intolerance. Hormonal disturbances during this phase tend to occur with lower intensity compared with the hypothyroid phase. As a result, the hyperthyroid phase may pass undetected. The second phase of hypothyroid symptoms is also transient and can occur anytime within the three- to twelve-month period postpartum. Women in this phase experience low energy, poor memory, impaired concentration, carelessness, dry skin, cold intolerance, and general aches and pains. After one year postpartum, euthyroid function resumes. Any case with hypothyroid symptoms extending beyond one year postpartum is not considered postpartum thyroiditis.Women who test positive for thyroid antibodies may be at increased risk of developing symptoms associated with postpartum depression than women without thyroid antibodies.
Cause
During pregnancy, immunologic suppression occurs which induces tolerance to the presence of the fetus. Without this suppression, the fetus would be rejected causing miscarriage. As a result, following delivery, the immune system rebounds causing levels of thyroids antibodies to rise in susceptible women.Specifically, the immunohistological features of susceptible women are indicated by:
antibodies to thyroglobulin (TgAb)
antibodies to thyroid peroxidase (TPOAb)
increase in TPOAb subclasses IgG1-IgG3
lymphocyte infiltration and follicle formation within thyroid gland (Hashimotos thyroiditis)
T-cell changes (increased CD4:CD8 ratio)
TSH-receptor antibodies (TSH-R Abs)
Diagnosis
This condition is commonly undiagnosed by physicians due to either unfamiliarity with the disease, the subtlety of symptoms, or the attribution of the symptoms to the stresses of having a newborn. Usual screening begins with assessing the thyroid stimulating hormone (TSH) level. A suppressed TSH could represent the hyperthyroid phase, but warrants further testing to investigate for possible Graves disease. A normal TSH with persistent symptoms could represent the shift between phases and requires repeat testing 4–6 weeks later; an elevated TSH at this time could indicate the hypothyroid phase.
Treatment
For most women, the hyperthyroid phase presents with very mild symptoms or is asymptomatic; intervention is usually not required. If symptomatic cases require treatment, a short course of beta-blockers would be effective.Assessing treatment for the hypothyroid is more complex. Women with symptoms or a very high TSH level, or both, are usually prescribed a course of levothyroxine. Asymptomatic women with slightly elevated TSH levels who are planning subsequent pregnancies, should consider a course of treatment until completion of the family to avoid possible developmental complications in future children. Otherwise, treatment could be discontinued after one year postpartum.
Prevalence
Women with type I diabetes mellitus have a threefold increase in the prevalence of postpartum thyroiditis than non-diabetic women in the same region.According to Johns Hopkins, 3 in 100 women develop postpartum thyroiditis. Some risk factors include antithyroid antibodies, type 1 diabetes, history of thyroid problems, and family history of thyroid problems. According to the National Institute of Health, postpartum thyroiditis is especially common in Pakistan because it is an iodine-deficient country.
References
Further reading
"Postpartum Thyroiditis." Johns Hopkins Medicine, www.hopkinsmedicine.org/health/conditions-and-diseases/postpartum-thyroiditis. Afzal, Rafia. "Thyroid disorders in pregnancy: An overview of literature from Pakistan." Indian journal of endocrinology and metabolism vol. 17,5 (2013): 943–5. doi:10.4103/2230-8210.117202 |
Argyria | Argyria or argyrosis is a condition caused by excessive exposure to chemical compounds of the element silver, or to silver dust. The most dramatic symptom of argyria is that the skin turns blue or blue-grey. It may take the form of generalized argyria or local argyria. Generalized argyria affects large areas over much of the visible surface of the body. Local argyria shows in limited regions of the body, such as patches of skin, parts of the mucous membrane or the conjunctiva.
The terms argyria and argyrosis have long been used interchangeably, with argyria being used more frequently. Argyrosis has been used particularly in referring to argyria of the conjunctiva, but the usage has never been consistent and cannot be relied on except where it has been explicitly specified. The term is from the Ancient Greek: ἄργυρος (argyros, silver).
Pathophysiology
In humans and other animals, chronic intake of silver products commonly leads to gradual accumulation of silver compounds in various parts of the body. As in photography (where silver is useful because of its sensitivity to light), exposure of pale or colourless silver compounds to sunlight decomposes them to silver metal or silver sulfides. Commonly these products deposit as microscopic particles in the skin, in effect a dark pigment. This condition is known as argyria or argyrosis.
Chronic intake also may lead to silver pigments depositing in other organs exposed to light, particularly the eyes. In the conjunctiva this is not generally harmful, but it also may affect the lens, leading to serious effects.
Localised argyria often results from topical use of substances containing silver, such as some kinds of eye drops. Generalized argyria results from chronically swallowing or inhaling silver compounds, either for home medicinal purposes, or as a result of working with silver or silver compounds.While silver is potentially toxic to humans at high doses, the risk of serious harm from low doses, given over a short term, is small. Silver is used in some medical appliances because of its anti-microbial nature, which stems from the oligodynamic effect. Chronic ingestion or inhalation of silver preparations (especially colloidal silver) can lead to argyria in the skin and other organs. This is not life-threatening, but is considered by most to be cosmetically undesirable.The reference dose, published by the United States Environmental Protection Agency in 1991, which represents the estimated daily exposure that is unlikely to incur an appreciable risk of deleterious effects during a lifetime, is 5 µg/(kg·d).Argyria worsens and builds up as exposure to silver continues, and does not resolve once exposure stops.
History
Since at least the mid-19th century, doctors have known that silver or silver compounds can cause some areas of the skin and other body tissues to turn grey or blue-grey. Argyria occurs in people who ingest or inhale silver in large quantities over a long period (several months to many years). People who work in factories that manufacture silver products can also breathe in silver or its compounds. In the past, some of these workers have become argyric. However, the level of silver in the air and the length of exposure that caused argyria in these workers is not known. Historically, colloidal silver, a liquid suspension of microscopic silver particles, was also used as an internal medication to treat a variety of diseases. In the 1940s, they were overtaken by the use of pharmaceutical antibiotics, such as penicillin.
Society and culture
A prominent case involving the ingestion of colloidal silver was that of Stan Jones of Montana, a Libertarian candidate for the United States Senate in 2002 and 2006. The peculiar coloration of his skin was featured prominently in media coverage of his unsuccessful campaign, though Jones contended that the best-known photo was "doctored". Jones promised that he was not using his silvery complexion as a gimmick. His purposeful consumption of colloidal silver was a self-prescribed measure undertaken in response to fears that the Y2K problem would make antibiotics unavailable, an event that did not occur. He is reported to have said that given the chance to go back, he would do it again. He maintains that his good health, excepting the unusual skin tone, is the result of his use of colloidal silver.In 2007, press reports described Paul Karason, an American man whose entire skin gradually turned blue after he took a homemade silver chloride colloid and used a silver salve on his face in an attempt to treat problems with his sinuses, dermatitis, acid reflux and other issues. At the time of the reports, Karason maintained his belief in silvers effectiveness and continued to take it, albeit in smaller doses. He died in 2013 of a heart attack; "a cause of death was not immediately known", but according to Jo Anna Karason, his estranged wife, "Paul Karason had suffered heart problems for years. He was a heavy smoker, despite undergoing triple bypass surgery about five years ago".Rosemary Jacobs is a prominent activist against alternative medicine. As a child, Jacobs was treated for allergies with nose drops that contained colloidal silver, and developed argyria as a result. Jacobs came to international attention after Paul Karason was on The Today Show in 2008. From 2010 to 2013, Jacobs posted about topics in health fraud, particularly naturopathy, on her blog.
Possible implications
Although research is still not definitive, the literature has suggested that argyria can cause a decrement in kidney function. Additionally, a lack of night vision may be present. The lack of night vision would most likely be due to damaged rods in the eye, from the exposure to silver or silver dust particles in the ocular region.
See also
Amalgam tattoo
Bismuthia
Carotenodermia
Chrysiasis
Methemoglobinemia, another condition known for causing blue skin coloration
References
External links
"Public Health Statement for Silver". Centers for Disease Control. December 1990. Retrieved February 24, 2007.
"Rosemarys Story." Rosemary Jacobs explains her argyria; includes photographs. Accessed February 24, 2007.
"Systemic Argyria Associated With Ingestion of Colloidal Silver." by Akhil Wadhera, MD and Max Fung, MD. Dermatology Journal Online. Accessed February 24, 1997.
"Blue Man Seeks Acceptance" about another victim of argyria due to colloidal silver.
"Man Turns Blue", by Duncan Hooper, telegraph.co.uk, Dec. 21, 2007.
"This Man Turned Blue (video)", NBC Today Show, Matt Lauer interview, aired January 7, 2008.
Chemistry behind the ‘blue man’ unlocked", by Josh Howgego, Chemistry World, 1 November 2012. |
Pitted keratolysis | Pitted keratolysis (also known as Keratolysis plantare sulcatum, Keratoma plantare sulcatum, and Ringed keratolysis) is a bacterial skin infection of the foot. The infection is characterized by craterlike pits on the sole of the feet and toes, particularly weight bearing areas.
The infection is caused by Corynebacterium species bacteria and Kytococcus sedentarius. Excessive sweating of the feet and use of occlusive footwear provide an environment in which these bacteria thrive and therefore increase the risk of developing pitted keratolysis.The condition is fairly common, especially in the military where wet shoes/boots are worn for extended periods of time without removing/cleaning. Skin biopsy specimens are not usually utilized, as the diagnosis of pitted keratolysis is often made by visual examination and recognition of the characteristic odor. Woods lamp examination results are inconsistent. Treatment of pitted keratolysis requires the application of antibiotics to the skin such as benzoyl peroxide, clindamycin, erythromycin, fusidic acid, or mupirocin. Prevention efforts aim to keep the feet dry by using moisture-wicking shoes and socks as well as antiperspirants.
Signs and symptoms
Pitted keratolysis typically presents with white discoloration of the skin and numerous discrete, "punched-out" pitted lesions or erosions, usually located on the soles of the feet. The pits are typically 1–7 millimeters in diameter. These circular and shallow pits are characteristic of pitted keratolysis, and often overlap to produce larger areas of erosion. The appearance of this condition’s characteristic lesions becomes more pronounced when the affected area is wet or submerged in water. Occasionally these lesions present with a green or brown hue around and within the pits.These superficial erosions are found under the toes and on the soles of the feet, and especially at the pressure bearing points such as the heel. Typically, both feet are equally affected. Rarely, the condition affects the palms.
Cause
The most common cause of pitted keratolysis is Corynebacterium species. However, several other bacteria may also cause the condition, particularly Actinomyces keratolytica, Dermatophilus congolensis, Kytococcus sedentarius, and Streptomyces. Less frequently, it is due to Acinetobacter, Clostridium, Klebsiella, and Pseudomonas species.
Pathogenesis
Pitted keratolysis is associated with excessive sweating of the palms or soles (palmoplantar hyperhidrosis.) The pits seen in pitted keratolysis are caused by bacteria secreting proteinase enzymes which cause the breakdown of the keratin proteins in the stratum corneum layer of the affected skin. This results in the formation of sulfur compounds which leads to a very strong and foul foot odor. The bacteria that cause pitted keratolysis thrive in warm and humid environments. Irritation is generally minimal, though occasionally burning, itching, and soreness are experienced with pitted keratolysis.
Diagnosis
The diagnosis of pitted keratolysis is based primarily on the physical examination, with recognition of the classic pitted lesions and pungent odor. Dermoscopic examination can facilitate visualization of pits and pit walls. A Woods lamp may show coral red fluorescence, as seen in erythrasma. However, this finding is not uniformly present, as the condition may be caused by bacteria that do not produce fluorescent pigments. Further laboratory testing is not typically required for the diagnosis. However, a potassium hydroxide preparation can help rule out the presence of a fungal infection. Imaging and biopsy are not necessary.
Differential diagnosis
Acid
Athletes foot (Tinea pedis)
Erythrasma
Hyperhidrosis
Treatment
As of 2014, there is little high-quality evidence to provide guidance and support one treatment method over another. Therefore, the optimal treatment approach for pitted keratolysis remains unclear as the condition has not been well-studied. One review suggested a treatment approach requiring modification of risk factors (e.g., keeping feet clean and dry) and treating the underlying bacterial infection. Effective antibiotic options include clindamycin, erythromycin, mupirocin, and fusidic acid. Topical clindamycin is generally preferred as the first-line choice due to lower cost and better availability. Fusidic acid is preferred over mupirocin in most cases due to less resistance to fusidic acid amongst Methicillin-sensitive staphylococcus aureus and Methicillin-resistant staphylococcus aureus. Benzoyl peroxide is an effective alternative over-the-counter option and is thought to be as effective as topical clindamycin. Clinical cure was typically seen after 2.5–3 weeks. Oral antibiotics are not typically recommended.Foot hygiene is important. The feet may be washed at least daily with soap and water, and dried thoroughly afterwards. Moisture-wicking socks and shoes may be worn and antiperspirants, such as aluminum chlorohydrate, may help to keep the feet dry. Injections of botulinum toxin have successfully induced cessation of sweating (anhidrosis) of the soles of the feet and led to resolution of pitted keratolysis. These injections are typically reserved for refractory cases of pitted keratolysis that have failed to respond to environmental modifications and antibiotics due to the high cost and pain associated with botulinum toxin injections.Pitted keratolysis can be reduced and eventually stopped by regularly applying a liberal amount of antiperspirant body powder to the inside of the shoes and socks of the affected person. Regular powder application will greatly reduce foot perspiration and keep the plantar surface of the foot dry therefore creating an environment hostile to the Corynebacterium.
Epidemiology
Pitted keratolysis occurs worldwide and in various climates. The infection is more common in people who live in tropical climates and walk barefoot, and those who spend a lot of time wearing occlusive footwear (e.g., tight shoes, rubber boots), such as in the military where wet shoes are worn for a prolonged period of time without removing and proper hygiene.
History
Pitted keratolysis was first named keratoma plantare sulcatum.
See also
List of cutaneous conditions
References
== External links == |
Congenital dyserythropoietic anemia | Congenital dyserythropoietic anemia (CDA) is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) in the body and a less than normal quantity of hemoglobin in the blood. CDA may be transmitted by both parents autosomal recessively or dominantly.
Signs and symptoms
The symptoms and signs of congenital dyserythropoietic anemia are consistent with:
Tiredness (fatigue)
Weakness
Pale skin
Types
Congenital dyserythropoietic anemia has four different subtypes, CDA Type I, CDA Type II, CDA Type III, and CDA Type IV. CDA type II (CDA II) is the most frequent type of congenital dyserythropoietic anemias.
Diagnosis
The diagnosis of congenital dyserythropoietic anemia can be done via sequence analysis of the entire coding region, types I, II, III and IV ( is a relatively new form of CDA that had been found, just 4 cases have been reported) according to the genetic testing registry.
Treatment
Treatment of individuals with CDA usually consist of frequent blood transfusions, but this can vary depending on the type that the individual has. Patients report going every 2–3 weeks for blood transfusions. In addition, they must undertake chelation therapy to survive; either deferoxamine, deferasirox, or deferiprone to eliminate the excess iron that accumulates. Removal of the spleen and gallbladder are common. Hemoglobin levels can run anywhere between 8.0 g/dl and 11.0 g/dl in untransfused patients, the amount of blood received by the patient is not as important as their baseline pre-transfusion hemoglobin level. This is true for ferritin levels and iron levels in the organs as well, it is important for patients to go regularly for transfusions in order to maximize good health, normal ferritin levels run anywhere between 24 and 336 ng/ml, hematologists generally do not begin chelation therapy until ferritin levels reach at least 1000 ng/ml. It is more important to check iron levels in the organs through MRI scans, however, than to simply get regular blood tests to check ferritin levels, which only show a trend, and do not reflect actual organ iron content.
Gene therapy
Gene therapy, as well as, bone marrow transplant are also possible treatments for the disorder, but each have their own risks at this point in time. Bone marrow transplantation is the more used method between the two, whereas researchers are still trying to definitively establish the results of gene therapy treatment. It generally requires a 10/10 HLA matched donor, however, who is usually a sibling. As most patients do not have this, they must rely on gene therapy research to potentially provide them with an alternative. CDA at both clinical and genetic aspects are part of a heterogeneous group of genetic conditions. Gene therapy is still experimental and has largely only been tested in animal models until now. This type of therapy has promise, however, as it allows for the autologous transplantation of the patients own healthy stem cells rather than requiring an outside donor, thereby bypassing any potential for graft vs. host disease (GVHD).In the United States, the FDA approved clinical trials on Beta thalassemia patients in 2012. The first study, which took place in July 2012, recruited human subjects with thalassemia major,
See also
Thalassemia
Hemoglobinopathy
List of hematologic conditions
References
Further reading
Greer, John P.; Arber, Daniel A.; Glader, Bertil; List, Alan F.; Means, Robert T.; Paraskevas, Frixos; Rodgers, George M. (2013-08-29). Wintrobes Clinical Hematology. Lippincott Williams & Wilkins. ISBN 9781469846224.
Iolascon, Achille; Delaunay, Jean; Wickramasinghe, Sunitha N.; Perrotta, Silverio; Gigante, Maddalena; Camaschella, Clara (2001-08-15). "Natural history of congenital dyserythropoietic anemia type II". Blood. 98 (4): 1258–1260. doi:10.1182/blood.V98.4.1258. ISSN 0006-4971. PMID 11493480.
== External links == |
GM1 gangliosidoses | The GM1 gangliosidoses, usually shortened to GM1, are gangliosidoses caused by mutation in the GLB1 gene resulting in a deficiency of beta-galactosidase. The deficiency causes abnormal storage of acidic lipid materials in cells of the central and peripheral nervous systems, but particularly in the nerve cells, resulting in progressive neurodegeneration. GM1 is a rare lysosomal storage disorder with a prevalence of 1 to every 100,000 to 200,000 live births worldwide, although rates are higher in some regions.
Cause
GM1 Gangliosidoses disorders are caused by mutations in the GLB1 gene, which codes for lysosomal hydrolase, acid beta-galactosidase (β-gal). Low levels of β-gal cause an accumulation of GM1 gangliosides. They are inherited, autosomal recessive sphingolipidoses, a class of lipid storage disorders.
Diagnosis
Diagnosis of GM1 can be obtained by genetic and enzymatic testing.
Types
GM1 has three forms classified by age of onset.
Type 1: early infantile
Type 2: late infantile/juvenile
Type 3: adult
Early infantile GM1
Symptoms of early infantile GM1 (the most severe subtype, with onset shortly after birth) may include neurodegeneration, seizures, liver enlargement (hepatomegaly), spleen enlargement (splenomegaly), coarsening of facial features, skeletal irregularities, joint stiffness, distended abdomen, muscle weakness, exaggerated startle response to sound, and problems with gait.About half of affected patients develop cherry-red spots in the eye.
Children may be deaf and blind by age 1 and often die by age 3 from cardiac complications or pneumonia.
Early psychomotor deterioration: decreased activity and lethargy in the first weeks; never sit; feeding problems - failure to thrive; visual failure (nystagmus noted) by 6 months; initial hypotonia; later spasticity with pyramidal signs; secondary microcephaly develops; decerebrate rigidity by 1 year and death by age 1–2 years (due to pneumonia and respiratory failure); some have hyperacusis.
Macular cherry-red spots in 50% by 6–10 months; corneal opacities in some
Facial dysmorphology: frontal bossing, wide nasal bridge, facial edema (puffy eyelids); peripheral edema, epicanthus, long upper lip, microretrognathia, gingival hypertrophy (thick alveolar ridges), macroglossia
Hepatomegaly by 6 months and splenomegaly later; some have cardiac failure
Skeletal deformities: flexion contractures noted by 3 months; early subperiosteal bone formation (may be present at birth); diaphyseal widening later; demineralization; thoracolumbar vertebral hypoplasia and beaking at age 3–6 months; kyphoscoliosis. *Dysostosis multiplex (as in the mucopolysaccharidoses)
10–80% of peripheral lymphocytes are vacuolated; foamy histiocytes in bone marrow; visceral mucopolysaccharide storage similar to that in Hurler disease; GM1 storage in cerebral gray matter is 10-fold elevated (20–50-fold increased in viscera)
Galactose-containing oligosacchariduria and moderate keratan sulfaturia
Morquio disease Type B: Mutations with higher residual beta-galactosidase activity for the GM1 substrate than for keratan sulfate and other galactose-containing oligosaccharides have minimal neurologic involvement but severe dysostosis resembling Morquio disease type A (Mucopolysaccharidosis type 4).
Late infantile/Juvenile GM1
Onset of late infantile GM1 is typically between ages 1 and 3 years. The juvenile form may be diagnosed into childhood. Some children live into adolescence or early adulthood. This subtype is characterized by a trajectory in which some developmental skills are gained, then they stabilize and delays occur, and these are followed by regression. Early symptoms include difficulty crawling and walking, hypotonia, speech and swallowing problems, and seizures. Neurological symptoms include ataxia, seizures, dementia, and difficulties with speech.
Adult GM1
Onset of adult GM1 is typically in adolescence or adulthood and is the slowest progressing of the subtypes.
Symptoms include muscle atrophy, neurological complications that are less severe and progress at a slower rate than in other forms of the disorder, corneal clouding in some patients, and dystonia (sustained muscle contractions that cause twisting and repetitive movements or abnormal postures). Angiokeratomas may develop on the lower part of the trunk of the body. Most patients have a normal size liver and spleen. Prenatal diagnosis is possible by measurement of Acid Beta Galactosidase in cultured amniotic cells.
Treatment
There is no cure for GM1, although several gene therapy trials are underway. More information for these can be found at ClinicalTrials.gov. Treatment for GM1 is symptom-based and palliative.
References
External links
CureGM1 Foundations mission is to fund research for the benefit of all those who suffer from GM1 gangliosidosis.
National Tay-Sachs & Allied Diseases Association (NTSAD) provides support for families Tay-Sachs, Canavan, GM1, and Sandhoff diseases by driving research, forging collaboration, and fostering community.
MPS Society is based in the UK and provides support and resources for families with MPS (Mucopolysaccharide), Fabry and related disorders, including GM1. |
Hepatoblastoma | Hepatoblastoma is a malignant liver cancer occurring in infants and children and composed of tissue resembling fetal liver cells, mature liver cells, or bile duct cells. They usually present with an abdominal mass. The disease is most commonly diagnosed during a childs first three years of life. Alpha-fetoprotein (AFP) levels are commonly elevated, but when AFP is not elevated at diagnosis the prognosis is poor.
Signs and symptoms
Patients are usually asymptomatic at diagnosis. As a result, disease is often advanced at diagnosis.
Pathophysiology
Hepatoblastomas originate from immature liver precursor cells, are typically unifocal, affect the right lobe of the liver more often than the left lobe, and can metastasize. They are categorized into two types: "Epithelial Type" and "Mixed Epithelial / Mesenchymal Type."Individuals with familial adenomatous polyposis (FAP), a syndrome of early-onset colonic polyps and adenocarcinoma, frequently develop hepatoblastomas. Also, beta-catenin mutations have been shown to be common in sporadic hepatoblastomas, occurring in as many as 67% of patients.Recently, other components of the Wnt signaling pathway have also demonstrated a likely role in constitutive activation of this pathway in the causation of hepatoblastoma. Accumulating evidence suggests that hepatoblastoma is derived from a pluripotent stem cell.Syndromes with an increased incidence of hepatoblastoma include Beckwith–Wiedemann syndrome, trisomy 18, trisomy 21, Acardi syndrome, Li–Fraumeni syndrome, Goldenhar syndrome, von Gierke disease, and familial adenomatous polyposis.
Diagnosis
The most common method of testing for hepatoblastoma is a blood test checking the alpha-fetoprotein level. Alpha-fetoprotein (AFP) is used as a biomarker to help determine the presence of liver cancer in children. At birth, infants have relatively high levels of AFP, which fall to normal adult levels by the second year of life. The normal level for AFP in children has been reported as lower than 50 nanograms per milliliter (ng/ml) and 10 ng/ml in adults. An AFP level greater than 500 ng/ml is a significant indicator of hepatoblastoma. AFP is also used as an indicator of treatment success. If treatments are successful in removing the cancer, the AFP level is expected to return to normal.
Treatment
Surgical removal of the tumor, neoadjuvant chemotherapy prior to tumor removal, and liver transplantation have been used to treat these cancers. Primary liver transplantation provides high, long term, disease-free survival rate in the range of 80%, in cases of complete tumor removal and adjuvant chemotherapy survival rates approach 100%. The presence of metastases is the strongest predictor of a poor prognosis.
References
External links
humpath #2775 (Pathology images) |
Erythropoietic protoporphyria | Erythropoietic protoporphyria (or commonly called EPP) is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the red blood cells (erythrocytes), plasma, skin, and liver. The severity varies significantly from individual to individual.
A clinically similar form of porphyria, known as X-Linked dominant protoporphyria, was identified in 2008.
Presentation
EPP usually presents in childhood with the most common mode of presentation as acute photosensitivity of the skin. It affects areas exposed to the sun and tends to be intractable. A few minutes of exposure to the sun induces pruritus, erythema, swelling and pain. Longer periods of exposure may induce second degree burns. After repetitive exposure, patients may present with lichenification, hypopigmentation, hyperpigmentation and scarring of the skin.EPP usually first presents in childhood, and most often affects the face and the upper surfaces of the arms, hands, and feet and the exposed surfaces of the legs. Most patients, if the EPP is not as severe, manifest symptoms with onset of puberty when the male and female hormone levels elevate during sexual development and maintenance. More severe EPP can manifest in infancy. EPP can be triggered through exposure to sun even though the patient is behind glass. Even the UV emissions from arc welding with the use of full protective mask have been known to trigger EPP. EPP can also manifest between the ages of 3 and 6.Prolonged exposure to the sun can lead to edema of the hands, face, and feet, rarely with blistering and petechiae. Skin thickening can sometimes occur over time.People with EPP are also at increased risk to develop gallstones. One study has noted that EPP patients suffer from vitamin D deficiency.
Liver failure
Protoporphyrin accumulates to toxic levels in the liver in 5–20% of EPP patients, leading to liver failure. The spectrum of hepatobiliary disease associated with EPP is wide. It includes cholelithiasis, mild parenchymal liver disease, progressive hepatocellular disease and end-stage liver disease.A lack of diagnostic markers for liver failure makes it difficult to predict which patients may experience liver failure, and the mechanism of liver failure is poorly understood. A retrospective European study identified 31 EPP patients receiving a liver transplant between 1983 and 2008, with phototoxic reactions in 25% of patients who were unprotected by surgical light filters. The same study noted a 69% recurrence of the disease in the grafted organ. Five UK liver transplants for EPP have been identified between 1987 and 2009. Frequent liver testing is recommended in EPP patients where no effective therapy has been identified to manage liver failure to date.
Pregnancy
EPP photosensitivity symptoms are reported to lessen in some female patients during pregnancy and menstruation, although this phenomenon is not consistent, and the mechanism is not understood.
Genetics
Most cases of EPP are results of inborn errors of metabolism but the metabolic defect in some patients may be acquired. Mutation of the gene that encodes for ferrochelatase in the long arm of chromosome 18 is found in majority of the cases. Ferrochelatase (FECH) catalyzes the insertion of ferrous iron into the protoporphyrin IX ring to form heme. EPP exhibits both recessive and dominant patterns of inheritance and a high degree of allelic heterogeneity with incomplete penetrance. Most heterozygotes are asymptomatic. Symptoms do not occur unless FECH activity is less than 30% of normal, but such low levels are not present in a majority of patients.
Pathophysiology
Cells which synthesize heme are predominantly erythroblasts/reticulocytes in the bone marrow (80%) and hepatocytes (20%). Deficiency of FECH results in increased release of protoporphyrin, which binds to albumin in plasma and subsequently undergoes hepatic extraction. Normally, most protoporphyrin in hepatocytes is secreted into bile; the remainder undergoes transformation into heme. Some protoporphyrin in bile is returned to the liver as a consequence of the enterohepatic circulation; the remaining protoporphyrin in the intestine undergoes fecal excretion. Protoporphyrin is insoluble and hence unavailable for renal excretion. In EPP, subnormal biotransformation of protoporphyrin into heme results in accumulation of protoporphyrin in hepatocytes.Since FECH deficiency is associated with increased concentrations of protoporphyrin in erythrocytes, plasma, skin and liver, retention of protoporphyrin in skin predisposes to acute photosensitivity. As a result of absorption of ultraviolet and visible light (peak sensitivity at 400 nm, with lesser peaks between 500-625 nm) by protoporphyrin in plasma and erythrocytes when blood circulates through the dermal vessels, free radicals are formed, erythrocytes become unstable and injury to the skin is induced.A significant increase in the hepatobiliary excretion of protoporphyrin can damage the liver through both cholestatic phenomena and oxidative stress - predisposing to hepatobiliary disease of varying degrees of severity
Diagnosis
EPP is generally suspected by the presence of acute photosensitivity of the skin and can be confirmed by detection of a plasmatic fluorescence peak at 634 nm. It is also useful to find increased levels of protoporphyrin in feces and the demonstration of an excess of free protoporphyrin in erythrocytes.Screening for FECH mutation on one allele or aminolevulinic acid synthase 2 gain-of-function mutation in selected family members may be useful, especially in genetic counseling.
Liver biopsy confirms hepatic disease in EPP by the presence of protoporphyrin deposits in the hepatocytes that can be observed as a brown pigment within the biliary canaliculi and the portal macrophages. Macroscopically, the cirrhotic liver can have a black color due to protoporphyrin deposits. Using polarized light the characteristic Maltese cross shape of birefringent crystalline pigment deposits is found. The examination of liver tissue under a Wood’s lamp reveals a red fluorescence due to protoporphyrin. Liver biopsy is not helpful for estimation of prognosis of liver disease.
Treatment
There is no cure for this disorder; however, symptoms can usually be managed by limiting exposure to daytime sun and some types of artificial lighting. Most types of artificial lighting emit light in the problematic wavelengths, with fluorescent lighting being the worst offender. Color temperature can be a good indicator of what light is most detrimental, as the higher the color temperature, the more violet light (380–450 nm) is emitted. Incandescent and LED lighting in the soft white range (2700–3000 K) produce the least problematic light. Additionally, selecting lower wattage bulbs can reduce the overall output of light.
Since the photosensitivity results from light in the visible spectrum, most sunscreens are of little use (with the exception of non-nano zinc oxide which provides uniform protection between 290–400 nm and some protection up to 700 nm). Sun protective clothing can also be very helpful, although clothing with UPF values are only rated based on their UV protection (up to 400 nm) and not on their protection from the visible spectrum. Some sun protective clothing manufacturers use zinc oxide in their fabrics, such as Coolibars ZnO Suntect line, which will offer protection from visible light.Some patients gradually build a protective layer of melanin by regularly exposing themselves for short times to ultraviolet radiation.Window films which block UV and visible light up to 450 nm can provide relief from symptoms if applied to the patients automobile and home windows. An example of such would be Madico Amber 81 which can protect through the 500 nm range.
Blue blocking screen protectors can help provide relief from symptoms caused by televisions, phones, tablets and computer screens.
EPP is considered one of the least severe of the porphyrias. Unless there is liver failure, it is not a life-threatening disease.
Approved therapies
Afamelanotide, developed by Australian-based Clinuvel Pharmaceuticals, was approved in Europe in December 2014 and in the United States in October 2019 for treatment or prevention of phototoxicity in adults with EPP.
Off-label therapies
Several drugs are used off label by patients with EPP:
Ursodeoxycholic acid is a bile acid that is administered to promote biliary secretion of protoporphyrin. Results of its use in EPP are controversial. However, it is known to alter the composition of bile, to protect hepatocytes from the cytotoxic effect of hydrophobic bile acids, and to stimulate biliary secretion by several distinct mechanisms.
Hematin appears to reduce excess protoporphyrin production in the bone marrow. It has been administered to patients with EPP (3–4 mg/kg iv) who develop a crisis after liver transplantation.
Plasmapheresis can also decrease the levels of protoporphyrin in plasma, however its use in treating acute episodes is controversial.
Cholestyramine is an orally administered resin which reduces circulating levels of protoporphyrin by binding to protoporphyrin in the intestine and, hence, interrupting the enterohepatic circulation. It is usually used in combination with other treatment approaches.
Activated carbon, like cholestyramine, binds to protoporphyrin in the intestine and prevents its absorption. It is cheap and readily available. It seems to be effective in reducing circulating protoporphyrin levels.Bone marrow transplantation, liver transplantation, acetylcysteine, extracorporeal albumin dialysis, parenteral iron and transfusion of erythrocytes are alternative plans for treatment of EEP.
Over-the-counter drug
Some over-the-counter drugs may help:
Proferrin is an oral heme supplement which may work similarly to Hematin.
B. subtilis (a gram-positive soil probiotic) produces ferrochelatase, which may be able to convert some of the protoporphyrin in the intestine into heme.
Beta carotene, though a recent meta analysis of carotene treatment has called its effectiveness into question.
Epidemiology
Case reports suggest that EPP is prevalent globally. The prevalence has been estimated somewhere between 1 in 75,000 and 1 in 200,000 however it has been noted that the prevalence of EPP may be increasing due to a better understanding of the disease and improved diagnosis. An estimated 5,000–10,000 individuals worldwide have EPP. EPP is considered the most common form of porphyria in children. The prevalence in Sweden has been published as 1:180,000.
History
Erythropoietic protoporphyria was first described in 1953 by Kosenow and Treibs and completed in 1960 by Magnus et al. at the St Johns Institute of Dermatology in London.
See also
Xeroderma pigmentosum
Porphyria cutanea tarda
List of cutaneous conditions
References
External links
Erythropoietic protoporphyria at NLM Genetics Home Reference |
Cerebrospinal fluid leak | A cerebrospinal fluid leak (CSF leak or CSFL) is a medical condition where the cerebrospinal fluid (CSF) surrounding the brain or spinal cord leaks out of one or more holes or tears in the dura mater. A cerebrospinal fluid leak can be either cranial or spinal, and these are two different disorders. A spinal CSF leak can be caused by one or more meningeal diverticula or CSF-venous fistulas not associated with an epidural leak.A CSF leak is either caused by trauma including that arising from medical interventions or spontaneously sometimes in those with predisposing conditions (known as a spontaneous cerebrospinal fluid leak or sCSF leak). Traumatic causes include a lumbar puncture noted by a post-dural-puncture headache, or a fall or other accident. Spontaneous CSF leaks are associated with heritable connective tissue disorders including Marfan syndrome and Ehlers–Danlos syndromes.A loss of CSF greater than its rate of production leads to a decreased volume inside the skull known as intracranial hypotension.
Any CSF leak is most often characterized by orthostatic headaches, which worsen when standing, and improve when lying down. Other symptoms can include neck pain or stiffness, nausea, vomiting, dizziness, fatigue, and a metallic taste in the mouth. A CT myelography scan can identify the site of a cerebrospinal fluid leakage. Once identified, the leak can often be repaired by an epidural blood patch, an injection of the patients own blood at the site of the leak, a fibrin glue injection, or surgery.
The set of symptoms associated with a sCSF leak is referred to as a spontaneous cerebrospinal fluid leak syndrome (SCSFLS). A sCSF leak is uncommon but not rare, affecting at least one in 20,000 people and many more who go undiagnosed every year. On average, the condition develops at age 42, and women are twice as likely to be affected. Some people with a sCSF leak have a chronic leak of cerebrospinal fluid despite repeated patching attempts, leading to long-term disability due to pain and being unable to be upright, and surgery is often needed. SCSFLS was first described by German neurologist Georg Schaltenbrand in 1938 and by American neurologist Henry Woltman of the Mayo Clinic in the 1950s.
Classification
Spontaneous cerebrospinal fluid leaks are classified into two main types: cranial leaks, and spinal leaks. The vast majority of leaks are spinal. Cranial leaks occur in the head, and in some of these cases, CSF can leak from the nose, or from the ear. Spinal leaks occur when one or more holes form in the dura along the spinal cord. Both cranial and spinal spontaneous CSF leaks cause neurological symptoms as well as spontaneous intracranial hypotension, diminished volume, and pressure of the cranium. While this symptom can be referred to as intracranial hypotension, the intracranial pressure may be normal, with the underlying issue instead being low CSF volume. For this reason, a SCSFL is referred to as CSF hypovolemia as opposed to CSF hypotension.Spontaneous intracranial hypotension, a subtype of CSF leak, refers to lower than normal than CSF volume due to an initially unknown or insidious cause. This differentiates it from CSF leaks of known causes such as cranial or spinal trauma, surgery or lumbar puncture or spinal anesthesia (most common cause of CSF leak). The International Classification of Headache Disorders (ICHD) Third Edition diagnostic criteria for spontaneous intracranial hypotension includes any headache attributed to low CSF pressure (low CSF opening pressure) or CSF leakage (evidence of CSF leakage on imaging). Further, the headache must have a temporal relation to the low CSF pressure or leakage and the headache cannot be better explained by another ICHD diagnosis. The final criteria is that in the rare cases of spontaneous intracranial hypotension with no headache present, the neurologic symptoms that are present must be attributable to low CSF or explained by the diagnosis of spontaneous intracranial hypotension.
Signs and symptoms
The most common symptom of a CSF leak is a fast-onset, extremely painful orthostatic headache or thunderclap headache. This headache is usually made worse by standing and typically becomes prominent throughout the day, with the pain becoming less severe when lying down. Orthostatic headaches can become chronic and disabling to the point of incapacitation. Some patients with a SCSFL will develop headaches that begin in the afternoon. This is known as second-half-of-the-day headache. This may be an initial presentation of a spontaneous CSF leak or appear after treatment such as an epidural patch, and likely indicates a slow CSF leak. While high CSF pressure can make lying down unbearable, low CSF pressure due to a leak can be relieved by lying flat on the back.About 50% of people with a CSFL experience neck pain or stiffness, nausea, and vomiting.Other symptoms of a CSF leak include photophobia, dizziness and vertigo, gait disturbances, tinnitus, facial numbness or weakness, visual disturbances, brain fog or difficulties with concentration, neuralgia, fatigue, fluid dripping from the nose or ears,Aural symptoms are also present in many cases of intracranial hypotension due to CSF leak; including muffled hearing, pulsatile tinnitus, hearing loss. Less common symptoms include double vision (due to cranial nerve 6 palsy) or tremor.Movement disorders are uncommon in spontaneous CSF leaks but occasionally can be one of the major components of the clinical presentation.Some cases of chronic intracranial hypotension due to CSF leak may present as personality changes, altered behaviors and impairment of executive functions, similar to behavioral-variant frontotemporal dementia as the frontal and temporal lobes are affected by downward sagging due to reduced intra-cranial pressures.An untreated CSF leak can result in coma or death as late stage findings as the brainstem herniates through the skull base or foramen magnum .
Causes
A spontaneous CSF leak is termed so as it has previously been thought to be idiopathic, meaning the cause is unknown. The evidence of the last decade suggests however, that these leaks result from either a discogenic pathology, such as microspur, osteophyte or intra-dural disc herniation that pierces the dura like a knife, connective tissue disorder (which can often lead to discogenic pathology), or spinal drainage problems.A cerebrospinal fluid leak can be a rare complication of an anterior cervical discectomy and fusion (ACDF). One study suggested a CSF leak to follow from 0.5% of operations. Another study suggests a CSF leak to follow from 1% of operations. In most of these cases repair is successful.
Discogenic causes
The most common cause of an intractable "sCSF" leak is discogenic, either from an intra-dural disc herniation, osteophyte or microspur on the disc or vertebral body. "Recent radiological and microsurgical investigations revealed that a calcified, degenerative bony microspur is often the culprit lesion in cases of intractable CSF leaks. Arising from the level of the intervertebrate disk space, these microspurs pierce the ventral dura and produce a slit-like defect a few millimeters in length. These microspurs and the associated CSF leak have to be localized exactly, and then they are amenable to surgical treatment."
Connective tissue theory
Various scientists and physicians have suggested that SCSFLs may be the result of an underlying connective tissue disorder affecting the spinal dura. It may also run in families and be associated with aortic aneurysms and joint hypermobility.Up to two thirds of those affected demonstrate some type of generalized connective tissue disorder. Marfan syndrome, Ehlers–Danlos syndrome, and autosomal dominant polycystic kidney disease are the three most common connective tissue disorders associated with SCSFLs. Roughly 20% of patients with a SCSFL exhibit features of Marfan syndrome, including tall stature, hollowed chest (pectus excavatum), joint hypermobility and arched palate. However, no other Marfan syndrome presentations are shown.
Spinal drainage theory
Some studies have proposed that issues with the spinal venous drainage system may cause a CSF leak. According to this theory, dural holes and intracranial hypotension are symptoms caused by low venous pressure in the epidural space. When inferior limb muscles pump blood towards the heart and pressure in the inferior vena cava vein becomes negative, the network of epidural veins is overdrained, causing CSF to be aspirated into the epidural space. True leaks can form at weak points in the spinal meninges. Therefore, the observed CSF hypotension is a result of CSF hypovolemia and reduced epidural venous pressure.
Other causes
Cranial CSF leaks result from intracranial hypertension in a vast majority of cases. The increased pressure causes a rupture of the cranial dura mater, leading to CSF leak and intracranial hypotension. Patients with a nude nerve root, where the root sleeve is absent, are at increased risk for developing recurrent CSF leaks. Lumbar disc herniation has been reported to cause CSF leaks in at least one case. Degenerative spinal disc diseases cause a disc to pierce the dura mater, leading to a CSF leak.CSF leaks can result from a lumbar puncture procedure.
Complications
Several complications can occur as a result of SCSFLS including decreased cranial pressure, brain herniation, infection, blood pressure problems, transient paralysis, and coma. The primary and most serious complication of SCSFLS is spontaneous intracranial hypotension, where pressure in the brain is severely decreased. This complication leads to the hallmark symptom of severe orthostatic headaches.People with cranial CSF leaks, the rarer form, have a 10% risk of developing meningitis per year. If cranial leaks last more than seven days, the chances of developing meningitis are significantly higher. Spinal CSF leaks cannot result in meningitis due to the sterile conditions of the leak site. When a CSF leak occurs at the temporal bone, surgery becomes necessary in order to prevent infection and repair the leak. Orthostatic hypotension is another complication that occurs due to autonomic dysfunction when blood pressure drops significantly. The autonomic dysfunction is caused by compression of the brainstem, which controls breathing and circulation.Low CSF volume can cause the cerebellar tonsil position to descend, which can be mistaken for Chiari malformation; however when the CSF leak is repaired the tonsil position often returns to normal (as seen in upright MRI) in this "pseudo-Chiari" condition.
A further, albeit rare, complication of CSF leak is transient quadriplegia due to a sudden and significant loss of CSF. This loss results in hindbrain herniation and causes major compression of the upper cervical spinal cord. The quadriplegia dissipates once the patient lies supine. An extremely rare complication of SCSFLS is third nerve palsy, where the ability to move ones eyes becomes difficult and interrupted due to compression of the third cranial nerve.There are documented cases of reversible frontotemporal dementia and coma. Coma due to a CSF leak has been successfully treated by using blood patches and/or fibrin glue and placing the person in the Trendelenburg position. Empty sella syndrome, a bony structure that surround the pituitary gland, occurs in CSF leak patients.
Pathophysiology
Cerebrospinal fluid is produced by the choroid plexus in the ventricles of the brain and contained by the dura and arachnoid layers of the meninges. The brain floats in CSF, which also transports nutrients to the brain and spinal cord. As holes form in the spinal dura mater, CSF leaks out into the surrounding space. The CSF is then absorbed into the spinal epidural venous plexus or soft tissues around the spine. Due to the sterile conditions of the soft tissues around the spine, there is no risk of meningitis.Lack of CSF pressure and volume can allow the brain to sag and descend through the foramen magnum (large opening) of the occipital bone, at the base of the skull. The lower portion of the brain is believed to stretch or impact one or more cranial nerve complexes, thereby causing a variety of sensory symptoms. Nerves that can be affected and their related symptoms are detailed in the table at right.
Diagnosis
Diagnosis of CSF leakage can be done by various imaging techniques, chemical tests of bodily fluid discharged from a head orifice, or clinical examination. The use of CT, MRI, and assays are the most common types of CSF leak instrumental tests. Many CSF leaks do not show up on imaging and chemical assays, thus such diagnostic tools are not definitive to rule out CSF leaks. A clinician may often depend upon patient history and exam to diagnose, for example: discharge of excessive amount of clear fluid from the nose upon bending over, the increase in headache following a Valsalva maneuver or the reduction of headache when the patient takes a prone position are positive indicators.
A clinical exam is often used as a means to diagnose CSF leaks. Improved patient response to conservative treatment may further define a positive diagnosis. The lack of clinician awareness of the signs -symptoms and ailments- of a CSF leak is the greatest challenge to proper diagnosis and treatment, in particular: the loss of the orthostatic characteristic of headache and that every chronic CSF leaker will have a unique symptom set that as a whole contributes to the underlying condition, and diagnosis of, a CSF leak.
The primary place of first complaint to a physician is a hospital emergency room. Up to 94% of those with SCSFLS are initially misdiagnosed. Incorrect diagnoses include migraines, meningitis, Chiari malformation, and psychiatric disorders. The average time from onset of symptoms until definitive diagnosis is 13 months. A 2007 study found a 0% success rate for proper diagnosis in the emergency department.
CT
Diagnosis of a cerebrospinal fluid leak is performed through a combination of measurement of the CSF pressure and a computed tomography myelogram (CTM) scan of the spinal column for fluid leaks. The opening fluid pressure in the spinal canal is obtained by performing a lumbar puncture, also known as a spinal tap. Once the pressure is measured, a radiocontrast agent is injected into the spinal fluid. The contrast then diffuses out through the dura sac before leaking through dural holes. This allows for a CTM with fluoroscopy to locate and image any sites of dura rupture via contrast seen outside the dura sac in the imagery.
MRI
There is disagreement over whether MRI should be the diagnostic tool of choice. Magnetic resonance imaging is less effective than CT at directly imaging sites of CSF leak. MRI studies may show pachymeningeal enhancement (when the dura mater looks thick and inflamed), sagging of the brain, pituitary enlargement, subdural hygromas, engorgement of cerebral venous sinuses, and other abnormalities. For 20% of patients, MRIs present as completely normal. MRIs performed with the patient seated upright (vs. laying supine) are not better for diagnosing CSF leaks, but are more than twice as effective at diagnosing cerebellar tonsillar ectopia, also known as Chiari malformation. Cerebellar tonsillar ectopia shares many of the same symptoms as CSF leak, but originates either congenitally or from trauma, including whiplash strain to the dura.An alternate method of locating the site of a CSF leak is to use heavily T2-weighted MR myelography. This has been effective in identifying the sites of a CSF leak without the need for a CT scan, lumbar puncture, and contrast and at locating fluid collections such as CSF pooling. Another highly successful method of locating a CSF leak is intrathecal contrast and MR Myelography.Contrast-enhanced brain MRI with sagittal reformats can assess for the following:
Subdural fluid collections
Enhancement of the meninges
Engorgement of venous structures
Pituitary swelling
Sagging of the brainFor suspected spinal CSF leaks, spine imaging can be used to guide treatment.
Assay
Fluid dripping from the nose (CSF rhinorrhoea) or ears (CSF otorrhea) should be collected and tested for the protein Beta-2 transferrin which would be highly accurate in identifying CS fluid and diagnosing a cranial CSF leak.
CSF analysis
Patients with CSF leaks have been noted to have very low or even negative opening pressures during lumbar puncture. However, patients with confirmed CSF leaks may also demonstrate completely normal opening pressures. In 18–46% of cases, the CSF pressure is measured within the normal range. Analysis of spinal fluid may demonstrate lymphocytic pleocytosis and elevated protein content or xanthochromia. This is hypothesized to be due to increased permeability of dilated meningeal blood vessels and a decrease of CSF flow in the lumbar subarachnoid space.
Myelography
A myelogram can be used to more precisely identify the location of a CSF leak by injecting a dye to further enhance the imaging. However, CSF leaks are frequently not visible on imaging.For patients with recalcitrant spontaneous intracranial hypotension and no leak found on conventional spinal imaging, digital subtraction myelography, CT myelography and dynamic myelography (a modified conventional myelography technique) should be considered to rule out a CSF-venous fistula. In addition, presence of a hyperdense paraspinal vein should be investigated in imaging as it is highly suggestive of a CSF venous fistula.
Treatment
Symptomatic treatment usually involves analgesics for both cranial and spinal CSF leaks. Initial measures can include rest, caffeine intake (via coffee or intravenous infusion), and hydration. Corticosteroids may provide transient relief for some patients. An abdominal binder, which increases intracranial pressure by compressing the abdomen, can temporarily relieve symptoms for some people. Sometimes a CSF leak will heal on its own. Otherwise, symptoms may last months or even years.
Epidural blood patch
The treatment of choice for this condition is the surgical application of epidural blood patches, which has a higher success rate than conservative treatments of bed rest and hydration. Through the injection of a persons own blood into the area of the hole in the dura, an epidural blood patch uses bloods clotting factors to clot the sites of holes. The volume of autologous blood and number of patch attempts for patients is highly variable. One-quarter to one-third of SCSFLS patients do not have relief of symptoms from epidural blood patching. Finding the location of a cerebrospinal fluid leak is not required prior to using an epidural blood patch as initial lumbar epidural blood patches often provide relief of symptoms and resolve the leak without further intervention.
Fibrin glue sealant
If blood patches alone do not succeed in closing the dural tears, placement of percutaneous fibrin glue can be used in place of blood patching, raising the effectiveness of forming a clot and arresting CSF leakage.
Surgical drain technique
In extreme cases of intractable CSF leak, a surgical lumbar drain has been used. This procedure is believed to decrease spinal CSF volume while increasing intracranial CSF pressure and volume. This procedure restores normal intracranial CSF volume and pressure while promoting the healing of dural tears by lowering the pressure and volume in the dura. This procedure has led to positive results leading to relief of symptoms for up to one year.
Neurosurgical repair
Surgery to treat a CSF-venous fistula in CSF leak patients is highly effective. Neurosurgery is available to directly repair leaking meningeal diverticula. The areas of dura leak can be tied together in a process called ligation and then a metal clip can be placed in order to hold the ligation closed. Alternatively, a small compress called a pledget can be placed over the dura leak and then sealed with gel foam and fibrin glue. Primary suturing is rarely able to repair a CSF leak, and in some patients exploration of the dura may be required to properly locate all sites of CSF leak.
Adjunct measures
The use of antibiotics to prevent meningitis in those with a CSF leak due to a skull fracture is of unclear benefit.
Prognosis
Long-term outcomes for people with SCSFLS remain poorly studied. Symptoms may resolve in as little as two weeks, or persist for months. Less commonly, patients may have unremitting symptoms for many years. People with chronic SCSFLS may be disabled and unable to work. Recurrent CSF leak at an alternate site after recent repair is common.
Epidemiology
A 1994 community-based study indicated that two out of every 100,000 people with SCSFLS, while a 2004 emergency room-based study indicated five per 100,000. SCSFLS generally affects the young and middle aged; the average age for onset is 42.3 years, but onset can range from ages 22 to 61. In an 11-year study, women were found to be twice as likely to be affected as men.Studies have shown that SCSFLS runs in families. It is suspected that genetic similarity in families includes weakness in the dura mater which leads to SCSFLS. Large scale population-based studies have not yet been conducted. While a majority of SCSFLS cases continue to be undiagnosed or misdiagnosed, an actual increase in occurrence is unlikely.
History
Spontaneous CSF leaks have been described by notable physicians and reported in medical journals dating back to the early 1900s. German neurologist Georg Schaltenbrand reported in 1938 and 1953 what he termed "aliquorrhea", a condition marked by very low, unobtainable, or even negative CSF pressures. The symptoms included orthostatic headaches and other features that are now recognized as spontaneous intracranial hypotension. A few decades earlier, the same syndrome had been described in French literature as "hypotension of spinal fluid" and "ventricular collapse". In 1940, Henry Woltman of the Mayo Clinic wrote about "headaches associated with decreased intracranial pressure". The full clinical manifestations of intracranial hypotension and CSF leaks were described in several publications reported between the 1960s and early 1990s. Modern reports of spontaneous CSF leak have been reported to medical journals since the late 1980s.
Research
Tetracosactide is a corticosteroid that causes the brain to produce additional spinal fluid to replace the volume of the lost CSF and alleviate symptoms, and has been given intravenously to treat CSF leaks.In three small studies of 1-2 patients with recurrent CSF leaks where repeated blood patches failed to form clots and relieve symptoms, the patients received temporary but complete resolution of symptoms with an epidural saline infusion. The saline infusion temporarily restores the volume necessary for a patient to avoid SIH until the leak can be repaired properly. Intrathecal saline infusion is used in urgent cases such as intractable pain or decreased consciousness.The gene TGFBR2 has been implicated in several connective tissue disorders including Marfan syndrome, arterial tortuosity, and thoracic aortic aneurysm. A study of patients with SCSFLS demonstrated no mutations in this gene. Minor features of Marfan syndrome have been found in 20% of CSF leak patients. Abnormal findings of fibrillin-1 have been documented in these CSF leak patients, but only one patient demonstrated a fibrillin-1 defect consistent with Marfan syndrome.
See also
Subdural effusion
References
External links
CFS leak info
Spinal CSF leak
Spinal CSF leak Canada |
Acute motor axonal neuropathy | Acute motor axonal neuropathy (AMAN) is a variant of Guillain–Barré syndrome. It is characterized by acute paralysis and loss of reflexes without sensory loss. Pathologically, there is motor axonal degeneration with antibody-mediated attacks of motor nerves and nodes of Ranvier.
Signs and symptoms
Causes
A link to Campylobacter jejuni was suspected when a young girl was admitted to Second Teaching Hospital. She had become ill after feeding the family chickens. She developed acute paralysis and respiratory failure. Investigators discovered that several of the chickens in the home displayed similar symptoms and C. jejuni was found in their droppings. Several of the paralysis patients were found to have antibodies to C. jejuni and anti-GD1a antibodies, suggesting a link between the pathogen and the disease. In 2015, Zika virus was linked to AMAN.
Diagnosis
The syndrome typically presents as a progressive flaccid symmetric paralysis with areflexia, often causing respiratory failure. Electromyographic studies and nerve conduction studies show normal motor conduction velocity and latency with decreased amplitude of compound muscle action potentials. Pathologically, it is a noninflammatory axonopathy without demyelination. Antibodies attack the coating of the motor neurons without causing inflammation or loss of myelin. It does not affect sensory neurons, so sensation remains intact despite loss of movement.
Treatment
the majority of patients have complete symptom resolution with 5-day intravenous immunoglobulin (IV Ig) treatment. Patients with AMAN continue to see improvements in ambulation and functional ability up to four years post-diagnosis.
History
AMAN, also known as Chinese Paralytic Syndrome, was first described by a group of Johns Hopkins University and University of Pennsylvania neurologists in collaboration with neurologists from the Second Teaching Hospital of Hebei Medical School and Beijing Childrens Hospital. In 1991, Guy Mckhann, Jack Griffin, Dave Cornblath and Tony Ho from Johns Hopkins University and Arthur Asbury from University of Pennsylvania visited China to study a mysterious epidemic of paralytic syndrome occurring in northern China. Every summer, hundreds of children from rural China developed acute paralysis and respiratory failure. Hospitals were overwhelmed with number of cases and often ran out of ventilators and hospital beds. Examination of these children showed that many of them had acute flaccid paralysis and areflexia but with little or no sensory loss. Electrophysiological testing of these children showed motor axonal loss with occasional conduction block with a lack of demyelinating features and normal sensory potentials. In contrast, the common form of Guillain–Barré syndrome in the West often presents with sensory loss and demyelination on electrophysiology testing and is more common in adults. Later, several autopsies confirmed the focus of the immune attack was at the motor axolemma especially around the nodes of Ranvier. These cases showed deposition of antibody and complement along the motor axolemma and associated macrophage infiltration.
References
== External links == |
Ataque de nervios | Ataque de nervios (Spanish pronunciation: [aˈtake ðe ˈneɾβjos], also known as "Puerto Rican syndrome") is a psychological syndrome mostly associated, in the United States, with Spanish-speaking people from the Caribbean, although commonly identified among all Iberian-descended cultures. Ataque de nervios translates into English as "attack of nerves", although it is used in its common cultural form to refer to a specific pattern of symptoms, rather than being a general term for feeling nervous. The condition appears in Appendix I of the revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) as a culture-bound syndrome.
Classification
Despite comparisons to panic attacks, investigators have identified ataque de nervios as a separate syndrome with measured differences in anxiety sensitivity, and types of attacks. Marlene Steinberg, an Associate Research Scientist at Yale University stated that because it is similar to Multiple Personality Disorder, some Hispanics may be misdiagnosed with an ataque de nervios syndrome instead.
Symptoms
Reported aspects of the syndrome include uncontrollable screaming or shouting, crying, trembling, sensations of heat rising in the chest and head, dissociative experiences, and verbal or physical aggression. The reaction is usually associated with a stressful event relating to the family, although it is not specifically defined as arising from such occurrences.
History
Ataque de nervios was first mentioned after studies were conducted by US psychiatrists who focused on healthcare for Hispanic populations, particularly individuals who were Puerto Rican and living in the United States .
See also
Dissociative identity disorder
Nervous breakdown
Susto
Women on the Verge of a Nervous Breakdown
Hwabyeong
Posttraumatic stress disorder
== References == |
Umbilical cord compression | Umbilical cord compression is the obstruction of blood flow through the umbilical cord secondary to pressure from an external object or misalignment of the cord itself. Cord compression happens in about one in 10 deliveries.
Causes
Nuchal cord, when the umbilical cord is (tightly) around the neck of the fetus
Entanglement of the cord
Knot in the cord
Cord prolapse, where the umbilical cord exits the birth canal before the baby, which can cause cord compression.
As a complication of oligohydramnios in which there is insufficient amniotic fluid
Compression during uterine contractions in childbirth
Diagnosis
On cardiotocography (CTG), umbilical cord compression can present with variable decelerations in fetal heart rate.
Treatment
Umbilical cord compression may be relieved by the mother switching to another position. In persistent severe signs of fetal distress, Cesarean section may be needed.
References
== External links == |
Keratoderma | Keratoderma is a hornlike skin condition.
Classification
The keratodermas are classified into the following subgroups:: 506
Congenital
Simple keratodermas
Diffuse palmoplantar keratodermas
Diffuse epidermolytic palmoplantar keratoderma
Diffuse nonepidermolytic palmoplantar keratoderma
mal de Meleda
Focal palmoplantar keratoderma
Striate palmoplantar keratoderma
Punctate palmoplantar keratoderma
Keratosis punctata palmaris et plantaris
Spiny keratoderma
Focal acral hyperkeratosis
Complex keratodermas
Diffuse palmoplantar keratoderma
Erythrokeratodermia variabilis
Palmoplantar keratoderma of Sybert
Olmsted syndrome
Naegeli–Franceschetti–Jadassohn syndrome
Focal palmoplantar keratoderma
Papillon–Lefèvre syndrome
Pachyonychia congenita type I
Pachyonychia congenita type II
Focal palmoplantar keratoderma with oral mucosal hyperkeratosis
Camisa disease
Ectodermal dysplasias
Cloustons hidrotic ectodermal dysplasia
Acrokeratotic poikiloderma
Dermatopathic pigmentosa reticularis
Syndromic keratodermas
Vohwinkel syndrome
Palmoplantar keratoderma associated with esophageal cancer
Palmoplantar keratoderma and spastic paraplegia
Naxos disease
Striate palmoplantar keratoderma, woolly hair, and left ventricular dilated cardiomyopathy
Keratitis-ichthyosis-deafness syndrome
Corneodermatosseous syndrome
Huriez syndrome
Oculocutaneous tyrosinemia
Cardiofaciocutaneous syndrome
Schöpf–Schulz–Passarge syndrome
Acquired
Acquired keratodermas
AIDS-associated keratoderma
Arsenical keratoses
Calluses
Climacteric keratoderma
Clavi (Corns)
Eczema
Human papillomavirus
Keratoderma blenorrhagicum
Lichen planus
Norwegian scabies
Paraneoplastic keratoderma
Psoriasis
Reactive arthritis
Secondary syphilis
Tinea pedis
Sézary syndrome
Tuberculosis verrucosa cutis
Drug-induced keratoderma
See also
Palmoplantar keratoderma
Skin lesion
List of cutaneous conditions
List of conditions caused by problems with junctional proteins
References
== External links == |
Laryngospasm | Laryngospasm is an uncontrolled or involuntary muscular contraction (spasm) of the vocal folds. The condition typically lasts less than 60 seconds, but in some cases can last 20–30 minutes and causes a partial blocking of breathing in, while breathing out remains easier. It may be triggered when the vocal cords or the area of the trachea below the vocal folds detects the entry of water, mucus, blood, or other substance. It is characterized by stridor or retractions. Some people have frequent laryngospasms, whether awake or asleep. In an ear, nose, and throat practice, it is typically seen in people who have silent reflux disease. It is also a well known, infrequent, but serious perioperative complication.It is likely that more than 10% of drownings involve laryngospasm, but the evidence suggests that it is not usually effective at preventing water from entering the trachea.
Signs and symptoms
The main symptom is choking and difficulty or inability to breathe or speak, a feeling of suffocation, which may be followed by hypoxia-induced loss of consciousness. As the airway reopens, breathing may cause a high-pitched sound called stridor. The episode seldom lasts over a couple of minutes before breathing is back to normal.
Causes
Various stimuli including asthma, allergies, exercise, stress, and irritants such as smoke, dust, fumes, liquids, and food can trigger laryngospasm. It is common in drowning, both as a direct response to inhalation of water, and as a complication during rescue and resuscitation due to aspiration of vomit.In some individuals laryngospasm can occur spontaneously or as a result of reflux or impaired swallowing. Gastroesophageal reflux disease (GERD) is a common cause of spontaneous laryngospasm. Treating GERD can lessen the frequency of spasms. The onset of spasms may be caused by a viral infection.It is also a complication associated with anesthesia. The spasm can happen often without any provocation, but tends to occur after tracheal extubation. In children, the condition can be particularly deadly, leading to cardiac arrest within 30–45 seconds, and is a possible cause of death associated with the induction of general anesthesia in the pediatric population. These situations are not to be confused with the benign laryngospam events seen in infants after feeding or due to reflux.It can sometimes occur during sleep, waking up the affected person. This usually occurs when the person has gastric acidity and develops re-flux during sleep, where the gastric acid causes irritation which will cause the spasm attack.It is also a symptom of hypoparathyroidism.It can also be caused by some medications such as lurasidone.
Diagnosis
Prevention
Due to the shape of the stomach and position of the esophagus, sleep-related laryngospasms may be prevented by sleeping on the left side, which can help in keeping stomach acid from entering the esophagus and reaching the vocal cords.When laryngospasm is coincident with a cold or flu, it may be helpful for some with the condition to take acid reflux medication to limit the irritants in the area. If a cough is present, then treat a wet cough; but limit coughing whenever possible, as it is only likely to trigger a spasm. Drink water or tea to keep the area from drying up. Saline drops also help to keep the area moist. Pseudoephederine may also help to clear any mucus that may cause coughing and thereby triggering more spasms.
Treatment
Minor laryngospasm will generally resolve spontaneously in the majority of cases.Laryngospasm in the operating room is treated by hyperextending the patients neck and administering assisted ventilation with 100% oxygen. In more severe cases it may require the administration of an intravenous muscle relaxant, such as Succinylcholine, and reintubation.When gastroesophageal reflux disease (GERD) is the trigger, treatment of GERD can help manage laryngospasm. Proton pump inhibitors such as Dexlansoprazole (Dexilant), Esomeprazole (Nexium), and Lansoprazole (Prevacid) reduce the production of stomach acids, making reflux fluids less irritant. Prokinetic agents reduce the amount of acid available by stimulating movement in the digestive tract.Patients who are prone to laryngospasm during illness can take measures to prevent irritation such as antacids to avoid acid reflux.For acute context, making an upright position of the upper part of the body has been shown to shorten the spasm episodes. Fixation of the arms on stabilization of the body and slowing of breathing is also recommended.
See also
Laryngotracheal stenosis
References
External links
Larson, Philip C., "Laryngospam -The Best Treatment", Anesthesiology, 11 1998, Vol.89, 1293–1294 |
Posterior cerebral artery syndrome | Posterior cerebral artery syndrome is a condition whereby the blood supply from the posterior cerebral artery (PCA) is restricted, leading to a reduction of the function of the portions of the brain supplied by that vessel: the occipital lobe, the inferomedial temporal lobe, a large portion of the thalamus, and the upper brainstem and midbrain.This event restricts the flow of blood to the brain in a near-immediate fashion. The blood hammer is analogous to the water hammer in hydrology and it consists of a sudden increase of the upstream blood pressure in a blood vessel when the bloodstream is abruptly blocked by vessel obstruction. Complete understanding of the relationship between mechanical parameters in vascular occlusions is a critical issue, which can play an important role in the future diagnosis, understanding and treatment of vascular diseases.Depending upon the location and severity of the occlusion, signs and symptoms may vary within the population affected with PCA syndrome. Blockages of the proximal portion of the vessel produce only minor deficits due to the collateral blood flow from the opposite hemisphere via the posterior communicating artery. In contrast, distal occlusions result in more serious complications. Visual deficits, such as agnosia, prosopagnosia or cortical blindness (with bilateral infarcts) may be a product of ischemic damage to occipital lobe. Occlusions of the branches of the PCA that supply the thalamus can result in central post-stroke pain and lesions to the subthalamic branches can produce “a wide variety of deficits”.Left posterior cerebral artery syndrome presents alexia without agraphia; the lesion is in the splenium of the corpus callosum.
Signs and symptoms
Peripheral Territory Lesions
Contralateral homonymous hemianopsia
cortical blindness with bilateral involvement of the occipital lobe branches
visual agnosia
prosopagnosia
dyslexia, Anomic aphasia, color naming and discrimination problems
memory defect
topographic disorientationCentral Territory Lesions
central post-stroke (thalamic) pain: spontaneous pain, dysesthesias and sensory impairments
involuntary movements: chorea, intention tremor, hemiballismus
contralateral hemiplegia
Weber’s syndrome: occulomotor nerve palsy
Bálints syndrome: loss of voluntary eye movements optic ataxia, asimultagnosia (inability to understand visual objects)
Diagnosis
1.CT
2.MRI
Treatment
References
== External links == |
Interrupted aortic arch | Interrupted aortic arch is a very rare heart defect (affecting 3 per million live births) in which the aorta is not completely developed. There is a gap between the ascending and descending thoracic aorta. In a sense it is the complete form of a coarctation of the aorta. Almost all patients also have other cardiac anomalies, including a ventricular septal defect (VSD), aorto-pulmonary window, and truncus arteriosus. There are three types of interrupted aortic arch, with type B being the most common. Interrupted aortic arch (especially Type B) is often associated with DiGeorge syndrome.
Signs and symptoms
Patients with an interrupted aortic arch usually have symptoms from birth, with nearly all presenting symptoms within two weeks (when the ductus arteriosus is usually closed).
Causes
It is thought that an interrupted aortic arch occurs through excessive apoptosis in the developing, embryonic aorta. Around 50% of patients have DiGeorge syndrome.
Diagnosis
It can be diagnosed with a standard echocardiogram. An echocardiogram can also aid in classifying the type of defect. The diagnosis can also be made prior to birth via ultrasound. Patients will have a loss of appetite, appear tired and weak, and exhibit rapid breathing and a rapid heart rate. If the condition progresses, the infant may turn pale, feel cold in the lower half of the body, and have a weak pulse due to insufficient blood flow. The pattern of pulse abnormalities is dependent upon the classification; e.g., for type B interrupted aortic arch, the right brachial pulse will be palpable and the left brachial and femoral pulses will be impalpable due to closure of the ductus arteriosus. Rarely, an interrupted aortic arch can be associated with an intracranial aneurysm. Signs of ischemia due to interrupted aortic arch can be separated by the organ system involved:
Liver injury: elevated serum glutamic oxaloacetic transaminase (SGOT) (also known as aspartate transaminase, AST) and lactic acid dehydrogenase (LDH)
Kidney injury: elevated serum creatinine
Intestinal injury: signs of necrotizing enterocolitis, such as bloody stoolsCHARGE syndrome, a specific, rare pattern of genetic abnormalities, commonly features conotruncal and aortic arch heart defects, which can include an interrupted aortic arch.
Classification
There are three primary classifications for an interrupted aortic arch, on the basis of the specific, anatomic anomaly. They are:
Type A: The aortic arch is interrupted after the left subclavian artery.
Type B: The aortic arch is interrupted between the left common carotid artery and the left subclavian artery. This is the most common form of the condition, and is the classification most often associated with DiGeorge syndrome.
Type C: The aortic arch is interrupted between the innominate artery and the left common carotid artery. This is the least common form of the condition.Each class can be divided into two subgroups, based upon whether the right subclavian artery originated in a normal, anatomical position (subgroup 1) or if it originated distal to the left subclavian artery and continues behind the esophagus (subgroup 2). However, these subgroups do not affect how the disease is diagnosed or treated.
Treatment
Prostaglandins
If the diagnosis is made prenatally, prostaglandin E1 (PGE1) is started after birth to avoid closure of the ductus arteriosus. Prostaglandin therapy is performed via a continuous infusion, due to how quickly prostaglandins are metabolized in the body. However, the diagnosis may go undetected, delaying treatment until closure of the ductus arteriosus produces symptoms.
Surgery
Curative treatment consists of open heart surgery soon after birth, preferably immediately after diagnosis. Often, a synthetic patch is used to recreate the lost section of aorta. Recent research has revealed that an initial single-stage repair using direct anastomoses and repair of any existing cardiac defects is the preferred surgical technique, as opposed to a two-stage surgical repair.Awaiting surgery, prostaglandin can be administered to keep the ductus arteriosus open, thereby allowing blood flow to the lower body. After successful treatment, the patient is monitored for the rest of their life by a specialist to ensure that problems do not occur.
Prognosis
Failure to treat the condition yields a mortality rate of 90% at a median age of 4 days. Death occurs due to increased blood flow from the left side of the heart (oxygenated blood) to the right side (deoxygenated blood), inducing heart failure; pulmonary edema; and eventual closing of the ductus arteriosus. For an infant with an interrupted aortic arch, a patent (open) ductus arteriosus allows for blood to bypass the "interruption," without which blood will be unable to reach the lower half of the body. As a result, the kidneys fail and the blood becomes acidic, resulting in death.With modern surgical techniques, 81% of children with an interrupted aortic arch survive to be 15 years-old. The fate of survivors in the long-term is still unclear.
Surgical complications
The most common, early complication of surgery is bleeding, the risk of which can be increased by prematurity, prolonged acidosis prior to surgery, and excessive tension on the anastamosis due to inadequate mobilization of the ascending and descending aorta. Other early complications include damage to the left recurrent laryngeal nerve and the phrenic nerve. Late complications include obstruction of the graft and obstruction of the left main bronchus (which passes underneath the aortic arch).
Epidemiology
The incidence of an interrupted aortic arch is extremely rare, occurring between three and twenty times per 1,000,000 births. In the context of other congenital cardiac abnormalities, interrupted aortic arch represents about 1.5% of cases.
History
The condition was first identified by Dr. Raphael Steidele, Professor of Obstetrics at the University of Vienna, in 1778. In the case Steidele described, the infant had a type A interrupted aortic arch, and survived only for "a few hours." In homage to the discoverer, the terminology of "Steideles complex" has been used to describe an interrupted aortic arch. The first type B interrupted aortic arch was reported by Seidel in 1818, and the first type C was reported by Weisman and Kesten in 1948. The classification system (Types A, B, and C) were defined by Celoria and Patton in 1959.The first successful repair of a Type A interrupted aortic arch was reported in 1961, in which the left subclavian artery was grafted into the descending thoracic aorta in a 14-year-old male patient. The first successful repair of a Type A interrupted aortic arch in an infant was in a 12-day-old infant in 1969, in which the left subclavian artery was connected to the descending thoracic aorta, the patent ductus arteriosus was closed, and the main pulmonary artery was banded.The first successful repair of a Type B interrupted aortic arch was in 1954, in which the 16 year-old, female patients own aorta was grafted from the arch to the descending thoracic aorta and the left subclavian artery was ligated. The first successful repair on a type B interrupted aortic arch in an infant was in 1973, in which a vein was used to connect the ascending aorta and the descending aorta.The first successful repair of a Type C interrupted aortic arch was in 1964, in which the 16-year-old female patients ascending aorta was grafted to the descending thoracic aorta. As of 1984, there had been no successful repairs on infants under one year old.The use of PGE1 dramatically improved the mortality rate after its introduction in 1976.
Research directions
While PGE1 is the standard of care for maintaining the ductus arteriosus, there is insufficient data on the proper dose, duration of therapy, safety, and long-term consequences of PGE1 on infants with ductal-dependent congenital heart defects (like interrupted aortic arch).
References
Further reading
Collins-Nakai, RL; Dick, M; Parisi-Buckley, L; Fyler, DC; Castaneda, AR (1976). "Interrupted aortic arch in infancy". The Journal of Pediatrics. 88 (6): 959–62. doi:10.1016/S0022-3476(76)81049-9. PMID 1271195.
== External links == |
Pendular nystagmus | Pendular nystagmus is a sinusoidal oscillation, which refers to the waveform of involuntary eye movements that may occur in any direction. It is characterized by the multidimensional slow eye movements of the eyes (1 Hz frequency) with an equal velocity in each direction that resembles the trajectory of a pendulum. These pattern of these movements may differ between the two eyes. Depending upon the pattern of movements, pendular nystagmus has been divided into different subtypes such as congenital nystagmus, acquired pendular nystagmus, and amaurotic nystagmus.
References
== External links == |
Intraocular lens | Intraocular lens (IOL) is a lens implanted in the eye as part of a treatment for cataracts or myopia. If the natural lens is left in the eye, the IOL is known as phakic, otherwise it is a pseudophakic, or false lens. Such a lens is typically implanted during cataract surgery, after the eyes cloudy natural lens (cataract) has been removed. The pseudophakic IOL provides the same light-focusing function as the natural crystalline lens. The phakic type of IOL is placed over the existing natural lens and is used in refractive surgery to change the eyes optical power as a treatment for myopia (nearsightedness). This is an alternative to LASIK.
IOLs usually consist of a small plastic lens with plastic side struts, called haptics, to hold the lens in place in the capsular bag inside the eye. IOLs were conventionally made of an inflexible material (PMMA), although this has largely been superseded by the use of flexible materials, such as silicone. Most IOLs fitted today are fixed monofocal lenses matched to distance vision. However, other types are available, such as a multifocal intraocular lens that provide multiple-focused vision at far and reading distance, and adaptive IOLs that provide limited visual accommodation. Multifocal IOLs can further be, Trifocal IOLs or extended depth of focus (EDOF) lenses.
More than six million lenses are implanted annually. The procedure can be done under local or topical anesthesia with the patient awake throughout the operation. The use of a flexible IOL enables the lens to be rolled for insertion into the capsular bag through a very small incision, thus avoiding the need for stitches. This procedure usually takes less than 30 minutes in the hands of an experienced ophthalmologist, and the recovery period is about 2–3 weeks. After surgery, patients should avoid strenuous exercise or anything else that significantly increases blood pressure. They should visit their ophthalmologists regularly for 3 weeks to monitor the implants.
IOL implantation carries several risks associated with eye surgeries, such as infection, loosening of the lens, lens rotation, inflammation and nighttime halos, but a systematic review of studies has determined that the procedure is safer than conventional laser eye treatment. Though IOLs enable many patients to have reduced dependence on glasses, most patients still rely on glasses for certain activities, such as reading. These reading glasses may be avoided if Multifocal IOLs, Trifocal IOLs or EDOF lenses are used.
Medical uses
Intraocular lenses have been used since 1999 for correcting larger errors in near-sighted, far-sighted, and astigmatic eyes. This type of IOL is also called phakic intraocular lens (PIOL), as it is implanted without removing the patients natural crystalline lens.Phakic IOL appear to be less dangerous than excimer laser surgery (LASIK) in those with significant nearsightedness.More commonly IOLs are implanted via Clear Lens Extraction And Replacement (CLEAR) surgery. During CLEAR, the crystalline lens is extracted and an IOL replaces it in a process that is very similar to cataract surgery: both involve lens replacement, local anesthesia, last approximately 30 minutes, and require making a small incision in the eye for lens insertion. People recover from CLEAR surgery 1–7 days after the operation. During this time, they should avoid strenuous exercise or anything else that significantly raises blood pressure. They should visit their ophthalmologists regularly for several weeks to monitor the IOL implants.
CLEAR has a 90% success rate (risks include wound leakage, infection, inflammation, and astigmatism). CLEAR can be performed only on patients ages 40 and older. This is to ensure that eye growth, which disrupts IOL lenses, will not occur post-surgery.
Once implanted, IOL lenses have three major benefits. First, they are an alternative to the excimer laser procedure (LASIK), a form of eye surgery that does not work for people with serious vision problems. Effective IOL implants also eliminate the need for glasses or contact lenses post-surgery for most patients. The cataract will not return, as the lens has been removed. The disadvantage is that the eyes ability to change focus (accommodate) has generally been reduced or eliminated, depending on the kind of lens implanted.
Some of the risks that FDA have been found so far during a three-year study of the Artisan are:
a yearly loss of 1.8% of the endothelial cells,
0.6% risk of retinal detachment,
0.6% risk of cataract (other studies have shown a risk of 0.5–1.0%), and
0.4% risk of corneal swelling.Other risks include:
0.03–0.05% eye infection risk, which in worst case can lead to blindness. (This risk exists in all eye surgery procedures and is not unique to IOLs.)
glaucoma,
astigmatism,
remaining near or far sightedness,
rotation of the lens inside the eye one or two days after surgery.One of the causes of the risks above is that the lens can rotate inside the eye if the PIOL is too short, if the eye was incorrectly measured, or because the sulcus has a slightly oval shape (the height is slightly smaller than the width). Toric IOLs must be powered and aligned inside the eye on a meridian that corrects the patients preexisting astigmatism. Again, these lenses can rotate inside the eye postoperatively or be placed incorrectly by the operating surgeon. Either way, the patients preexisting astigmatism may not be corrected completely or may even increase.
When standard IOLs are implanted with a CLEAR procedure, in substitution of the patients crystalline, astigmatism is typically not corrected, as astigmatism is mainly attributable to a deformation of the cornea. Toric IOLs may be used during the CLEAR procedure to correct astigmatism.
The surgeon can ascertain the astigmatic, or steepest, meridian in a number of ways, including manifest refraction or corneal topography. Manifest refraction is the familiar test where the eye doctor rotates lenses in front of the eye, asking the patient, "Which is better (or clearer), this one or this one?" Corneal topography is considered a more quantitative test, and for purposes of aligning a toric IOL, most surgeons use a measurement called simulated keratometry (SimK), which is calculated by the internal programming of the corneal topography machine, to determine the astigmatic meridian on the surface of the cornea. The astigmatic meridian can also be identified using corneal wavefront technology or paraxial curvature matching.
Type of surgery
Implants with or without removal of natural crystalline
Phakia is the presence of the natural crystalline lenses. Phakic IOL (PIOL) refers to an intraocular lens implanted without removal of the patients original crystalline lens, and this is performed solely to correct refractive error in the presence of a clear crystalline lens.
Aphakia is the absence of the natural crystalline lens. The aphakic state is usually due to surgery to remove a cataractous lens, but post-surgical aphakia is rare nowadays because of the ubiquity of intraocular lenses. Rarely, aphakia can be post-traumatic or congenital in nature. Aphakic IOL refers to a lens implanted secondarily in an eye already aphakic from previous surgery or trauma some time ago.
Pseudophakia is the substitution of the natural crystalline lens with an IOL, as is often done after cataract extraction or to correct refractive error. Pseudophakic IOL refers to a lens implanted during cataract surgery, immediately after removal of the patients crystalline lens.Many aphakic and pseudophakic IOLs such as anterior chamber IOLs or 3 piece posterior chamber IOLs can be used interchangeably. The exception are one piece IOLs, which must be placed within the capsular bag at the time of cataract surgery and hence cannot be used as secondary implants.
Location of implant
Posterior chamber IOL (PCIOL). This is by far the most common type of implanted lens after cataract surgery in the United States.
Anterior chamber IOL (ACIOL). A less-common type of intraocular lens, which is sometimes used if a PCIOL is not an option for a patient or if the situation requires a phakic IOL (PIOL).
Pseudophakic IOLs
Pseudophakic IOLs are lenses implanted during cataract surgery, immediately after removal of the patients crystalline lens.
Monofocal
Monofocal IOLs are standard lenses used in cataract surgery. One of the major disadvantages of these conventional IOLs is that they can only be focused for one particular distance - either optical infinity (rendering the eye emmetropic) or a fixed finite distance (rendering the eye myopic). Patients who undergo a standard IOL implantation no longer experience clouding from cataracts, but they are unable to accommodate (change focus from near to far, far to near, and to distances in between). This is not a concern for most cataract surgeries, as they are primarily performed on elderly people that are already completely presbyopic. However, it can be a problem for patients that are not yet presbyopic (or are in the early stages of presbyopia) undergoing refractive lens exchange for the sake of correcting refractive errors. Monovision, in which one eye is made emmetropic and the other myopic, can partially compensate for the loss of accommodation and enable clear vision at multiple distances. More versatile types of lenses (multifocal and accommodating IOLs) were introduced in 2003 in the United States, with the approval by the Food and Drug Administration. These come at an additional cost to the recipient beyond what Medicare will pay and each has advantages and disadvantages.
Multifocal
Multifocal IOLs attempt to provide simultaneous viewing of distance vision and near vision. Trifocal IOLs can provide intermediate vision. Many multifocal IOL designs attempt to achieve this simultaneous viewing focus using a concentric ring design, which alternates distance and near focal points. However, many concentric ring multifocal lenses used today are prone to glare and mildly compromised focus at all ranges of vision.
People who have a multifocal IOL after their cataract is removed may be less likely to need additional glasses compared with people who have standard monofocal lenses. However, people receiving multifocal lenses may experience more visual problems than with monofocal lenses.
The most common adverse visual effects from multifocal IOLs include glare, halos (rings around lights), and a loss of contrast sensitivity in low-light conditions.
Adjustable Lens
An adjustable IOL is unlike any other lens as its prescription power can be adjusted after surgery once all healing is complete. All other IOLs require surgeons to use pre-surgery measurements to determine a patients post-surgery lens power. The drawback of this is that pre-surgery measurements are taken while a patient still has cataracts, and they cant account for minuscule shifts that occur during healing. An adjustable IOL allows surgeons to implant it and then, once healing is complete, use an Ultra Violet light delivery device to fine tune it until it suits the patient. An early example being the (RxSight) Light Adjustable Lens (LAL).
Accommodating
Some newer lens designs attempt to allow the eye to regain some partial focusing ability in order to change focus from distance to near (accommodation). However, many accommodating IOLs used today only achieve a very limited improvements in near vision which reduced over time. Accommodative intraocular lenses may also have a slightly higher risk of developing posterior capsule opacification (PCO), though there is some uncertainty around this finding. PCO is a common side-effect of many cataract surgeries and is easily treatable with a one-time laser capsulotomy procedure (see below).
Accommodating IOLs interact with ciliary muscles and zonules, using hinges at both ends to "latch on" and move forward and backward inside the eye using the same mechanism as normal accommodation. These IOLs have a 4.5-mm square-edged optic and a long hinged plate design with polyimide loops at the end of the haptics. The hinges are made of an advanced silicone called BioSil that was thoroughly tested to make sure it was capable of unlimited flexing in the eye.
Toric
A toric IOL is a type of toric lens used to correct preexisting corneal astigmatism at the time of cataract surgery. Astigmatism can also be treated with limbal relaxing incisions or an excimer laser procedure. About 40% of Americans have significant astigmatism and thus may be candidates for a toric IOL. Cataract surgery with implantation of a toric IOL is essentially the same as cataract surgery with a conventional IOL. Like toric contact lenses, toric IOLs have different powers in different meridians of the lens, and they must be positioned on the correct meridian to reverse the preexisting astigmatism. If the toric IOL is not on the correct meridian, it may need to be repositioned in a second procedure.
Multifocal toric
Standard toric IOLs are monofocal, permanently focused on distant objects. Multifocal toric IOLs are also available. These lenses provide the patient not only with correction of preexisting astigmatism, but also with multiple-focused vision at far and reading distance
Phakic IOLs
Phakic IOLs (PIOLs) are intraocular lenses which are placed in an eye that still contains a natural human crystalline lens. PIOLs are sometimes referred to as an implantable contact lenses (ICLs). As with other IOLs, PIOLs can be either spheric or toric. Toric PIOLs have to be aligned with the meridian of astigmatism; toric IOL misalignment or rotation can lead to residual or even greater astigmatism postoperatively.Depending on their attachment site to the eye, PIOLs can be divided into three categories:
Angle-supported PIOLs, placed in the anterior chamber. They are notorious for their negative impact on the corneal endothelial lining, which is vital for maintaining a healthy clear cornea.
Iris-fixated PIOLs, attached by claws to the mid-peripheral iris by a technique called enclavation. It is believed to have a lesser effect on corneal endothelium. The main complication with this type is their tendency to cause endothelial cell reduction.
Sulcus-supported PIOLs, placed in the posterior chamber in front of the natural crystalline lens. This type of PIOLs is gaining more and more popularity. They have special vaulting so as not to be in contact with the normal lens. The main complication with older versions was a small possibility of cataract formation.
Blue-light filtering IOLs
Blue light filtering IOLs filter the UV and high-energy blue light present in natural and artificial light, both of which can cause vision problems; however too much filtering of blue light can increase depression, especially in the winter months (SAD). The trademarked "Natural Yellow" material is available in three hydrophilic IOLs. Dr. Patrick H. Benz of Benz Research and Development created the first IOL material to incorporate the same UV-A blocking and violet light filtering chromophore thats present in the human crystalline lens in order to attempt to protect the retina after cataract extraction of the natural crystalline lens.
A Cochrane Review found little evidence of important differences between blue‐light filtering and non‐blue‐light filtering lenses for protecting the macula (back of the eye) after cataract surgery. This was due to studies being too small and too short‐term to provide reliable results.
Posterior capsule opacification
Posterior capsule opacification (PCO), often referred to as "after cataract", is the most common complication of cataract surgery.In a small percentage of patients, posterior chamber intraocular lenses may form PCOs a few months after implantation. They are easily treatable, and typically only require a one-time capsulotomy procedure (using a Nd:YAG laser) to clarify.
Materials
The materials that have been used to manufacture intraocular lens implants include polymethylmethacrylate (PMMA), silicone, hydrophobic acrylate, hydrophilic acrylate and collamer. Polymethylmethacrylate (PMMA) was the first material to be used successfully in intraocular lenses. British ophthalmologist Sir Harold Ridley observed that Royal Air Force pilots who sustained eye injuries during World War II involving PMMA windshield material did not show any rejection or foreign body reaction. Deducing that the transparent material was inert and useful for implantation in the eye, Ridley designed and implanted the first intraocular lens in a human eye.
Advances in technology have brought about the use of silicone and acrylic glass, both of which are soft foldable inert materials. This allows the lens to be folded and inserted into the eye through a smaller incision. Specifically, acrylic lenses are a better choice in people who have a history of uveitis or are likely to have to undergo retinal surgery requiring vitrectomy with replacement by silicone oil, such as persons with proliferative diabetic retinopathy or who are at high risk of retinal detachment, such as persons with high myopia. A study found that in participants with a history of uveitis, eyes treated with hydrophobic acrylic IOLs were over twice as likely to have a best corrected visual acuity of 20/40 or more, compared to eyes treated with silicone IOLs.
History
Sir Harold Ridley was the first to successfully implant an intraocular lens on 29 November 1949, at St Thomas Hospital at London. That lens was manufactured by the Rayner company of Brighton, East Sussex, England from Perspex CQ polymethylmethacrylate (PMMA) made by ICI (Imperial Chemical Industries). It is said the idea of implanting an intraocular lens came to him after an intern asked him why he was not replacing the lens he had removed during cataract surgery. The acrylic plastic material was chosen because Ridley noticed it was inert after seeing RAF (Royal Air Force) pilots of World War II with pieces of shattered canopies in their eyes (this acrylic resin is known by several trade names including Lucite and Plexiglas).
The intraocular lens did not find widespread acceptance in cataract surgery until the 1970s, when further developments in lens design and surgical techniques had come about.
As of the early 2000s, more than a million IOLs were implanted annually in the United States. That number was estimated by the World Health Organization to have increased to 20 million annually worldwide by 2010 (for cataract surgery), and has projected increased IOL surgeries to reach 32 million worldwide by 2020.
See also
Cataract surgery
Aphakia
Capsulorhexis
Contact lens
Adjustable-focus eyeglasses
IOLVIP
Phacoemulsification
Uveitis–Glaucoma–Hyphema syndrome
== References == |
Glucose-6-phosphate dehydrogenase deficiency | Glucose-6-phosphate dehydrogenase deficiency (G6PDD), which is the most common enzyme deficiency worldwide, is an inborn error of metabolism that predisposes to red blood cell breakdown. Most of the time, those who are affected have no symptoms. Following a specific trigger, symptoms such as yellowish skin, dark urine, shortness of breath, and feeling tired may develop. Complications can include anemia and newborn jaundice. Some people never have symptoms.It is an X-linked recessive disorder that results in defective glucose-6-phosphate dehydrogenase enzyme. Glucose-6-phosphate dehydrogenase is an enzyme which protects red blood cells, which carry oxygen from the lungs to tissues throughout the body. A defect of the enzyme results in the premature breakdown of red blood cells. This destruction of red blood cells is called hemolysis. Red blood cell breakdown may be triggered by infections, certain medication, stress, or foods such as fava beans. Depending on the specific mutation the severity of the condition may vary. Diagnosis is based on symptoms and supported by blood tests and genetic testing.Affected persons must avoid dietary triggers, notably fava beans. This can be difficult, as fava beans may be called "broad beans" and are used in many foods, whole or as flour. Falafel is probably the best known, but fava beans are also often used as filler in meatballs and other foods. Since G6PD deficiency is not an allergy, food regulations in most countries do not require that fava beans be highlighted as an allergen on the label.Treatment of acute episodes may include medications for infection, stopping the offending medication, or blood transfusions. Jaundice in newborns may be treated with bili lights. It is recommended that people be tested for G6PDD before certain medications, such as primaquine, are taken.About 400 million people have the condition globally. It is particularly common in certain parts of Africa, Asia, the Mediterranean, and the Middle East. Males are affected more often than females. In 2015 it is believed to have resulted in 33,000 deaths.
Signs and symptoms
Most individuals with G6PD deficiency are asymptomatic.Most people who develop symptoms are male, due to the X-linked pattern of inheritance, but female carriers can be affected due to unfavorable lyonization or skewed X-inactivation, where random inactivation of an X-chromosome in certain cells creates a population of G6PD-deficient red blood cells coexisting with unaffected red blood cells. A female with one affected X chromosome will show the deficiency in approximately half of her red blood cells. However, in some cases, including double X-deficiency, the ratio can be much more than half, making the individual almost as sensitive as males.Red blood cell breakdown (also known as hemolysis) in G6PD deficiency can manifest in a number of ways, including the following:
Prolonged neonatal jaundice, possibly leading to kernicterus (arguably the most serious complication of G6PD deficiency)
Hemolytic crises in response to:
Illness (especially infections)
Certain drugs (see below)
Certain foods, most notably broad beans, from which the word favism derives
Certain chemicals
Diabetic ketoacidosis
Hemoglobinuria (red or brown urine)
Very severe crisis can cause acute kidney injuryFavism is a hemolytic response to the consumption of fava beans, also known as broad beans. Though all individuals with favism show G6PD deficiency, not all individuals with G6PD deficiency show favism. The condition is known to be more prevalent in infants and children, and G6PD genetic variant can influence chemical sensitivity. Other than this, the specifics of the chemical relationship between favism and G6PD are not well understood.
Cause
G6PD deficiency results from mutations in the G6PD gene. G6PD gene contributes to the production of glucose-6-phosphate dehydrogenase. Chemical reactions involving glucose-6-phosphate dehydrogenase produce compounds that prevent reactive oxygen species from building up to toxic levels within red blood cells. If reduction in the amount of glucose-6-phosphate dehydrogenase or alteration of structure occurs due to the mutations of G6PD gene, the enzyme loses it protective role and leads to the accumulation of reactive oxygen species and thus damage of red blood cells.
Triggers
Carriers of the underlying mutation do not show any symptoms unless their red blood cells are exposed to certain triggers, which can be of four main types:
Foods (fava beans is the hallmark trigger for G6PD mutation carriers),
Certain medicines including aspirin, quinine and other antimalarials derived from quinine.
Moth balls (naphthalene)
Stress from a bacterial or viral infection.
Drugs
Many substances are potentially harmful to people with G6PD deficiency. Variation in response to these substances makes individual predictions difficult. Antimalarial drugs that can cause acute hemolysis in people with G6PD deficiency include primaquine, pamaquine, chloroquine, and hydroxychloroquine. There is evidence that other antimalarials may also exacerbate G6PD deficiency, but only at higher doses. Sulfonamides (such as sulfanilamide, sulfamethoxazole, and mafenide), thiazolesulfone, methylene blue, and naphthalene should also be avoided by people with G6PD deficiency as they antagonize folate synthesis, as should certain analgesics (such as phenazopyridine and acetanilide) and a few non-sulfa antibiotics (nalidixic acid, nitrofurantoin, isoniazid, dapsone, and furazolidone). Henna has been known to cause hemolytic crisis in G6PD-deficient infants. Rasburicase is also contraindicated in G6PD deficiency. High dose intravenous vitamin C has also been known to cause haemolysis in G6PD deficiency carriers; therefore, G6PD deficiency testing is routine before infusion of doses of 25 g or more.
Genetics
Two variants (G6PD A− and G6PD Mediterranean) are the most common in human populations. G6PD A− has an occurrence of 10% of Africans and African-Americans while G6PD Mediterranean is prevalent in the Middle East. The known distribution of the mutated allele is largely limited to people of Mediterranean origins (Spaniards, Italians, Greeks, Armenians, Sephardi Jews and other Semitic peoples). Both variants are believed to stem from a strongly protective effect against Plasmodium falciparum and Plasmodium vivax malaria. It is particularly frequent in the Kurdish Jewish population, wherein approximately 1 in 2 males have the condition and the same rate of females are carriers. It is also common in African American, Saudi Arabian, Sardinian males, some African populations, and Asian groups.All mutations that cause G6PD deficiency are found on the long arm of the X chromosome, on band Xq28. The G6PD gene spans some 18.5 kilobases. The following variants and mutations are well-known and described:
Pathophysiology
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate pathway (see image, also known as the HMP shunt pathway). G6PD converts glucose-6-phosphate into 6-phosphoglucono-δ-lactone and is the rate-limiting enzyme of this metabolic pathway that supplies reducing energy to cells by maintaining the level of the reduced form of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH in turn maintains the supply of reduced glutathione in the cells that is used to mop up free radicals that cause oxidative damage.The G6PD / NADPH pathway is the only source of reduced glutathione in red blood cells (erythrocytes). The role of red cells as oxygen carriers puts them at substantial risk of damage from oxidizing free radicals except for the protective effect of G6PD/NADPH/glutathione.People with G6PD deficiency are therefore at risk of hemolytic anemia in states of oxidative stress. Oxidative stress can result from infection and from chemical exposure to medication and certain foods. Broad beans, e.g., fava beans, contain high levels of vicine, divicine, convicine and isouramil, all of which create oxidants.When all remaining reduced glutathione is consumed, enzymes and other proteins (including hemoglobin) are subsequently damaged by the oxidants, leading to cross-bonding and protein deposition in the red cell membranes. Damaged red cells are phagocytosed and sequestered (taken out of circulation) in the spleen. The hemoglobin is metabolized to bilirubin (causing jaundice at high concentrations). The red cells rarely disintegrate in the circulation, so hemoglobin is rarely excreted directly by the kidney, but this can occur in severe cases, causing acute kidney injury.Deficiency of G6PD in the alternative pathway causes the buildup of glucose and thus there is an increase of advanced glycation endproducts (AGE). The deficiency also reduces the amount of NADPH, which is required for the formation of nitric oxide (NO). The high prevalence of diabetes mellitus type 2 and hypertension in Afro-Caribbeans in the West could be directly related to the incidence of G6PD deficiency in those populations.Although female carriers can have a mild form of G6PD deficiency (dependent on the degree of inactivation of the unaffected X chromosome – see lyonization), homozygous females have been described; in these females there is co-incidence of a rare immune disorder termed chronic granulomatous disease (CGD).
Diagnosis
The diagnosis is generally suspected when patients from certain ethnic groups (see epidemiology) develop anemia, jaundice and symptoms of hemolysis after challenges from any of the above causes, especially when there is a positive family history.Generally, tests will include:
Complete blood count and reticulocyte count; in active G6PD deficiency, Heinz bodies can be seen in red blood cells on a blood film;
Liver enzymes (to exclude other causes of jaundice);
Lactate dehydrogenase (elevated in hemolysis and a marker of hemolytic severity)
Haptoglobin (decreased in hemolysis);
A "direct antiglobulin test" (Coombs test) – this should be negative, as hemolysis in G6PD is not immune-mediated;When there are sufficient grounds to suspect G6PD, a direct test for G6PD is the "Beutler fluorescent spot test", which has largely replaced an older test (the Motulsky dye-decolouration test). Other possibilities are direct DNA testing and/or sequencing of the G6PD gene.The Beutler fluorescent spot test is a rapid and inexpensive test that visually identifies NADPH produced by G6PD under ultraviolet light. When the blood spot does not fluoresce, the test is positive; it can be falsely negative in patients who are actively hemolysing. It can therefore only be done 2–3 weeks after a hemolytic episode.When a macrophage in the spleen identifies a RBC with a Heinz body, it removes the precipitate and a small piece of the membrane, leading to characteristic "bite cells". However, if a large number of Heinz bodies are produced, as in the case of G6PD deficiency, some Heinz bodies will nonetheless be visible when viewing RBCs that have been stained with crystal violet. This easy and inexpensive test can lead to an initial presumption of G6PD deficiency, which can be confirmed with the other tests.Testing during and for many weeks after a haemolytic episode will lead to false negative results as the G6PD deficient RBC will have been excreted and the young RBC (reticulocytes)will not yet be G6PD deficient. False negative results will also be likely following any blood transfusions. For this reason, many hospitals wait for 3 months after a haemolytic episode before testing for G6PD deficiency. Females should have their G6PD activity measured by quantitative assay to avoid being misclassified by screening tests.
Classification
The World Health Organization classifies G6PD genetic variants into five classes, the first three of which are deficiency states.
Class I: Severe deficiency (<10% activity) with chronic (nonspherocytic) hemolytic anemia
Class II: Severe deficiency (<10% activity), with intermittent hemolysis
Class III: Moderate deficiency (10-60% activity), hemolysis with stressors only
Class IV: Non-deficient variant, no clinical sequelae
Class V: Increased enzyme activity, no clinical sequelae
Differential diagnosis
6-phosphogluconate dehydrogenase (6PGD) deficiency has similar symptoms and is often mistaken for G6PD deficiency, as the affected enzyme is within the same pathway, however these diseases are not linked and can be found within the same person.
Treatment
The most important measure is prevention – avoidance of the drugs and foods that cause hemolysis. Vaccination against some common pathogens (e.g. hepatitis A and hepatitis B) may prevent infection-induced attacks.In the acute phase of hemolysis, blood transfusions might be necessary, or even dialysis in acute kidney failure. Blood transfusion is an important symptomatic measure, as the transfused red cells are generally not G6PD deficient and will live a normal lifespan in the recipients circulation. Those affected should avoid drugs such as aspirin.Some patients may benefit from removal of the spleen (splenectomy), as this is an important site of red cell destruction. Folic acid should be used in any disorder featuring a high red cell turnover. Although vitamin E and selenium have antioxidant properties, their use does not decrease the severity of G6PD deficiency.
Prognosis
G6PD-deficient individuals do not appear to acquire any illnesses more frequently than other people, and may have less risk than other people for acquiring ischemic heart disease and cerebrovascular disease.
However, a recent study revealed that G6PD deficiency increases the cardiovascular risk up to 70%. The risk conferred by G6PD deficiency is moderate compared with the impact of primary cardiovascular risk factors.
Besides, a published review hypothesized that G6PD deficiency could reduce the antiplatelet efficacy of clopidogrel (clopidogrel resistance).
Epidemiology
G6PD deficiency is the second most common human enzyme defect after ALDH2 deficiency, being present in more than 400 million people worldwide. G6PD deficiency resulted in 4,100 deaths in 2013 and 3,400 deaths in 1990. African, Middle Eastern and South Asian people are affected the most, including those who have these ancestries. A side effect of this disease is that it confers protection against malaria, in particular the form of malaria caused by Plasmodium falciparum, the most deadly form of malaria. A similar relationship exists between malaria and sickle-cell disease. One theory to explain this is that cells infected with the Plasmodium parasite are cleared more rapidly by the spleen. This phenomenon might give G6PD deficiency carriers an evolutionary advantage by increasing their fitness in malarial endemic environments.
In vitro studies have shown that the Plasmodium falciparum is very sensitive to oxidative damage. This is the basis for another theory, that is that the genetic defect confers resistance due to the fact that the G6PD-deficient host has a higher level of oxidative agents that, while generally tolerable by the host, are deadly to the parasite.
History
The modern understanding of the condition began with the analysis of patients who exhibited sensitivity to primaquine. The discovery of G6PD deficiency relied heavily upon the testing of prisoner volunteers at Illinois State Penitentiary, a type of study which today is considered unethical and cannot be performed. When some prisoners were given the drug primaquine, some developed hemolytic anemia but others did not. In spite of these results, the US military administered the drug widely during the Korean War to prevent the relapsing infection caused by Plasmodium vivax hypnozoites. Numerous cases of hemolytic anemia were observed in US soldiers of North African and Mediterranean descent.After studying the mechanism through Cr51 testing, it was conclusively shown that the hemolytic effect of primaquine was due to an intrinsic defect of erythrocytes.
Society and culture
In both legend and mythology, favism has been known since antiquity. The priests of various Greco-Roman era cults were forbidden to eat or even mention beans, and Pythagoras had a strict rule that to join the society of the Pythagoreans one had to swear off beans. This ban was supposedly because beans resembled male genitalia, but it is possible that this was because of a belief that beans and humans were created from the same material.
References
External links
Family Practice Notebook/G6PD Deficiency (Favism) |
Megaesophagus | Megaesophagus, also known as esophageal dilatation, is a disorder of the esophagus in humans and other mammals, whereby the esophagus becomes abnormally enlarged. Megaesophagus may be caused by any disease which causes the muscles of the esophagus to fail to properly propel food and liquid from the mouth into the stomach (that is, a failure of peristalsis). Food can become lodged in the flaccid esophagus, where it may decay, be regurgitated, or maybe inhaled into the lungs (leading to aspiration pneumonia).
Humans
Megaesophagus may occur secondary to diseases such as achalasia or Chagas disease. Achalasia is caused by a loss of ganglion cells in the myenteric plexus. There is a marked lack of contraction within the muscles involved in peristalsis with a constant contraction of the lower esophageal sphincter. Dilation of the esophagus results in difficulty swallowing. Retention of food bolus is also noted.
Other animals
Dogs
Megaesophagus can also be a symptom of the disease myasthenia gravis. Myasthenia gravis is a neuromuscular disease where the primary symptom is weakness in various body parts of the dog. However, when myasthenia gravis occurs in older dogs it is thought of as an immune-mediated disease. Often when myasthenia gravis is diagnosed in older dogs the first symptom the dog may manifest is megaesophagus. Myasthenia gravis occurs when acetylcholine receptors (nicotinic acetylcholine receptors) fail to function properly, so that the muscle is not stimulated to contract. There is an invention known as the "bailey chair" that uses the force of gravity to push down liquids and food into the dogs stomach. Usually dogs are known to understand when its time to eat in their bailey chair, and this helps prevent issues. Bailey chairs can be made and are sold. Also, a simple chair turned upside down can be successfully used for this purpose.
In two unrelated incidents in Latvia and Australia megaesophagus developed in dogs that had eaten certain brands of dog food, however no agent that could have caused the disorder has been found in lab tests of the food.
Diagnosis
An important distinction in recognizing megaesophagus is the difference between when a dog regurgitates or vomits. When a dog regurgitates there is usually not as much effort involved as when a dog vomits. Often when regurgitating, the dog will tip its head down and the liquid and/or food will almost appear to "spill out" of its throat.One of the primary dangers to a dog with megaesophagus is aspiration pneumonia. Because the food stays lodged in the throat, it can often be inhaled into the lungs causing aspiration pneumonia. One way to avoid this is to make sure that every time the dog eats or drinks anything, that the dog sits for at least 10 minutes afterward or is held in a sitting up or begging position. This disorder has a guarded prognosis, however, a successful management technique is vertical feeding in a Bailey Chair.
Affected breeds
Cats
Affected breeds:
American Shorthair
Persian (cat)
Siamese (cat)
Horses
Megaesophagus is rare in horses. It is more frequently reported in Friesian horses than in other breeds. Congenital megaesophagus is usually identified when a foal begins to eat solid food from the ground; prior to this, as the foal nurses milk from its mother, the milk passes easily down into the stomach. The most common signs are difficulty swallowing (dysphagia) and inhalational pneumonia.
References
External links
Canine megaesophagus |
Subdural hygroma | A subdural hygroma (SDG) is a collection of cerebrospinal fluid (CSF), without blood, located under the dural membrane of the brain. Most subdural hygromas are believed to be derived from chronic subdural hematomas. They are commonly seen in elderly people after minor trauma but can also be seen in children following infection or trauma. One of the common causes of subdural hygroma is a sudden decrease in pressure as a result of placing a ventricular shunt. This can lead to leakage of CSF into the subdural space especially in cases with moderate to severe brain atrophy. In these cases the symptoms such as mild fever, headache, drowsiness and confusion can be seen, which are relieved by draining this subdural fluid.
Etiology and Pathophysiology
Subdural hygromas require two conditions in order to occur. First, there must be a separation in the layers of dura mater of the brain. Second, the resulting subdural space that occurs from the separation of layers must remain uncompressed in order for CSF to accumulate in the subdural space resulting in the hygroma. The arachnoid mater is torn and cerebrospinal fluid (CSF) from the subarachnoid space accumulates in the subdural space. Hygromas also push the subarachnoid vessels away from the inner table of the skull. Subdural hygroma can appear in the first day, but the mean time of appearance is 9 days on CT scan. Subdural hygroma does not have internal membranes that can easily rupture like subdural haematoma, but hygroma can sometimes occur together with hemorrhage to become hematohygroma.Subdural hygromas most commonly occur when events such as head trauma, infections, or cranial surgeries happen in tandem with brain atrophy, severe dehydration, prolonged spinal drainage, or any other event that causes a decrease in intracranial pressure. This provides the basis for why subdural hygromas more commonly occur in infants and elderly; infants have compressible brains while elderly patients have a greater amount of space for fluid to accumulate due to brain atrophy from age.
Signs and symptoms
Most subdural hygromas are small and clinically insignificant. A majority of patients with SDG will not experience symptoms. However, some commonly reported, but nonspecific, symptoms of SDG that have been reported include headache and nausea. Focal neurologic deficits and seizures have also been reported but are nonspecific to SDG. Larger hygromas may cause secondary localized mass effects on the adjacent brain parenchyma, enough to cause a neurologic deficit or other symptoms. Acute subdural hygromas can be a potential neurosurgical emergency, requiring decompression. Acute hygromas are typically a result of head trauma—they are a relatively common posttraumatic lesion—but can also develop following neurosurgical procedures, and have also been associated with a variety of conditions, including dehydration in the elderly, lymphoma and connective tissue diseases.
Diagnosis
In CT scan, subdural hygroma will have same density as the normal CSF. Meanwhile, in MRI, subdural hygroma will have same intensity with CSF. If iodinated contrast is administered during CT scan, the hygroma will produce high density because of the contrast at 120 kVp. However, at 190 kVp, hygroma with contrast will have intermediate density.In the majority of cases, if there has not been any acute trauma or severe neurologic symptoms, a small subdural hygroma on the head CT scan will be an incidental finding. If there is an associated localized mass effect that may explain the clinical symptoms, or concern for a potential chronic SDH that could rebleed, then an MRI, with or without neurologic consultation, may be useful.
It is not uncommon for chronic subdural hematomas (SDHs) on CT reports for scans of the head to be misinterpreted as subdural hygromas, and vice versa. Magnetic resonance imaging (MRI) should be done to differentiate a chronic SDH from a subdural hygroma, when clinically warranted. Elderly patients with marked cerebral atrophy, and secondary widened subarachnoid CSF spaces, can also cause confusion on CT. To distinguish chronic subdural hygromas from simple brain atrophy and CSF space expansion, a gadolinium-enhanced MRI can be performed. Visualization of cortical veins traversing the collection favors a widened subarachnoid space as seen in brain atrophy, whereas subdural hygromas will displace the cortex and cortical veins.
Treatment
Most subdural hygromas that are asymptomatic do not require any treatment. Some might opt to perform a simple burr-holes to alleviate intracranial pressure (ICP). Occasionally a temporary drain is placed for 24-48 hours post op. In recurrent cases a craniotomy may be performed to attempt to locate the location of the CSF Leak. In certain cases a shunt can be placed for additional drainage. Great caution is used when choosing to look for the CSF leak due to them generally being difficult to spot.
References
Taveras, Juan M. et al., eds. Radiology: Diagnosis, Imaging, Intervention. 1994- ISBN 0-397-57115-1; ch. 37: 9-13.
Brain Inj 1998 Jul;12(7):595-603.
McCluney KW, Yeakley JW, Fenstermacher MJ, et al. «Subdural hygroma versus atrophy on MR brain scans: "the cortical vein sign"». AJNR Am J Neuroradiol 1992;13: 1335–39.
External links
https://thejns.org/focus/view/journals/neurosurg-focus/26/6/article-pE8.xml |
Pseudolymphoma | Pseudolymphoma is a benign lymphocytic infiltrate that resembles cutaneous lymphoma histologically, clinically, or both.
Lymphoma cutis is the most important type of pseudolymphoma.
Presentation
It manifests with diarrhoea, hepatosplenomegaly, moderate lymph node enlargement without histopathological changes and evidence of the reticulo-endothelial system involvement.
Cause
It is an adverse effect of phenytoin.
Diagnosis
References
== External links == |
Early pregnancy bleeding | Early pregnancy bleeding (also called first trimester bleeding) refers to vaginal bleeding before 14 weeks of gestational age. If the bleeding is significant, hemorrhagic shock may occur. Concern for shock is increased in those who have loss of consciousness, chest pain, shortness of breath, or shoulder pain.Common causes of early pregnancy bleeding include ectopic pregnancy, threatened miscarriage, and pregnancy loss. Most miscarriages occur before 12 weeks gestation age. Other causes include implantation bleeding, gestational trophoblastic disease, polyps, and cervical cancer. Tests to determine the underlying cause usually include a speculum examination, ultrasound, and hCG.Treatment depends on the underlying cause. If tissue is seen at the cervical opening it should be removed. For those in whom the pregnancy is intrauterine and who have fetal heart sounds, watchful waiting is generally appropriate. Anti-D immune globulin is usually recommended in those who are Rh-negative. Occasionally, surgery is required.About 30% of pregnant people have bleeding in the first trimester (0 to 14 weeks gestational age). Bleeding in the second trimester (12 to 24 weeks gestational age) is less common. About 15% of those who realize they are pregnant have a miscarriage. Ectopic pregnancy occurs in under 2% of pregnancies.
Differential diagnosis
The differential diagnosis depends on whether the bleeding occurs in the first trimester or in the second or third trimesters.
Obstetric causes of first trimester bleeding include the following:
Early pregnancy loss is a term often used interchangeably with spontaneous abortion and miscarriage and refers to pregnancy loss during the first trimester. It is the most common cause of early pregnancy bleeding and is associated only with heavy (versus light) bleeding. However, patients typically remain hemodynamically stable.
Threatened early pregnancy loss, often considered a type of early pregnancy loss, refers vaginal bleeding in the presence of an intrauterine pregnancy and a closed cervix. The presence of fetal heart rate largely determines whether the pregnancy will progress to a viable outcome.
Ectopic pregnancy refers to a pregnancy outside the uterus, commonly in the fallopian tube. It is a less common but more serious cause of early pregnancy bleeding. Ectopic pregnancies can rupture, leading to internal bleeding that can be fatal if untreated.
Implantation bleeding involves a small amount of bleeding that may occur 10 to 14 days after implantation of the fertilized egg. However, there is little evidence to support the existence of such bleeding.
Chorionic hematoma is the pooling of blood (hematoma) between the chorion, a membrane surrounding the embryo, and the uterine wall. It occurs in about 3.1% of all pregnancies and is the most common cause of first trimester bleeding.
Gestational trophoblastic neoplasia, which refers to pregnancy-related tumors that be either cancerous or non-cancerous. This cause is extremely rare with non-cancerous gestational trophoblastic neoplasia found in 23 to 1,299 cases per 100,000 pregnancies and cancerous forms with a 10-fold lower incidence.Obstetric causes of second/third trimester bleeding include the following:
Bloody show refers to the passage of a small amount of blood or blood-tinged mucus resulting from labor or cervical weakness.
Pregnancy loss refers to death of the fetus at any time during pregnancy. Pregnancy loss most commonly occurs during the first trimester, when it is referred to as early pregnancy loss.
Placenta praevia or vasa praevia refers to the placenta or fetal blood vessels, respectively, covering or being located close to the opening of the uterus. More than half of patients affected by placenta praevia (51.6)% have bleeding before delivery. Vasa praevia occurs in about 0.6 per 1000 pregnancies.
Placental abruption involves the separation of the placental lining from the uterus of the mother. It occurs most commonly around 25 weeks of pregnancy.
Uterine rupture is when the muscular wall of the uterus tears during childbirth or, less commonly, during pregnancy.
Nontubal ectopic pregnancy refers to an ectopic pregnancy that occurs in the ovary, cervix, or intra-abdominal cavity.Other causes of early pregnancy bleeding include the following:
Postcoital bleeding, which is vaginal bleeding after sexual intercourse that can be normal with pregnancy.
Iatrogenic causes, or bleeding due to medical treatment or intervention, such as sex steroids, anticoagulants, or intrauterine contraceptive devices.
Vaginal or cervical bleeding, which may arise from many causes including fibroids, polyps, warts, tumors, vaginitis, or trauma. Importantly, these causes may co-occur with other causes of early pregnancy bleeding.
Lower genitourinary tract bleeding, which may result from a urinary tract infection (UTI), strenuous exercise, or bladder cancer.
Pathophysiology
Early pregnancy bleeding is usually from a parental source rather than a fetal one. The parental source may be a disruption in the vessels of the decidua or a lesion in the cervix or vagina. In the earlier stages of pregnancy, the cervix can be vulnerable to bleeding as new blood vessels are being grown. Vasa praevia is a rare condition that can result in bleeding from the fetoplacental circulation. Vasa praevia happens most often when the umbilical cord grows in a way that it directly enters the membrane, and therefore blood vessels that are unprotected by the umbilical cord or placental tissue can rupture and lead to bleeding. Another common source of bleeding can be due to abnormal development of the embryo. The most common early fetal abnormality is abnormal number of chromosomes causing loss of the pregnancy and bleeding.
Diagnostic approach
The initial assessment of vaginal bleeding in early pregnancy must first consider hemodynamic stability and the degree of pain or bleeding. A hemodynamically unstable patient would necessitate an immediate transfer to the emergency department . It is important to recognize that patients may suffer significant blood loss before any signs of hemodynamic instability are evident.The initial evaluation of early pregnancy bleeding involves a history and physical examination. The relevant history includes determining the gestational age of fetus and characterizing the bleeding. Bleeding that is at least as heavy as menstrual bleeding or associated with clots, tissue, lightheadedness, or pelvic discomfort is associated with increased risks of ectopic pregnancy and spontaneous abortion. Discomfort in the middle of the abdomen is more closely associated with spontaneous abortion; discomfort on a side of the abdomen is more closely associated with ectopic pregnancy. Risk factors for ectopic pregnancy or spontaneous abortion should also be considered.The physical examination includes assessing vital signs and performing an abdominal and pelvic examination. Signs of hemodynamic instability or peritonitis require emergent intervention. A pelvic examination may reveal non-obstetric causes of bleeding such as bleeding from the vagina or cervix. It may also show visible products of conception suggestive of an incomplete abortion.If the person is stable and a pelvic exam is unrevealing, transvaginal ultrasonography and/or serial measurement of hCG is generally recommended to assess fetal location and viability. Reviewed data from observational studies determined that ultrasound examination and hCG concentration could replace pelvic examination in the initial evaluation of early pregnancy bleeding. Transvaginal ultrasound is frequently used in the evaluation of bleeding in early pregnancy.Before 10 weeks gestation, a slower than normal increase in hCG suggests early pregnancy loss or ectopic pregnancy. By approximately 10 weeks, hCG plateaus and ultrasound is preferred to determine the location of the pregnancy (i.e., intrauterine or ectopic). In the presence of prior pelvic imaging, fetal heart tracing with Doppler sonography is sufficient to assess fetal viability beginning at 10–12 weeks of gestation. Bleeding associated with an intrauterine, viable pregnancy suggests threatened early pregnancy loss. Bleeding associated with an intrauterine, nonviable pregnancy suggests early pregnancy loss. If the viability of an intrauterine pregnancy is uncertain, repeat ultrasonography coupled with laboratory measurement of progesterone and/or serial hCG can be helpful. The absence of either intrauterine or ectopic pregnancy on imaging is suggestive of a complete early pregnancy loss (if the pregnancy was previously seen on imaging) or a pregnancy of unknown location (if the pregnancy was not previously seen on imaging).
Management
The management of early pregnancy bleeding depends on its severity and cause.Patients with significant first-trimester bleeding (more than spotting) should have a red blood cell antibody screen. Patients who are Rh-negative are usually given anti-D immune globulin to prevent RhD isoimmunization. People with significant blood loss who become hemodynamically unstable require rapid intervention.
Early pregnancy loss can be treated with watchful waiting, medication, or uterine aspiration based on shared decision-making between the patient and provider. For those with incomplete abortion, watchful waiting is the recommended method as more than 90% of these patients will complete the process spontaneously within four week. Patients who decide on expectant management may experience more days of bleeding and longer completion time as compared to surgical management. Serious complications of watchful waiting are rare. Effective medical management entails 200 mg of oral mifepristone (Mifeprex) followed 24 hours later by 800 mcg of vaginally administered misoprostol. Bed rest and progesterone therapy have not been shown to increase the likelihood of a viable outcome.Ectopic pregnancy is treated with methotrexate therapy or surgery. Typically, an intramuscular injection of 50 mg per m^2 of methotrexate is given followed by close monitoring of b-hCG levels 4 and 7 days after injection. B-hCG levels should decrease by at least 15% between those two timepoints. Surgery is required for patients who have failed or have contraindications to methotrexate therapy, are experiencing significant blood loss, or have signs of ectopic rupture.
Epidemiology
First trimester bleeding is more common than second or third trimester bleeding. First trimester bleeding may be associated with complications in later pregnancy, including placental abruption, smaller estimated fetal weight, stillbirth, and perinatal death.
== References == |
Hemimegalencephaly | Hemimegalencephaly (HME), or unilateral megalencephaly, is a rare congenital disorder affecting all or a part of a cerebral hemisphere. It causes severe seizures, which are often frequent and hard to control. A minority might have seizure control with medicines, but most will need removal or disconnection of the affected hemisphere as the best chance. Uncontrolled, they often cause progressive intellectual disability and brain damage and stop development.
Symptoms and signs
Seizures are the main symptom. There can be as many as hundreds of seizures a day. Seizures tend to begin soon after birth, but may sometimes commence during later infancy or, rarely, during early childhood.
Other symptoms
Asymmetrical or enlarged head
Developmental delay
Progressive weakness of half the body
Progressive blindness of half the body
Genetics
Somatic activation of AKT3 causes hemispheric developmental brain malformations.
Pathophysiology
It is a disorder related to excessive neuronal proliferation and hamartomatous overgrowth affecting the cortical formation. The excessive proliferation is postulated to occur early and to possibly continue beyond the normal proliferative period. Epidermal growth factor is thought to play an important role in the excessive proliferation and the pathogenesis of HME.
Diagnosis
It should be suspected in infants or children with intractable, frequent seizures. On a CT scan, the affected part is distorted and enlarged. It can be diagnosed prenatally, but a lot of cases go undiagnosed until seizures begin. Ultrasound can display asymmetrical brain hemispheres.
Treatment
Although there have been a few reports of medical treatment, the main treatment is radical: remove or disconnect the affected side. However, it has a high mortality, and there have been reports of a vegetative state and seizures resuming, this time in the healthy hemisphere.Surgery should be done as early as possible to minimize damage caused by seizures. However, a trial with drugs can be attempted for a few months before surgery, and there is a slim chance of it succeeding. The earlier surgery be done, the more the remaining side will do the missing sides job.Benzodiazepines might control the seizures.
References
== External links == |
Polysyndactyly | Polysyndactyly is a hereditary anatomical malformation combining polydactyly and syndactyly. There is also a type called crossed polysyndactyly.
Signs and symptoms
The way polysyndactyly presents itself varies; when the webbing is mild, it gives the appearance of the extra digit being partially connected to the (otherwise normal) digit next to it, when the webbing is extreme, the extra digit and the digit next to it will have the appearance of one rather enlarged digit (macrodactyly) and will have two or more finger/toe nails growing in the same digit (polyonychia). How the nails look will also vary, from separate supernumerary finger/toe nails to one very wide finger/toe nail.
References
External links
Polysyndactyly and Marfans syndrome The case of an Egyptian Jewish family with 17 affected members. The mother also had Marfans syndrome, which she passed on to a daughter who did not have polysyndactyly. |
Peripheral artery disease | Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain. When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular disease. Peripheral artery disease most commonly affects the legs, but other arteries may also be involved – such as those of the arms, neck, or kidneys. The classic symptom is leg pain when walking which resolves with rest, known as intermittent claudication. Other symptoms include skin ulcers, bluish skin, cold skin, or abnormal nail and hair growth in the affected leg. Complications may include an infection or tissue death which may require amputation; coronary artery disease, or stroke. Up to 50% of people with PAD do not have symptoms.The greatest risk factor for PAD is cigarette smoking. Other risk factors include diabetes, high blood pressure, kidney problems, and high blood cholesterol. The most common underlying mechanism of peripheral artery disease is atherosclerosis, especially in individuals over 40 years old. Other mechanisms include artery spasm, blood clots, trauma, fibromuscular dysplasia, and vasculitis. PAD is typically diagnosed by finding an ankle-brachial index (ABI) less than 0.90, which is the systolic blood pressure at the ankle divided by the systolic blood pressure of the arm. Duplex ultrasonography and angiography may also be used. Angiography is more accurate and allows for treatment at the same time; however, it is associated with greater risks.It is unclear if screening for peripheral artery disease in people without symptoms is useful as it has not been properly studied. In those with intermittent claudication from PAD, stopping smoking and supervised exercise therapy improve outcomes. Medications, including statins, ACE inhibitors, and cilostazol may also help. Aspirin does not appear to help those with mild disease but is usually recommended in those with more significant disease due to the increased risk of heart attacks. Anticoagulants such as warfarin are not typically of benefit. Procedures used to treat the disease include bypass grafting, angioplasty, and atherectomy.In 2015, about 155 million people had PAD worldwide. It becomes more common with age. In the developed world, it affects about 5.3% of 45- to 50-year-olds and 18.6% of 85- to 90-year-olds. In the developing world, it affects 4.6% of people between the ages of 45 and 50 and 15% of people between the ages of 85 and 90. PAD in the developed world is equally common among men and women, though in the developing world, women are more commonly affected. In 2015 PAD resulted in about 52,500 deaths, which is an increase from the 16,000 deaths in 1990.
Signs and symptoms
The signs and symptoms of peripheral artery disease are based on the part of the body that is affected. About 66% of patients affected by PAD either do not have symptoms or have atypical symptoms. The most common presenting symptom is intermittent claudication, which causes pain and severe cramping when walking or exercising. The pain is usually located in the calf muscles of the affected leg and relieved by rest. This occurs because during exercise the muscles of the leg need more oxygen. Normally, the arteries would be able to increase the amount of blood flow and therefore increase the amount of oxygen going to the exercised leg. However, in PAD, the artery is unable to respond appropriately to the increased demand for oxygen by the muscles, as a result, the leg muscles are overly saturated with lactic acid, resulting in pain of the muscle that only goes away with rest.Other symptoms may include
Pain, aches, and/or cramps in the buttocks, hip, or thigh
Muscle atrophy (muscle loss) of the affected limb
Hair loss of the affected limb
Skin that is smooth, shiny, or cool to the touch in the affected area
Decreased or absent pulse in feet
Cold and/or numbness in the toes
Sores/ulcers on the affected limb that do not healIn individuals with severe PAD, complications may arise, including critical limb ischemia and gangrene. Critical limb ischemia occurs when the obstruction to blood flow in the artery is compromised to the point where the blood is unable to maintain oxygenation of tissue at rest. This can lead to pain at rest, feeling of cold, or numbness in the affected foot and toes. Other complications of severe PAD include lower limb tissue loss, arterial insufficiency ulcers, erectile dysfunction, and gangrene. People with diabetes are affected by gangrene of the feet at a rate that is 30 times higher than the unaffected population. Many of these severe complications are irreversible.
Causes
Risk factor
Factors contributing to increased risk of PAD are the same as those for atherosclerosis. These include age, sex, and ethnicity. PAD is two times as common in males as females. In terms of ethnicity, PAD is more common in people of color compared to the white population in a 2:1 ratio. The factors with the greatest risk association are hyperlipidemia, hypertension, diabetes mellitus, chronic kidney disease, and smoking. Presenting three of these factors or more increases the risk of developing PAD ten-fold.
Smoking – tobacco use in any form is the single greatest risk factor of peripheral artery disease internationally. Smokers have up to a 10-fold increase in risk of PAD in a dose-response relationship. Exposure to second-hand smoke has also been shown to promote changes in the lining of blood vessels (endothelium), which can lead to atherosclerosis. Smokers are 2–3 times more likely to have lower extremity PAD than coronary artery disease. Greater than 80%-90% of patients with lower extremity peripheral arterial disease are current or former smokers. The risk of PAD increases with the number of cigarettes smoked per day and the number of years smoked.
High blood sugar – Diabetes mellitus is shown to increase risk of PAD by 2–4 fold. It does this by causing endothelial and smooth-muscle cell dysfunction in peripheral arteries. The risk of developing lower extremity peripheral arterial disease is proportional to the severity and duration of diabetes.
High blood cholesterol – Dyslipidemia, which is an abnormally high level of cholesterol or fat in the blood. Dyslipidemia is caused by a high level of a protein called low-density lipoprotein (LDL cholesterol), low levels of high-density lipoprotein (HDL cholesterol), elevation of total cholesterol, and/or high triglyceride levels. This abnormality in blood cholesterol levels have been correlated with accelerated peripheral artery disease. Management of Dyslipidemia by diet, exercise, and/or medication is associated with a major reduction in rates of heart attack and stroke.
High blood pressure – Hypertension or elevated blood pressure can increase a persons risk of developing PAD. Similarly to PAD, there is a known association between high blood pressure and heart attacks, strokes and abdominal aortic aneurysms. High blood pressure increases the risk of intermittent claudication, the most common symptom of PAD, by 2.5- to 4-fold in men and women, respectively.
Other risk factors which are being studied include levels of various inflammatory mediators such as C-reactive protein, fibrinogen, homocysteine, and lipoprotein A. Individuals with increased levels of homocysteine in their blood have a 2-fold risk of peripheral artery disease. While there are genetics leading to risk factors for peripheral artery disease, including diabetes and high blood pressure; there have been no specific genes or gene mutations directly associated with the development of peripheral artery disease.
High risk populations
Peripheral arterial disease is more common in these populations:
All people who have leg symptoms with exertion (suggestive of claudication) or ischemic rest pain
All people aged 65 years and over regardless of risk factor status
All people between 50 and 69 and who have a cardiovascular risk factor (particularly diabetes or smoking)
Age less than 50 years, with diabetes and one other atherosclerosis risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia)
Individuals with an abnormal lower extremity pulse examination
Those with known atherosclerotic coronary, carotid, or renal artery disease
All people with a Framingham risk score of 10%–20%
All people who have previously experienced chest pain
Mechanism
As previously mentioned, the most common cause of peripheral artery disease, especially in patients over 40 years old, is atherosclerosis. Atherosclerosis is a narrowing of the arteries caused by lipid or fat build up and calcium deposition in the wall of the affected arteries. The most commonly affected site occurs at arterial branch points, because there is an increase in turbulence and stress on the artery at these areas where the artery branches to supply distant structures. Disease of distant structures, including feet and toes, are usually caused by diabetes and seen in the elderly population.Additional mechanisms of peripheral artery disease including arterial spasm, thrombosis, and fibromuscular dysplasia. The mechanism of arterial spasm is still being studied, but it can occur secondary to trauma. The symptoms of claudication ensue when the artery spasms, or clamps down on itself, creating an obstruction. Similar to atherosclerosis, this leads to decreased blood flow to the tissue downstream of the obstruction. Thrombosis, or the formation of a blood clot, occurs usually due stasis or trauma. Damage to the lining of the blood vessel begins the process of clot formation. The blood clot ultimately creates a narrowing in the artery preventing adequate blood flow and oxygen to the tissue further down.
Diagnosis
Diagnosing or identifying peripheral artery disease requires history of symptoms and a physical exam followed by confirmatory testing. These tests could include CT scans (Computed Tomagraphic Angiography), MRA scans (Magnetic Resonance Angiography), or ultrasounds for imaging.In the setting of symptoms consistent with peripheral artery disease a physician will then examine an individual for specific exam findings. Abnormal physical exam findings can lead a health care provider to consider a specific diagnosis. However, in order to confirm a diagnosis, confirmatory testing is required.These findings are associated with peripheral artery disease:
Decreased or absent pulses
Muscle atrophy or wasting
Noticeable blueness of the affected limb
Decreased temperature (coolness) in affected limb when compared to the other
Thickened nails
Smooth or shiny skin and hair loss
Buergers test can check for pallor when the affected limb is in an elevated position. The limb is then moved from elevated to sitting position and is checked for redness, which is called reactive hyperemia. Buergers test is an assessment of arterial sufficiency, which is the ability of the artery to supply oxygenated blood to the tissue that it goes to.
Nonhealing lower extremity woundIf peripheral artery disease is suspected, the initial study is the ankle–brachial index (ABI). The ABI is a simple, non-invasive test, which measures the ratio of systolic blood pressure in the ankle to the systolic blood pressure in the upper arm. This is based on the idea that if blood pressure readings in the ankle are lower than those in the arm, a blockage in the arteries that provide blood from the heart to the ankle is suspected.An ABI range of 0.90 to 1.40 is considered normal. A person is considered to have PAD when the ABI is ≤ 0.90. However, PAD can be further graded as mild to moderate if the ABI is between 0.41 and 0.90, and severe if an ABI is less than 0.40. These categories can provide insight into the disease course. Furthermore, ABI values of 0.91 to 0.99 are considered borderline and values >1.40 indicate noncompressible arteries. If an ABI >1.40 is calculated, this could indicate vessel wall stiffness caused by calcification, which can occur in people with uncontrolled diabetes. Abnormally high ABIs (>1.40) are usually considered false negatives and thus, such results merit further investigation and higher-level studies. Individuals with noncompressible arteries have an increased risk of cardiovascular mortality within a two-year period.In individuals with suspected PAD with normal ABIs can undergo exercise testing of ABI. A baseline ABI is obtained prior to exercise. The patient is then asked to exercise (usually patients are made to walk on a treadmill at a constant speed) until claudication pain occurs (for a maximum of 5 minutes), after which the ankle pressure is again measured. A decrease in ABI of 15%–20% would be diagnostic of PAD.If ABIs are abnormal, the next step is generally a lower limb Doppler ultrasound to look at the site of obstruction and extent of atherosclerosis. Other imaging can be performed by angiography, where a catheter is inserted into the common femoral artery and selectively guided to the artery in question. While injecting a radio-dense contrast agent, an X-ray is taken. Any blood flow-limiting blockage found in the X-ray can be identified and treated by procedures including atherectomy, angioplasty, or stenting. Contrast angiography is the most readily available and widely used imaging technique. Modern computerized tomography (CT) scanners provide direct imaging of the arterial system as an alternative to angiography.Magnetic resonance angiography (MRA) is a noninvasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images of blood vessels inside the body. The advantages of MRA include its safety and ability to provide high-resolution, three-dimensional imaging of the entire abdomen, pelvis and lower extremities in one sitting.
Classification
The two most commonly used methods to classify peripheral artery disease are the Fontaine and the Rutherford systems of classification. The Fontaine stages, were introduced by René Fontaine in 1954 to define severity of chronic limb ischemia:
Stage I: asymptomatic
Stage IIa: intermittent claudication after walking a distance of more than 200 meters
Stage IIb: intermittent claudication after walking a distance of less than 200 meters
Stage III: rest pain
Stage IV: ulcers or gangrene of the limbThe Rutherford classification was created by the Society for Vascular Surgery and International Society of Cardiovascular Surgery, introduced in 1986 and revised in 1997 (and known as the Rutherford classification after the lead author, Robert B. Rutherford). This classification system consists of four grades and seven categories (categories 0–6):
Grade 0, Category 0: asymptomatic
Grade I, Category 1: mild claudication
Grade I, Category 2: moderate claudication
Grade I, Category 3: severe claudication
Grade II, Category 4: rest pain
Grade III, Category 5: minor tissue loss; ischemic ulceration not exceeding ulcer of the digits of the foot
Grade IV, Category 6: major tissue loss; severe ischemic ulcers or frank gangreneModerate to severe PAD classified by Fontaines stages III to IV or Rutherfords categories 4 to 5, presents limb threat (risk of limb loss) in the form of critical limb ischemia.Recently, the Society for Vascular Surgery came out with a classification system based on "wound, ischemia and foot Infection" (WIfI). This classification system, published in 2013 was created to account for the demographic changes that have occurred over the past forty years including increased incidence of high blood sugar and evolving techniques and ability for revascularization. This system was created on the basis of ischemia and angiographic disease patterns not being the sole determinants of amputation risk. The WIfI classification system is broken up into two parts: wounds and ischemia. Wounds are graded 0 through 3 on the presence of ulceration and/or gangrene and ischemia.
Grade 0: no ulcer, no gangrene
Grade 1: small, shallow ulcer; no gangrene
Grade 2: deep ulcer with exposed tendon or bone, gangrene limited to toes
Grade 3: extensive, full-thickness ulcer; gangrene extending to forefoot or midfootIschemia is graded 0 through 3 based on ABI, ankle systolic pressure, and toe pressure.
Grade 0: ABI 0.8 or higher, ankle
Grade 1: arterial brachial index 0.6 to 0.79, ankle pressure 70 to 100 mm Hg, toe pressure 40 to 59 mm Hg
Grade 2: ABI 0.4–0.59, ankle pressure 50 to 70 mm Hg, toe pressure 30 to 39 mm HgThe TASC (and TASC II) classification suggested PAD treatment is based on the severity of disease seen on angiogram.
Screening
It is not clear if screening for disease in the general population is useful as it has not been properly studied. This includes screening with the ankle-brachial index.Testing for coronary artery disease or carotid artery disease is of unclear benefit. While PAD is a risk factor for abdominal aortic aneurysms (AAA), there is no data on screening individuals with asymptomatic PAD for abdominal aortic aneurysms. In people with symptomatic PAD screening by ultrasound for AAA is not unreasonable.
Treatment
Depending on the severity of the disease, these steps can be taken, according to these guidelines:
Lifestyle
Stopping smoking (cigarettes promote PAD and are a risk factor for cardiovascular disease)
Regular exercise for those with claudication helps open up alternative small vessels (collateral flow) and the limitation in walking often improves. Treadmill exercise (35 to 50 minutes, three or four times per week) has been reviewed as another treatment with a number of positive outcomes, including reduction in cardiovascular events and improved quality of life. Supervised exercise programs increase pain-free walking time and the maximum walking distance in people with PAD.
Medication
Management of diabetes
Management of hypertension
Management of high cholesterol, and antiplatelet drugs such as aspirin and clopidogrel. Statins reduce clot formation and cholesterol levels, respectively, can help with disease progression, and address the other cardiovascular risks that the affected person is likely to have.According to guidelines, taking aspirin or clopidogrel is recommended to reduce AMI ("heart attack"), stroke, and other causes of vascular death in people with symptomatic peripheral artery disease. It is recommended that aspirin and clopidogrel be taken alone and not in conjunction with one another (i.e., not as dual antiplatelet therapy). The recommended daily dosage of aspirin for treating PAD is between 75 and 325 mg, while the recommended daily dosage for clopidogrel is 75 mg. The effectiveness of both aspirin and clopidogrel to reduce risk of cardiovascular ischemic events in people with symptomatic PAD is not well established. Research also suggests that low-dose rivaroxaban plus aspirin is effective as a new anti-thrombotic regimen for PAD.Cilostazol can improve symptoms in some. Pentoxifylline is of unclear benefit. Cilostazol may improve walking distance for people who experience claudication due to peripheral artery disease, but no strong evidence suggests that it improves the quality of life, decreases mortality, or decreases the risk of cardiovascular events.Treatment with other drugs or vitamins are unsupported by clinical evidence, "but trials evaluating the effect of folate and vitamin B12 on hyperhomocysteinemia, a putative vascular risk factor, are near completion".
Revascularization
After a trial of the best medical treatment outline above, if symptoms persist, patients may be referred to a vascular or endovascular surgeon. The benefit of revascularization is thought to correspond to the severity of ischemia and the presence of other risk factors for limb loss such as wound and infection severity.
Angioplasty (or percutaneous transluminal angioplasty) can be done on solitary lesions in large arteries, such as the femoral artery, but may not have sustained benefits. Patency rates following angioplasty are highest for iliac arteries, and decrease with arteries towards the toes. Other criteria that affect outcome following revascularization are length of lesion and number of lesions. There does not appear to be long term advantages or sustained benefit to placing a stent following angioplasty in order to hold the narrowing of the subsartorial artery open.
Atherectomy, in which the plaque is scraped off of the inside of the vessel wall (albeit with no better results than angioplasty).
Vascular bypass grafting can be performed to circumvent a diseased area of the arterial vasculature. The great saphenous vein is used as a conduit if available, although artificial (Gore-Tex or PTFE) material is often used for long grafts when adequate venous conduit is unavailable.
When gangrene has set in, amputation may be required to prevent infected tissues from causing sepsis, a life-threatening illness.
Thrombolysis and thrombectomy are used in cases of arterial thrombosis or embolism.
Guidelines
A guideline from the American College of Cardiology and American Heart Association for the diagnosis and treatment of lower extremity, renal, mesenteric, and abdominal aortic PAD was compiled in 2013, combining the 2005 and 2011 guidelines. For chronic limb threatening ischemia the ACCF/AHA guidelines recommend balloon angioplasty only for people with a life expectancy of 2 years or less or those who do not have an autogenous vein available. For those with a life expectancy greater than 2 years, or who have an autogenous vein, bypass surgery is recommended.
Prognosis
Individuals with PAD have an "exceptionally elevated risk for cardiovascular events and the majority will eventually die of a cardiac or cerebrovascular etiology"; prognosis is correlated with the severity of the PAD as measured by an ABI. Large-vessel PAD increases mortality from cardiovascular disease significantly. PAD carries a greater than "20% risk of a coronary event in 10 years".The risk is low that an individual with claudication will develop severe ischemia and require amputation, but the risk of death from coronary events is three to four times higher than matched controls without claudication. Of patients with intermittent claudication, only "7% will undergo lower-extremity bypass surgery, 4% major amputations, and 16% worsening claudication", but stroke and heart attack events are elevated, and the "5-year mortality rate is estimated to be 30% (versus 10% in controls)".
Epidemiology
The prevalence of PAD in the general population is 3–7%, affecting up to 20% of those over 70; 70%–80% of affected individuals are asymptomatic; only a minority ever require revascularisation or amputation. Peripheral artery disease affects one in three diabetics over the age of 50. In the US, it affects 12–20 percent of Americans age 65 and older. Around 10 million Americans have PAD. Despite its prevalence and cardiovascular risk implications, only 25% of PAD patients are undergoing treatment.In people aged 40 years and older in the United States in 2000, rates of PAD was 4.3%. Rates were 14.5% people aged 70 years or over. Within age groups, rates were generally higher in women than men. Non-Hispanic blacks had a rates of 7.9% compared to 4.4% in Non-Hispanic whites and 3.0% (1.4%–4.6%) in Mexican Americans.The incidence of symptomatic PAD increases with age, from about 0.3% per year for men aged 40–55 years to about 1% per year for men aged over 75 years. The prevalence of PAD varies considerably depending on how PAD is defined, and the age of the population being studied. Diagnosis is critical, as people with PAD have a four- to five-fold higher risk of heart attack or stroke.The Diabetes Control and Complications Trial, and the U.K. Prospective Diabetes Study trials, in people with type 1 and type 2 diabetes, respectively, demonstrated that glycemic control is more strongly associated with microvascular disease than macrovascular disease. Pathologic changes occurring in small vessels may be more sensitive to chronically elevated glucose levels than is atherosclerosis occurring in larger arteries.
Research
Research is being done on therapies to prevent progression of PAD. In those who have developed critically poor blood flow to the legs, the benefit of autotransplantation of autologous mononuclear cells is unclear.Only one randomized controlled trial has been conducted comparing vascular bypass to angioplasty for the treatment of severe PAD. The trial found no difference in amputation-free survival between vascular bypass and angioplasty at the planned clinical endpoint, but the trial has been criticized as being underpowered, limiting endovascular options, and comparing inappropriate endpoints. As of 2017, two randomized clinical trials are being conducted to better understand the optimal revascularization technique for severe PAD and critical limb ischemia (CLI), the BEST-CLI (Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia) Trial, and the BASIL-2 (Bypass Versus Angioplasty in Severe Ischaemia of the Leg – 2 )Trial.In 2011, pCMV-vegf165 was registered in Russia as the first-in-class gene therapy drug for treatment of PAD, including the advanced stage of critical limb ischemia.
References
External links
"Peripheral Arterial Disease" at the National Heart, Lung and Blood Institute
Peripheral Arterial Disease (P.A.D.) at the American College of Foot and Ankle Surgeons
Gerhard-Herman, Marie D.; Gornik, Heather L.; Barrett, Coletta; Barshes, Neal R.; Corriere, Matthew A.; et al. (November 13, 2016). "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary". Circulation. 135 (12): e686–e725. doi:10.1161/CIR.0000000000000470. PMC 5479414. PMID 27840332. |
Bloom syndrome | Bloom syndrome (often abbreviated as BS in literature) is a rare autosomal recessive genetic disorder characterized by short stature, predisposition to the development of cancer, and genomic instability. BS is caused by mutations in the BLM gene which is a member of the RecQ DNA helicase family. Mutations in other members of this family, namely WRN and RECQL4, are associated with the clinical entities Werner syndrome and Rothmund–Thomson syndrome, respectively. More broadly, Bloom syndrome is a member of a class of clinical entities that are characterized by chromosomal instability, genomic instability, or both and by cancer predisposition.
Cells from a person with Bloom syndrome exhibit a striking genomic instability that includes excessive crossovers between homologous chromosomes and sister chromatid exchanges (SCEs). The condition was discovered and first described by New York dermatologist Dr. David Bloom in 1954.Bloom syndrome has also appeared in the older literature as Bloom–Torre–Machacek syndrome.
Presentation
The most prominent feature of Bloom syndrome is proportional small size. The small size is apparent in utero. At birth, neonates exhibit rostral to caudal lengths, head circumferences, and birth weights that are typically below the third percentile.The second most commonly noted feature is a rash on the face that develops early in life as a result of sun exposure. The facial rash appears most prominently on the cheeks, nose, and around the lips. It is described as erythematous, that is red and inflamed, and telangiectatic, that is characterized by dilated blood vessels at the skins surface. The rash commonly also affects the backs of the hands and neck, and it can develop on any other sun-exposed areas of the skin. The rash is variably expressed, being present in a majority but not all persons with Bloom syndrome, and it is on average less severe in females than in males. Moreover, the sun sensitivity can resolve in adulthood. There are other dermatologic changes, including hypo-pigmented and hyper-pigmented areas, cafe-au-lait spots, and telangiectasias, which can appear on the face and on the ocular surface.There is a characteristic facial appearance that includes a long, narrow face; prominent nose, cheeks, and ears; and micrognathism or undersized jaw. The voice is high-pitched and squeaky.
There are a variety of other features that are commonly associated with Bloom syndrome. There is a moderate immune deficiency, characterized by deficiency in certain immunoglobulin classes and a generalized proliferative defect of B and T cells. The immune deficiency is thought to be the cause of recurrent pneumonia and middle ear infections in persons with the syndrome. Infants can exhibit frequent gastrointestinal upsets, with reflux, vomiting, and diarrhea, and there is a remarkable lack in interest in food. There are endocrine disturbances, particularly abnormalities of carbohydrate metabolism, insulin resistance and susceptibility to type 2 diabetes, dyslipidemia, and compensated hypothyroidism. Persons with Bloom syndrome exhibit a paucity of subcutaneous fat. There is reduced fertility, characterized by a failure in males to produce sperm (azoospermia) and premature cessation of menses (premature menopause) in females. Despite these reductions, several women with Bloom syndrome have had children, and there is a single report of a male with Bloom syndrome bearing children.Although some persons with Bloom syndrome can struggle in school with subjects that require abstract thought, there is no evidence that intellectual disability is more common in Bloom syndrome than in other people.The most serious and frequent complication of Bloom syndrome is cancer. In the 281 persons followed by the Bloom Syndrome Registry, 145 persons (51.6%) have been diagnosed with a malignant neoplasm, and there have been 227 malignancies. The types of cancer and the anatomic sites at which they develop resemble the cancers that affect persons in the general population. The age of diagnosis for these cancers is earlier than for the same cancer in normal persons. And many persons with Bloom syndrome have been diagnosed with multiple cancers. The average life span is approximately 27 years. The most common cause of death in Bloom syndrome is from cancer. Other complications of the disorder include chronic obstructive lung disease and type 2 diabetes.There are a variety of excellent sources for more detailed clinical information about Bloom syndrome.There is a closely related entity that is now referred to as Bloom-syndrome-like disorder (BSLD) which is caused by mutations in components of the same protein complex to which the BLM gene product belongs, including TOP3A, which encodes the type I topoisomerase, topoisomerase 3 alpha, RMI1, and RMI2. The features of BSLD include small size and dermatologic findings, such as cafe-au-lait spots, and the presence of the once pathognomonic elevated SCEs is reported for persons with mutations in TOP3A and RMI1.Bloom syndrome shares some features with Fanconi anemia possibly because there is overlap in the function of the proteins mutated in this related disorder.
Genetics
Bloom syndrome is an autosomal recessive disorder, caused by mutations in the maternally- and paternally-derived copies of the gene BLM. As in other autosomal recessive conditions, the parents of an individual with Bloom syndrome do not necessarily exhibit any features of the syndrome. The mutations in BLM associated with Bloom syndrome are nulls and missense mutations that are catalytically inactive. The cells from persons with Bloom syndrome exhibit a striking genomic instability that is characterized by hyper-recombination and hyper-mutation. Human BLM cells are sensitive to DNA damaging agents such as UV and methyl methanesulfonate, indicating deficient repair capability. At the level of the chromosomes, the rate of sister chromatid exchange in Blooms syndrome is approximately 10 fold higher than normal and quadriradial figures, which are the cytologic manifestations of crossing-over between homologous chromosome, are highly elevated. Other chromosome manifestations include chromatid breaks and gaps, telomere associations, and fragmented chromosomes. The hyper-recombination can also be detected by molecular assays The BLM gene is a member of the protein family referred to as RecQ helicases. The diffusion of BLM has been measured to 1.34
μ
m
2
s
{\displaystyle {\tfrac {\mathrm {\mu m} ^{2}}{\mathrm {s} }}}
in nucleoplasm and 0.13
μ
m
2
s
{\displaystyle \textstyle {\tfrac {\mathrm {\mu m} ^{2}}{\mathrm {s} }}}
at nucleoli DNA helicases are enzymes that attach to DNA and temporarily unravel the double helix of the DNA molecule. DNA helicases function in DNA replication and DNA repair. BLM very likely functions in DNA replication, as cells from persons with Bloom syndrome exhibit multiple defects in DNA replication, and they are sensitive to agents that obstruct DNA replication.The BLM helicase is a member of a protein complex with topoisomerase III alpha, RMI1 and RMI2, also known as BTRR, Bloom Syndrome complex or the dissolvasome. Disruption of the proper assembly of the Bloom Syndrome complex leads to genome stability, genetic dependence on cellular nucleases GEN1 and MUS81, and loss of normal cell growth. Bloom-like phenotypes have been associated with mutations in topoisomerase III alpha, RMI1 and RMI2 genes.
Relationship to cancer and aging
As noted above, there is greatly elevated rate of mutation in Bloom syndrome and the genomic instability is associated with a high risk of cancer in affected individuals. The cancer predisposition is characterized by 1) broad spectrum, including leukemias, lymphomas, and carcinomas, 2) early age of onset relative to the same cancer in the general population, and 3) multiplicity, that is, synchronous or metachronous cancers. There is at least one person with Bloom syndrome who had five independent primary cancers. Persons with Bloom syndrome may develop cancer at any age. The average age of cancer diagnoses in the cohort is approximately 26 years old.
Pathophysiology
When a cell prepares to divide to form two cells, the chromosomes are duplicated so that each new cell will get a complete set of chromosomes. The duplication process is called DNA replication. Errors made during DNA replication can lead to mutations. The BLM protein is important in maintaining the stability of the DNA during the replication process. Lack of BLM protein or protein activity leads to an increase in mutations; however, the molecular mechanism(s) by which BLM maintains stability of the chromosomes is still a very active area of research.Persons with Bloom syndrome have an enormous increase in exchange events between homologous chromosomes or sister chromatids (the two DNA molecules that are produced by the DNA replication process); and there are increases in chromosome breakage and rearrangements compared to persons who do not have Blooms syndrome. Direct connections between the molecular processes in which BLM operates and the chromosomes themselves are under investigation. The relationships between molecular defects in Bloom syndrome cells, the chromosome mutations that accumulate in somatic cells (the cells of the body), and the many clinical features seen in Bloom syndrome are also areas of intense research.
Diagnosis
Bloom syndrome is diagnosed using any of three tests - the presence of quadriradial (Qr, a four-armed chromatid interchange) in cultured blood lymphocytes, and/or the elevated levels of sister chromatid exchange in cells of any type, and/or the mutation in the BLM gene. The US Food and Drug Administration (FDA) announced on February 19, 2015, that they have authorized marketing of a direct-to-consumer genetic test from 23andMe. The test is designed to identify healthy individuals who carry a gene that could cause Bloom Syndrome in their offspring.
Treatment
Bloom syndrome has no specific treatment; however, avoiding sun exposure and using sunscreens can help prevent some of the cutaneous changes associated with photo-sensitivity. Efforts to minimize exposure to other known environmental mutagens are also advisable.
Epidemiology
Bloom syndrome is an extremely rare disorder in most populations and the frequency of the disease has not been measured in most populations. However, the disorder is relatively more common amongst people of Central and Eastern European Ashkenazi Jewish background. Approximately 1 in 48,000 Ashkenazi Jews are affected by Bloom syndrome, who account for about one-third of affected individuals worldwide.
Blooms Syndrome Registry
The Blooms Syndrome Registry lists 265 individuals reported to have this rare disorder (as of 2009), collected from the time it was first recognized in 1954. The registry was developed as a surveillance mechanism to observe the effects of cancer in the patients, which has shown 122 individuals have been diagnosed with cancer. It also acts as a report to show current findings and data on all aspects of the disorder.
See also
Accelerated aging disease
Bloom syndrome (gene)
DNA repair
Progeria
Tumor M2-PK
References
Flanagan M, Cunniff CM (February 14, 2019) [March 22, 2006]. Adam MP, Ardinger HH, Pagon RA, et al. (eds.). "Bloom syndrome". GeneReviews. Seattle (WA): University of Washington. PMID 20301572. Retrieved July 14, 2019.
Further reading
Adam, M. P.; Mirzaa, G. M.; Pagon, R. A.; Wallace, S. E.; Bean LJH; Gripp, K. W.; Amemiya, A. (1993). Margaret P Adam; Holly H Ardinger; Roberta A Pagon; Stephanie E Wallace; et al. (eds.). GeneReviews. Seattle (WA): University of Washington. ISSN 2372-0697. PMID 20301295.
External links
Bloom syndrome at NLM Genetics Home Reference |
Mirizzis syndrome | Mirizzis syndrome is a rare complication in which a gallstone becomes impacted in the cystic duct or neck of the gallbladder causing compression of the common hepatic duct, resulting in obstruction and jaundice. The obstructive jaundice can be caused by direct extrinsic compression by the stone or from fibrosis caused by chronic cholecystitis (inflammation). A cholecystocholedochal fistula can occur.
Presentation
Mirizzis syndrome has no consistent or unique clinical features that distinguish it from other more common forms of obstructive jaundice. Symptoms of recurrent cholangitis, jaundice, right upper quadrant pain, and elevated bilirubin and alkaline phosphatase may or may not be present. Acute presentations of the syndrome include symptoms consistent with cholecystitis.
Surgery is extremely difficult as Calots triangle is often obliterated and the risks of causing injury to the CBD are high.
Pathophysiology
Multiple and large gallstones can become impacted in the Hartmanns pouch of the gallbladder, leading to chronic inflammation—which leads to compression of the common bile duct (CBD), necrosis, fibrosis, and ultimately fistula formation into the adjacent common hepatic duct (CHD) or common bile duct (CBD). As a result, the CHD/CBD becomes obstructed by either scar or stone, resulting in obstructive jaundice. It can be divided into four types.
Type I – No fistula present
Type IA – Presence of the cystic duct
Type IB – Obliteration of the cystic ductTypes II–IV – Fistula present
Type II – Defect smaller than 33% of the CHD diameter
Type III – Defect 33–66% of the CHD diameter
Type IV – Defect larger than 66% of the CHD diameter
Diagnosis
Imaging by ultrasonography, MRCP, or CT scan usually make the diagnosis. MRCP can be used to define the lesion anatomically prior to surgery.
Occasionally Mirizzis syndrome is diagnosed or confirmed on ERCP when requested to alleviate obstructive jaundice or cholangitis by means of an endoscopically placed stent, or when USS has been wrongly reported as choledocolithiasis.
Treatment
Simple cholecystectomy is suitable for type I patients. For types II–IV, subtotal cholecystectomy can be performed to avoid damage to the main bile ducts. Cholecystectomy and bilioenteric anastomosis may be required. Roux-en-Y hepaticojejunostomy has shown good outcome in some studies.
Epidemiology
Mirizzis syndrome occurs in approximately 0.1% of patients with gallstones. It is found in 0.7 to 2.5 percent of cholecystectomies.It affects males and females equally, but tends to affect older people more often. There is no evidence of race having any bearing on the epidemiology.
Eponym
It is named for Pablo Luis Mirizzi (1893–1964), an Argentinian physician. Mirizzi was educated and trained in his hometown and later visited some of the best hospitals throughout the United States for further education and training. Mirizzi specialized in abdominal and thoracic surgery and would write prolifically on related surgical topics.
References
== External links == |
Keratosis pilaris atrophicans | Keratosis pilaris atropicans includes many forms of keratosis pilaris with cicatricial alopecia.: 762 Variants include keratosis pilaris atrophicans faciei, atrophoderma vermiculatum, keratosis follicularis spinulosa decalvans, and ichthyosis follicularis.: 762
See also
Cicatricial alopecia
List of cutaneous conditions
== References == |
Retinal correspondence | Retinal correspondence is the inherent relationship between paired retinal visual cells in the two eyes. Images from one object stimulate both cells, which transmit the information to the brain, permitting a single visual impression localized in the same direction in space.
Types
Normal retinal correspondence (NRC) is a binocular condition in which both foveas work together as corresponding retinal points, with resultant images fused in the occipital cortex of the brain.Abnormal retinal correspondence (ARC), also called Anomalous retinal correspondence is binocular sensory adaptation to compensate for a long-standing eye deviation (i.e. strabismus). The fovea of the straight (non-deviated) eye and non-foveal retinal point of the deviated eye work together, sometimes permitting single binocular vision.
See also
Bagolini Striated Glasses Test
Binocular vision
Haploscope
Stereopsis
Orthoptist
References
External links
Bhola, Rahul. Binocular Vision. University of Iowa Department of Ophthalmology & Visual Sciences: EyeRounds.org. January 23, 2006.
International Orthoptics Association
Orthoptics Association of Australia |
Gonadal dysgenesis | Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system
in the male or female. It is the atypical development of the gonads in an embryo,
with reproductive tissue replaced with functionless, fibrous tissue, termed streak gonads.
Streak gonads are a form of aplasia, resulting in hormonal failure that manifests as sexual infantism and infertility, with no initiation of puberty and secondary sex characteristics.Gonadal development is a genetically controlled process by the chromosomal sex (XX or XY) which directs the formation of the gonad (ovary or testis).Differentiation of the gonads requires a tightly regulated cascade of genetic, molecular and morphogenic events.
At the formation of the developed gonad, steroid production influences local and distant receptors for continued morphological and biochemical changes.
This results in the appropriate phenotype corresponding to the karyotype (46,XX for females and 46,XY for males).Gonadal dysgenesis arises from the failure of signalling in this tightly regulated process during early foetal development.Manifestations of gonadal dysgenesis are dependent on the aetiology and severity of the underlying defect.
Causes
Pure gonadal dysgenesis 46,XX also known as XX gonadal dysgenesis
Pure gonadal dysgenesis 46,XY also known as XY gonadal dysgenesis
Mixed gonadal dysgenesis also known as partial gonadal dysgenesis, and 45,X/46,XY mosaicism
Turner syndrome also known as 45,X or 45,X0
Endocrine disruptions
Pathogenesis
46,XX gonadal dysgenesis
46,XX gonadal dysgenesis is characteristic of female hypogonadism with a karyotype of 46,XX.
Streak ovaries are present with non-functional tissues unable to produce the required sex steroid oestrogen.
Low levels of oestrogen effect the HPG axis with no feedback to the anterior pituitary to inhibit the secretion of FSH and LH.
FSH and LH are secreted at abnormal elevated levels.
Improper levels of these hormones will cause a failure to initiate puberty, undergo menarche, and develop secondary sex characteristics.
If sufficient functional ovarian tissue is present, limited menstrual cycles can occur.The pathogenesis of 46,XX gonadal dysgenesis is unclear, as it can manifest from a variety of dysregulations.
Interruption during ovarian development in embryogenesis can cause 46,XX gonadal dysgenesis with cases of abnormalities in the FSH receptor
and mutations in steroidogenic acute regulatory protein (StAR protein) which regulates steroid hormone production.
46,XY gonadal dysgenesis
46,XY gonadal dysgenesis is characteristic of male hypogonadism with karyotype 46,XY.In embryogenesis, the development of the male gonads is controlled by the testis determining factor located on the sex-determining region of the Y chromosome (SRY).
The male gonad is dependent on SRY and the signalling pathways initiated to several other genes to facilitate testis development.The aetiology of 46,XY gonadal dysgenesis can be caused by mutations in the genes involved in testis development such as SRY, SOX9, WT1, SF1, and DHH.
If a single or combination of these genes are mutated or deleted, downstream signalling is disrupted, leading to malformation of male external genitalia.SRY acts on gene SOX9 which drives Sertoli cell formation and testis differentiation.
An absence in SRY causes SOX9 to not be expressed at the appropriate time or concentration, leading to a deficiency in testosterone and anti-Müllerian hormone production.
Inadequate levels of testosterone and anti-Müllerian hormone disrupts the development of Wolffian ducts and internal genitalia that are key to male reproductive tract development.
The lack of the male associated steroid hormones drives Müllerian duct development and promotes the development of female genitalia.Gonadal streaks replace the tissues of the testes, resembling ovarian stroma absent of follicles.
46,XY gonadal dysgenesis can remain unsuspected until delayed pubertal development is observed.Approximately 15% of cases of 46,XY gonadal dysgenesis carry de novo mutations in the SRY gene,
with an unknown causation for the remaining portion of 46,XY gonadal dysgenesis patients.
Mixed gonadal dysgenesis
Mixed gonadal dysgenesis, also known as X0/XY mosaicism or partial gonadal dysgenesis,
is a sex development disorder associated with sex chromosome aneuploidy and mosaicism of the Y chromosome.
Mixed gonadal dysgenesis is the presence of two or more germ line cells.The degree of development of the male reproductive tract is determined by the ratio of germ line cells expressing the XY genotype.Manifestations of mixed gonadal dysgenesis are highly variable with asymmetry in gonadal development of testis and streak gonad, accounted for by the percentage of cells expressing XY genotype.
The dysgenic testis can have adequate functional tissue to produce satisfactory levels of testosterone to cause masculinisation.Mixed gonadal dysgenesis is poorly understood at the molecular level.
The loss of the Y chromosome can occur from deletions, translocations, or migration failure of paired chromosomes during cell division.
The chromosomal loss results in partial expression of the SRY gene, giving rise to abnormal development of the reproductive tract and altered hormone levels.
Turner syndrome
Turner syndrome, also known as 45,X or 45,X0, is a chromosomal abnormality characterised by a partial or completely missing second X chromosome,
giving a chromosomal count of 45, instead of the typical count of 46 chromosomes.Dysregulation in meiosis signalling to germ cells during embryogenesis may result in nondisjunction and monosomy X from separation failure of chromosomes in either the parental gamete or during early embryonic divisions.The aetiology of Turner syndrome phenotype can be the result of haploinsufficiency, where a portion of critical genes are rendered inactive during embryogenesis.
Normal ovarian development requires these vital regions of the X chromosome that are inactivated.
Clinical manifestation include primary amenorrhea, hypergonadotropic hypogonadism, streak gonads, infertility, and failure to develop secondary sex characteristics.
Turner syndrome is not diagnosed until a delayed onset of puberty with Müllerian structures found to be in infantile stage.
Physical phenotypic characteristics include short stature, dysmorphic features and lymphedema at birth.Comorbidities include heart defects, vision and hearing problems, diabetes, and low thyroid hormone production.
Endocrine disruptions
Endocrine disruptors interfere with the endocrine system and hormones.
Hormones are critical for the correct events in embryogenesis to occur.Foetal development relies on the proper timing of the delivery of hormones for cellular differentiation and maturation.
Disruptions can cause sexual development disorders leading to gonadal dysgenesis.
Diagnosis
Management
History
Turner syndrome was first described independently by Otto Ulrich in 1930 and Henry Turner in 1938. 46,XX pure gonadal dysgenesis was first reported in 1960. 46,XY pure gonadal dysgenesis, also known as Swyer syndrome, was first described by Gim Swyer in 1955.
See also
(DoDI) 6130.03, 2018, section 5, 13f and 14m
Ovotestis
46 XX
References
== External links == |
Hot tub folliculitis | Hot tub folliculitis (pseudomonal folliculitis) is a common type of folliculitis, a condition which causes inflammation of hair follicles.: 272 This condition is caused by an infection of hair follicles by a non-pathogenic strain of the bacterium Pseudomonas aeruginosa. The bacterium is commonly found in hot tubs, water slides, and rarely in swimming pools. Children are more prone because they typically stay in the water longer than adults. Hot tub folliculitis appears on the skin in the form of a rash, roughly resembling chicken pox and then develops further to appear as a pimple. Hot tub folliculitis can be extremely painful and/or itchy, and left alone without scratching will go away much more quickly. If the rash is aggravated, it can stay, worsen, and spread, lasting for months. By that time, it is much more difficult to treat. In an immunocompetent person, the rash is self-limited and will usually resolve after about 7 to 10 days but the condition can leave a hyperpigmented lesion that goes away after a few months.Normally, the rash does not need specific treatment and will go away on its own. Antibiotics may be prescribed in some cases. If the rash continues to appear longer than the 7- to 10-day time period, a physician should be consulted. Folliculitis that is not treated properly could worsen and cause abscesses.
See also
Skin lesion
== References == |
Vocal cord hemorrhage | Vocal cord hemorrhage occurs when a blood vessel in the vocal cords ruptures, which results in leakage of blood into the superficial lamina propria and dysphonia (hoarseness). The rupture usually results from overly forceful or incorrect vocalization, and may be a one-time occurrence or occur repeatedly. According to News Medical.net, "professional singers are at an increased risk of vocal hemorrhage, particularly in cases where gruelling performance schedules are followed". The treatment is vocal rest as failure to rest the voice can result in permanent scarring.
== References == |
Erythema elevatum diutinum | Erythema elevatum diutinum is a form of vasculitis.: 835 It has been described as a paraneoplastic syndrome.
See also
Cutaneous small-vessel vasculitis
List of cutaneous conditions
References
== External links == |
Early onset dementia | Early onset dementia is dementia in which symptoms first appear before the age of 65. The term favored until about 2000 was presenile dementia; young onset dementia is also used.Early onset dementia may be caused by degenerative or vascular disease, or it may be due to other causes, such as alcohol-related dementia and other inflammatory or infectious processes. Early-onset Alzheimers disease, vascular dementia and frontotemporal lobar degeneration are the most common forms of early onset dementia, with Alzheimers accounting for between 30 and 40%. Early onset dementia may also occur, less frequently, in the Lewy body dementias (dementia with Lewy bodies and Parkinsons disease dementia), multiple sclerosis, Huntingtons disease and other conditions.
References
Further reading
Collins JD, Henley SM, Suárez-González A (July 2020). "A systematic review of the prevalence of depression, anxiety, and apathy in frontotemporal dementia, atypical and young-onset Alzheimers disease, and inherited dementia". Int Psychogeriatr (Review): 1–20. doi:10.1017/S1041610220001118. PMID 32684177. S2CID 220653830.
Ducharme S, Dols A, Laforce R, et al. (June 2020). "Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders". Brain (Review). 143 (6): 1632–1650. doi:10.1093/brain/awaa018. PMC 7849953. PMID 32129844.
Nwadiugwu M (September 2021). "Early-onset dementia: key issues using a relationship-centred care approach". Postgrad Med J (Review). 97 (1151): 598–604. doi:10.1136/postgradmedj-2020-138517. PMC 8408578. PMID 32883770.
Roman de Mettelinge T, Calders P, Cambier D (2021). "The Effects of Aerobic Exercise in Patients with Early-Onset Dementia: A Scoping Review". Dement Geriatr Cogn Disord (Review). 50 (1): 9–16. doi:10.1159/000516231. PMID 33957623. S2CID 233983643. |
Gingival enlargement | Gingival enlargement is an increase in the size of the gingiva (gums). It is a common feature of gingival disease. Gingival enlargement can be caused by a number of factors, including inflammatory conditions and the side effects of certain medications. The treatment is based on the cause. A closely related term is epulis, denoting a localized tumor (i.e. lump) on the gingiva.
Classification
The terms gingival hyperplasia and gingival hypertrophy have been used to describe this topic in the past. These are not precise descriptions of gingival enlargement because these terms are strictly histologic diagnoses, and such diagnoses require microscopic analysis of a tissue sample. Hyperplasia refers to an increased number of cells, and hypertrophy refers to an increase in the size of individual cells. As these identifications cannot be performed with a clinical examination and evaluation of the tissue, the term gingival enlargement is more properly applied. Gingival enlargement has been classified according to cause into 5 general groups:
Inflammatory enlargement
Drug induced enlargement
Enlargement associated with systemic diseases or conditions
Neoplastic enlargement
False enlargement.
Causes
Inflammatory enlargement
Gingival enlargement has a multitude of causes. The most common is chronic inflammatory gingival enlargement, when the gingivae are soft and discolored. This is caused by tissue edema and infective cellular infiltration caused by prolonged exposure to bacterial plaque, and is treated with conventional periodontal treatment, such as scaling and root planing.Gingivitis and gingival enlargement are often seen in mouth breathers, as a result of irritation brought on by surface dehydration, but the manner in which it is caused has not been demonstrated.The accumulation and retention of plaque is the chief cause of inflammatory gingival enlargement. Risk factors include poor oral hygiene, as well as physical irritation of the gingiva by improper restorative and orthodontic appliances.
Drug-induced enlargement
This type of gingival enlargement is sometimes termed "drug induced gingival enlargement" or "drug influenced gingival overgrowth", abbreviated to "DIGO". Gingival enlargement may also be associated with the administration of three different classes of drugs, all producing a similar response: Gingival overgrowth is a common side effect of phenytoin, termed "Phenytoin-induced gingival overgrowth" (PIGO).
anticonvulsants (such as phenytoin, phenobarbital, lamotrigine, vigabatrin, ethosuximide, topiramate and primidone NOT common for valproate)
calcium channel blockers (antihypertensives such as nifedipine, amlodipine, and verapamil). The dihydropyridine derivative isradipidine can replace nifedipine and does not induce gingival overgrowth.
cyclosporine, an immunosuppressant.Of all cases of DIGO, about 50% are attributed to phenytoin, 30% to cyclosporins and the remaining 10-20% to calcium channel blockers.
Drug-induced enlargement has been associated with a patients genetic predisposition, and its association with inflammation is debated. Some investigators assert that underlying inflammation is necessary for the development of drug-induced enlargement, while others purport that the existing enlargement induced by the drug effect compounds plaque retention, thus furthering the tissue response. Careful attention to oral hygiene may reduce the severity of gingival hyperplasia. In most cases, discontinuing the culprit drug resolves the hyperplasia.
Enlargement associated with systemic factors
Many systemic diseases can develop oral manifestations that may include gingival enlargement, some that are related to conditions and others that are related to disease:
Conditioned enlargement
pregnancy
puberty
vitamin C deficiency
nonspecific, such as a pyogenic granuloma
Systemic disease causing enlargement
leukemia
granulolomatous diseases, such as granulomatosis with polyangiitis, sarcoidosis, or orofacial granulomatosis.
neoplasm
benign neoplasms, such as fibromas, papillomas and giant cell granulomas
malignant neoplasms, such as a carcinoma or malignant melanoma
false gingival enlargements, such as when there is an underlying bony or dental tissue lesion
Mechanism
Drug Induced gingival overgrowth:
Fibrotic type:
Elevated CTGF (a.k.a. CCN2) which is a matricellular protein known to be reliable for fibrosis.TGF-β increases drives CTGF/CCN2 (current molecular mechanisms unknown), but supports TGF-β as a therapeutic target.
CTGF is not down regulated in presence of inflammatory mediators (such as PGE2), unlike other tissues fibroblasts (such as kidney) which have their CTGF levels down regulated by the same PGE2.
Inflammatory Type
Management
The first line management of gingival overgrowth is improved oral hygiene, ensuring that the irritative plaque is removed from around the necks of the teeth and gums. Situations in which the chronic inflammatory gingival enlargement include significant fibrotic components that do not respond to and undergo shrinkage when exposed to scaling and root planing are treated with surgical removal of the excess tissue, most often with a procedure known as gingivectomy.In DIGO, improved oral hygiene and plaque control is still important to help reduce any inflammatory component that may be contributing to the overgrowth. Reversing and preventing gingival enlargement caused by drugs is as easy as ceasing drug therapy or substituting to another drug. However, this is not always an option; in such a situation, alternative drug therapy may be employed, if possible, to avoid this deleterious side effect. In the case of immunosuppression, tacrolimus is an available alternative which results in much less severe gingival overgrowth than cyclosporin, but is similarly as nephrotoxic. The dihydropyridine derivative isradipidine can replace nifedipine for some uses of calcium channel blocking and does not induce gingival overgrowth.
Epidemiology
Gingival enlargement is common.
Other animals
It is commonly seen in Boxer dogs and other brachycephalic breeds, and in the English Springer Spaniel. It usually starts around middle age and progresses. Some areas of the gingiva can become quite large but have only a small attachment to the rest of the gingiva, and it may completely cover the teeth. Infection and inflammation of the gingiva is common with this condition. Under anesthesia, the enlarged areas of gingiva can be cut back with a scalpel blade or CO2 laser, but it often recurs. Gingival enlargement is also a potential sequela of gingivitis. As in humans, it may be seen as a side effect to the use of ciclosporin.Gingival enlargement is an autosomal recessive disease with predominance in males, and is correlated with selection for superior fur quality in European farmed foxes
References
== External links == |
Nasal glial heterotopia | Nasal glial heterotopia refers to congenital malformations of displaced normal, mature glial tissue, which are no longer in continuity with an intracranial component. This is distinctly different from an encephalocele, which is a herniation of brain tissue and/or leptomeninges, that develops through a defect in the skull, where there is a continuity with the cranial cavity.
Signs and symptoms
Patients come to clinical attention early in life (usually at birth or within the first few months), with a firm subcutaneous nodule at bridge of nose, or as a polypoid mass within the nasal cavity, or somewhere along the upper border of the nasal bow. If the patient presents with an intranasal mass, there may be obstruction, chronic rhinosinusitis, or nasal drainage. If there is a concurrent cerebrospinal fluid (CSF) leak, then an encephalocele is much more likely.This lesion is separated into two types based on the anatomic site of presentation:
Extranasal (60%): Subcutaneous bridge of nose
Intranasal (30%): Superior nasal cavity
Mixed (10%): Subcutaneous tissues and nasal cavity (larger lesions)
Pathology
The cut surface shows a smooth, homogeneous glistening to slippery cut surface, showing an appearance similar to brain. Sometimes, it is quite firm, especially when there is a large amount of associated fibrosis. The lesions are usually <2 cm in greatest dimension.
The overlying skin or squamous mucosa is intact and uninvolved by the process. There is normal glial tissue set within a fibrous connective tissue stroma. There is such blending, that the underlying process may be difficult to detect without special studies. In a few cases, large gemistocytes, neurons, choroid plexus, ependyma, and retinal pigmented cells may be seen.
Histochemistry
A trichrome stain will highlight the dual components well, with the glial tissue staining red, while the background fibrosis stains a bright blue.
Immunohistochemistry
The glial tissue is highlighted with S100 protein and with glial fibrillary acidic protein, although the latter is much more sensitive for glial tissue.
Diagnosis
Differential diagnoses
The most common missed lesion is within the nasal cavity, where a fibrosed nasal polyp may be considered. However, it does not have glial tissue. Further, a polyp usually has mucoserous glands. The lesion is frequently misinterpreted as scar in the subcutaneous tissues, but scar in a < 2-year-old child would be uncommon. Special stains are frequently required to highlight the diagnosis.
Imaging findings
Imaging studies are performed before surgery or biopsy to preclude an intracranial connection. Images usually show a sharply circumscribed but expansile mass. It may be difficult to exclude the intracranial connection if the defect is small whether employing computed tomography or magnetic resonance.
Classification
While nasal glial heterotopia (NGH) is the preferred term, synonyms have included nasal glioma. However, this term is to be discouraged, as it implies a neoplasm or tumor, which it is not. By definition, nasal glial heterotopia is a specific type of choristoma. It is not a teratoma, however, which is a neoplasm comprising all three germ cell layers (ectoderm, endoderm, mesoderm). As a congenital malformation or ectopia, it is distinctly different from the trauma or iatrogenic development of an encephalocele.
Management
Although surgery is the treatment of choice, it must be preceded by imaging studies to exclude an intracranial connection. Potential complications include meningitis and a cerebrospinal fluid leak. Recurrences or more correctly persistence may be seen in up to 30% of patients if not completely excised.
Epidemiology
Nasal glial heterotopia is rare, while an encephalocele is uncommon. NGH usually presents in infancy, while encephalocele may present in older children and adults. It is seen in both genders equally.
References
Further reading
Lester D. R. Thompson; Bruce M. Wenig (2011). Diagnostic Pathology: Head and Neck: Published by Amirsys. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 1:1–2. ISBN 978-1-931884-61-7. |
Webbed penis | Webbed penis also known as buried or concealed penis is an acquired or congenital condition in which the scrotal skin extends onto the ventral penile shaft. The penile shaft is buried in the scrotum or tethered to the scrotal midline by a fold or web of skin. The urethra and erectile bodies are usually normal. Webbed penis is usually asymptomatic, but the cosmetic appearance is often unacceptable. This condition may be corrected by surgical techniques.In the congenital form, the deformity represents an abnormality of the attachment between the penis and the scrotum; the penis, the urethra, and the remainder of the scrotum typically are normal.
Webbed penis may also be acquired (iatrogenic) after circumcision or other penile surgery, resulting from excessive removal of ventral penile skin; the penis can retract into the scrotum, resulting in secondary phimosis (trapped penis).
Signs and symptoms
Since the penis does not protrude when a man has this disorder, his ability to pass urine when he is standing or to participate in sexual intercourse will be impaired.
Visible signs may include but are not limited to:
Excessive skin and fat around the penis.
Tight, scarred preputial orifice.
Straining to urinate.
Cause
Webbed penis can be caused by various things such as:
Morbid obesity: which is known as excess fat around the genital area and abdomen, which makes the penis appear as though it is hidden.
Abnormalities that are there during birth – ligaments that attach the penis to underlying structures may be weaker than it is supposed to be.
Lymphedema: this is when swelling occurs around the scrotum area due to collection of lymph fluid, which may cause the penis to be buried inside tissue.
Acquired (iatrogenic) after circumcision or other penile surgery – resulting from excessive removal of ventral penile skin.
Mechanism and pathophysiology
Concealed penis is due to a lack of skin or an inelasticity of the penile skin and a weak penile skin fixation or excessive suprapubic fat, the penile webbed is characterized by a ventral fold of skin that connects the distal shaft and a penoscrotum, and a penis which is tucked away with the scar tissue that exists.
Concealed penis is an unusual circumcision complication. The excision of excess preputial skin occurs, although inadequate internal preputial epithelium is cut out. The new preputial orifice is thus distal to the gland and pushes the penile shaft into the supra-pubic fat at the level of mons pubis. In these cases, the released shaft includes a skin graft or local flaps. The other probability of this mechanism is that, since the penis continues to shrink into the mons pubis, the healed scarred pre-utile opening gradually becomes subcutaneously stuck. In such cases, the released shaft needs no skin graft or local flaps. For both mechanisms, the preputial skin is inadequately excised, causing the preputial holes to be distal from the pulse, trapping the pulp when the procedure is complete.In relation to lymphedema – When the lymph system operates normally, the lymph circulates through a series of vessels and ducts throughout the body. It then returns to the bloodstream with lymph. A blocking or failure in the genital area of this system may lead to a lymphatic leak into the soft tissues surrounding the system.
In relation to obesity – Obesity is a general cause of adult acquired buried penis. There are some parallels with buried penis seen in infants, frequently associated with poor skin suspension, abnormal excess fat accumulation in the pubic region, penis webbing, or penis trapping due to scarring post-circumcision. Similarly, adult buried penis is often associated with a laxity of connective tissue between the dart fascia and the penis, allowing the penis to tunnel more closely through the pre-pubic skin due to "hypermobility." This is exacerbated by obesity and weight gain as the phallus is covered by the suprapubic fat pad.
Diagnosis
Typically a physical examination may be used to diagnose a person with a buried penis. A doctor should be able to differentiate between buried penis and a tiny penis, known as micropenis.
Treatment
Adults with a buried penis either deal with or are subject to weight loss services. Weight loss programs are however sluggish and frequently do not "unbury" the penis; in addition, bad urine hygiene can lead to soft tissue infection.While the condition can resolve without intervention in young children, if infection is present, patients may ultimately need a definite reconstruction and urgent procedure. Surgeons who treat this disorder are either urologic or plastic surgeons.Operational options can include ligament separation between penis base and pubic bone; skin graft output to cover penis areas requiring additional skin; liposuction using catheters to suck out fat cells from the region around the penis from below the skin; abdominoplasty that removes excess skin and fat from the area; an escutheonectomy to remove a fat pad just above the pubic area; or a panniculectomy in which pannicles are extracted, excess tissues and skin that hangs on the genitals and thighs.A form of prevention for this condition could be avoiding getting a circumcision in order to avoid complications along the line. On the other hand, proper circumcision is a key factor in preventing this complication of circumcision. This condition requires the liberation of the concealed penis by carefully widening the close preputial hole and optimizing the circumcision, depending upon the etiology and formation process, with or without skin reconstruction.
Doing skin grafts to cover areas of the penis where skin covering is needed; this may be required if circumcision removes too much skin.
Suction lipectomy, which uses catheters to suck out fat cells from the area around the penis under the skin.
Detachment of the ligaments that connect the base of the penis to the pubic bone.
Panniculectomy that removes the pannus, excess fat and skin that hangs over the genitals and thighs.
Prognosis
A person with a concealed penis will have a normal life expectancy. In the studies that have been performed, it is shown that there are no current known side effects post-op. However, a patient might have a slight edema for about a month or two. The only side effect would be an operation scar.
Epidemiology
Webbed penis is considered to be a very uncommon condition, however, its prevalence is still unknown. Due to the fact that it occurs at birth, a high percentage of cases with the condition are found in young children.
Research directions
Webbed penis is when the penis is partially or completely concealed beneath the scrotum or when there is excess skin or fat around the pubic area. Various research is being conducted on this condition: for example, Webbed penis: A new classification is a study that was conducted to suggest an operative method that can be planned based of the severity of the webbing condition. Other research has tried to test the introduction of a modified surgical procedure for repairing a concealed penis and compared the efficacy and feasibility of modified repair with traditional repair.An interesting research study was done between the years 2010 and 2014 to test a new surgical technique for concealed penis using an advanced musculocutaneous scrotal flap. The research showed that the advanced musculocutaneous scrotal flap technique for correcting concealed penis is technically easy and safe and the surgical method provided patients with a good cosmetic appearance, functional outcomes, and excellent postoperative satisfaction grades.
See also
Buried penis
== References == |
Sarcoidosis | Sarcoidosis (also known as Besnier-Boeck-Schaumann disease) is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly affected are the eyes, liver, heart, and brain. Any organ, however, can be affected. The signs and symptoms depend on the organ involved. Often, no, or only mild, symptoms are seen. When it affects the lungs, wheezing, coughing, shortness of breath, or chest pain may occur. Some may have Löfgren syndrome with fever, large lymph nodes, arthritis, and a rash known as erythema nodosum.The cause of sarcoidosis is unknown. Some believe it may be due to an immune reaction to a trigger such as an infection or chemicals in those who are genetically predisposed. Those with affected family members are at greater risk. Diagnosis is partly based on signs and symptoms, which may be supported by biopsy. Findings that make it likely include large lymph nodes at the root of the lung on both sides, high blood calcium with a normal parathyroid hormone level, or elevated levels of angiotensin-converting enzyme in the blood. The diagnosis should only be made after excluding other possible causes of similar symptoms such as tuberculosis.Sarcoidosis may resolve without any treatment within a few years. However, some people may have long-term or severe disease. Some symptoms may be improved with the use of anti-inflammatory drugs such as ibuprofen. In cases where the condition causes significant health problems, steroids such as prednisone are indicated. Medications such as methotrexate, chloroquine, or azathioprine may occasionally be used in an effort to decrease the side effects of steroids. The risk of death is 1–7%. The chance of the disease returning in someone who has had it previously is less than 5%.In 2015, pulmonary sarcoidosis and interstitial lung disease affected 1.9 million people globally and they resulted in 122,000 deaths. It is most common in Scandinavians, but occurs in all parts of the world. In the United States, risk is greater among black people as opposed to white people. It usually begins between the ages of 20 and 50. It occurs more often in women than men. Sarcoidosis was first described in 1877 by the English doctor Jonathan Hutchinson as a non-painful skin disease.
Signs and symptoms
Sarcoidosis is a systemic inflammatory disease that can affect any organ, although it can be asymptomatic and is discovered by accident in about 5% of cases. Common symptoms, which tend to be vague, include fatigue (unrelieved by sleep; occurs in up to 85% of cases ), lack of energy, weight loss, joint aches and pains (which occur in about 70% of cases), arthritis (14–38% of cases), dry eyes, swelling of the knees, blurry vision, shortness of breath, a dry, hacking cough, or skin lesions. Less commonly, people may cough up blood. Sarcoidosis is also accompanied by psychological distress and symptoms of anxiety and depression, which are also associated with fatigue. The cutaneous symptoms vary, and range from rashes and noduli (small bumps) to erythema nodosum, granuloma annulare, or lupus pernio. Sarcoidosis and cancer may mimic one another, making the distinction difficult.The combination of erythema nodosum, bilateral hilar lymphadenopathy, and joint pain is called Löfgren syndrome, which has a relatively good prognosis. This form of the disease occurs significantly more often in Scandinavian patients than in those of non-Scandinavian origin.
Respiratory tract
Localization to the lungs is by far the most common manifestation of sarcoidosis. At least 90% of those affected experience lung involvement. Overall, about 50% develop permanent pulmonary abnormalities, and 5 to 15% have progressive fibrosis of the lung parenchyma. Sarcoidosis of the lung is primarily an interstitial lung disease in which the inflammatory process involves the alveoli, small bronchi, and small blood vessels. In acute and subacute cases, physical examination usually reveals dry crackles. At least 5% of cases include pulmonary arterial hypertension. The upper respiratory tract (including the larynx, pharynx, and sinuses) may be affected, which occurs in between 5 and 10% of cases.The four stages of pulmonary involvement are based on radiological stage of the disease, which is helpful in prognosis:
Stage I: bilateral hilar lymphadenopathy (BHL) alone
Stage II: BHL with pulmonary infiltrates
Stage III: pulmonary infiltrates without BHL
Stage IV: fibrosisUse of the Scadding scale only provides general information regarding the prognosis of the pulmonary disease over time. Caution is recommended, as it only shows a general relation with physiological markers of the disease and the variation is such that it has limited applicability in individual assessments, including treatment decisions.
Skin
Sarcoidosis involves the skin in between 9 and 37% of cases and is more common in African Americans than in European Americans. The skin is the second-most commonly affected organ after the lungs. The most common lesions are erythema nodosum, plaques, maculopapular eruptions, subcutaneous nodules, and lupus pernio. Treatment is not required, since the lesions usually resolve spontaneously in 2–4 weeks. Although it may be disfiguring, cutaneous sarcoidosis rarely causes major problems. Sarcoidosis of the scalp presents with diffuse or patchy hair loss.
Heart
Histologically, sarcoidosis of the heart is an active granulomatous inflammation surrounded by reactive oedema. The distribution of affected areas is patchy with localised enlargement of heart muscles. This causes scarring and remodelling of the heart, which leads to dilatation of heart cavities and thinning of heart muscles. As the situation progresses, it leads to aneurysm of heart chambers. When the distribution is diffuse, there would be dilatation of both ventricles of the heart, causing heart failure and arrhythmia. When the conduction system in the intraventricular septum is affected, it would lead to heart block, ventricular tachycardia and ventricular arrhythmia, causing sudden death. Nevertheless, the involvement of pericardium and heart valves are uncommon.The frequency of cardiac involvement varies and is significantly influenced by race; in Japan, more than 25% of those with sarcoidosis have symptomatic cardiac involvement, whereas in the US and Europe, only about 5% of cases present with cardiac involvement. Autopsy studies in the US have revealed a frequency of cardiac involvement of about 20–30%, whereas autopsy studies in Japan have shown a frequency of 60%. The presentation of cardiac sarcoidosis can range from asymptomatic conduction abnormalities to fatal ventricular arrhythmia.Conduction abnormalities are the most common cardiac manifestations of sarcoidosis in humans and can include complete heart block. Second to conduction abnormalities, in frequency, are ventricular arrhythmias, which occurs in about 23% of cases with cardiac involvement. Sudden cardiac death, either due to ventricular arrhythmias or complete heart block is a rare complication of cardiac sarcoidosis. Cardiac sarcoidosis can cause fibrosis, granuloma formation, or the accumulation of fluid in the interstitium of the heart, or a combination of the former two. Cardiac sarcoidosis may also cause congestive heart failure when granulomas cause myocardial fibrosis and scarring. Congestive heart failure affects 25-75% of those with cardiac sarcoidosis. Diabetes mellitus and sarcoidosis-related arrhythmias are believed to be strong risk factors of heart failure in sarcoidosis. A small (20-40%) increased risk of acute myocardial infarction has also been described. Pulmonary arterial hypertension occurs by two mechanisms in cardiac sarcoidosis: reduced left heart function due to granulomas weakening the heart muscle or from impaired blood flow.
Eye
Eye involvement occurs in about 10–90% of cases. Manifestations in the eye include uveitis, uveoparotitis, and retinal inflammation, which may result in loss of visual acuity or blindness. The most common ophthalmologic manifestation of sarcoidosis is uveitis. The combination of anterior uveitis, parotitis, VII cranial nerve paralysis and fever is called uveoparotid fever or Heerfordt syndrome (D86.8). Development of scleral nodule associated with sarcoidosis has been observed.
Nervous system
Any of the components of the nervous system can be involved. Sarcoidosis affecting the nervous system is known as neurosarcoidosis. Cranial nerves are most commonly affected, accounting for about 5–30% of neurosarcoidosis cases, and peripheral facial nerve palsy, often bilateral, is the most common neurological manifestation of sarcoidosis. It occurs suddenly and is usually transient. The central nervous system involvement is present in 10–25% of sarcoidosis cases. Other common manifestations of neurosarcoidosis include optic nerve dysfunction, papilledema, palate dysfunction, neuroendocrine changes, hearing abnormalities, hypothalamic and pituitary abnormalities, chronic meningitis, and peripheral neuropathy. Myelopathy, that is spinal cord involvement, occurs in about 16–43% of neurosarcoidosis cases and is often associated with the poorest prognosis of the neurosarcoidosis subtypes. Whereas facial nerve palsies and acute meningitis due to sarcoidosis tend to have the most favourable prognosis, another common finding in sarcoidosis with neurological involvement is autonomic or sensory small-fiber neuropathy. Neuroendocrine sarcoidosis accounts for about 5–10% of neurosarcoidosis cases and can lead to diabetes insipidus, changes in menstrual cycle and hypothalamic dysfunction. The latter can lead to changes in body temperature, mood, and prolactin (see the endocrine and exocrine section for details).
Endocrine and exocrine
Prolactin is frequently increased in sarcoidosis, between 3 and 32% of cases have hyperprolactinemia this frequently leads to amenorrhea, galactorrhea, or nonpuerperal mastitis in women. It also frequently causes an increase in 1,25-dihydroxy vitamin D, the active metabolite of vitamin D, which is usually hydroxylated within the kidney, but in sarcoidosis patients, hydroxylation of vitamin D can occur outside the kidneys, namely inside the immune cells found in the granulomas the condition produces. 1,25-dihydroxy vitamin D is the main cause for hypercalcemia in sarcoidosis and is overproduced by sarcoid granulomata. Gamma-interferon produced by activated lymphocytes and macrophages plays a major role in the synthesis of 1 alpha, 25(OH)2D3. Hypercalciuria (excessive secretion of calcium in ones urine) and hypercalcemia (an excessively high amount of calcium in the blood) are seen in <10% of individuals and likely results from the increased 1,25-dihydroxy vitamin D production.Thyroid dysfunction is seen in 4.2–4.6% of cases.Parotid enlargement occurs in about 5–10% of cases. Bilateral involvement is the rule. The gland is usually not tender, but firm and smooth. Dry mouth can occur; other exocrine glands are affected only rarely. The eyes, their glands, or the parotid glands are affected in 20–50% of cases.
Gastrointestinal and genitourinary
Symptomatic gastrointestinal (GI) involvement occurs in less than 1% of cases (if one excludes the liver), and most commonly the stomach is affected, although the small or large intestine may also be affected in a small portion of cases. Studies at autopsy have revealed GI involvement in less than 10% of people. These cases would likely mimic Crohns disease, which is a more commonly intestine-affecting granulomatous disease. About 1–3% of people have evidence of pancreatic involvement at autopsy. Symptomatic kidney involvement occurs in just 0.7% of cases, although evidence of kidney involvement at autopsy has been reported in up to 22% of people and occurs exclusively in cases of chronic disease. Symptomatic kidney involvement is usually nephrocalcinosis, although granulomatous interstitial nephritis that presents with reduced creatinine clearance and little proteinuria is a close second. Less commonly, the epididymis, testicles, prostate, ovaries, fallopian tubes, uterus, or the vulva may be affected, the latter may cause vulva itchiness. Testicular involvement has been reported in about 5% of people at autopsy. In males, sarcoidosis may lead to infertility.Around 70% of people have granulomas in their livers, although only in about 20–30% of cases, liver function test anomalies reflecting this fact are seen. About 5–15% of patients exhibit hepatomegaly. Only 5–30% of cases of liver involvement are symptomatic. Usually, these changes reflect a cholestatic pattern and include raised levels of alkaline phosphatase (which is the most common liver function test anomaly seen in those with sarcoidosis), while bilirubin and aminotransferases are only mildly elevated. Jaundice is rare.
Blood
Abnormal blood tests are frequent, accounting for over 50% of cases, but are not diagnostic. Lymphopenia is the most common blood anomaly in sarcoidosis. Anemia occurs in about 20% of people with sarcoidosis. Leukopenia is less common and occurs in even fewer cases but is rarely severe. Thrombocytopenia and hemolytic anemia are fairly rare. In the absence of splenomegaly, leukopenia may reflect bone marrow involvement, but the most common mechanism is a redistribution of blood T cells to sites of disease. Other nonspecific findings include monocytosis, occurring in the majority of sarcoidosis cases, increased hepatic enzymes or alkaline phosphatase. People with sarcoidosis often have immunologic anomalies like allergies to test antigens such as Candida or purified protein derivative. Polyclonal hypergammaglobulinemia is also a fairly common immunologic anomaly seen in sarcoidosis.Lymphadenopathy (swollen glands) is common in sarcoidosis and occurs in 15% of cases. Intrathoracic nodes are enlarged in 75 to 90% of all people; usually this involves the hilar nodes, but the paratracheal nodes are commonly involved. Peripheral lymphadenopathy is very common, particularly involving the cervical (the most common head and neck manifestation of the disease), axillary, epitrochlear, and inguinal nodes. Approximately 75% of cases show microscopic involvement of the spleen, although only in about 5–10% of cases does splenomegaly appear.
Bone, joints, and muscles
Sarcoidosis can be involved with the joints, bones, and muscles. This causes a wide variety of musculoskeletal complaints that act through different mechanisms.
About 5–15% of cases affect the bones, joints, or muscles.Arthritic syndromes can be categorized as acute or chronic.
Sarcoidosis patients with acute arthritis often also have bilateral hilar lymphadenopathy and erythema nodosum. These three associated syndromes often occur together in Löfgren syndrome. The arthritis symptoms of Löfgren syndrome occur most frequently in the ankles, followed by the knees, wrists, elbows, and metacarpophalangeal joints. Usually, true arthritis is not present, but instead, periarthritis appears as a swelling in the soft tissue around the joints that can be seen by ultrasonographic methods.
These joint symptoms tend to precede or occur at the same time as erythema nodosum develops. Even when erythema nodosum is absent, it is believed that the combination of hilar lymphadenopathy and ankle periarthritis can be considered as a variant of Löfgren syndrome.Enthesitis also occurs in about one-third of patients with acute sarcoid arthritis, mainly affecting the Achilles tendon and heels. Soft-tissue swelling of the ankles can be prominent, and biopsy of this soft tissue reveals no granulomas, but does show panniculitis similar to erythema nodosum.Chronic sarcoid arthritis usually occurs in the setting of more diffuse organ involvement. The ankles, knees, wrists, elbows, and hands may all be affected in the chronic form and often this presents itself in a polyarticular pattern. Dactylitis similar to that seen in psoriatic arthritis, that is associated with pain, swelling, overlying skin erythema, and underlying bony changes may also occur. Development of Jaccoud arthropathy (a nonerosive deformity) is very rarely seen.Bone involvement in sarcoidosis has been reported in 1–13% of cases. The most frequent sites of involvement are the hands and feet, whereas the spine is less commonly affected. Half of the patients with bony lesions experience pain and stiffness, whereas the other half remain asymptomatic.Periostitis is rarely seen in sarcoidosis and has been found to present itself at the femoral bone.
Cause
The exact cause of sarcoidosis is not known. The current working hypothesis is, in genetically susceptible individuals, sarcoidosis is caused through alteration to the immune response after exposure to an environmental, occupational, or infectious agent. Some cases may be caused by treatment with tumor necrosis factor (TNF) inhibitors like etanercept.
Genetics
The heritability of sarcoidosis varies according to ethnicity. About 20% of African Americans with sarcoidosis have a family member with the condition, whereas the same figure for European Americans is about 5%. Additionally, in African Americans, who seem to experience more severe and chronic disease, siblings and parents of sarcoidosis cases have about a 2.5-fold increased risk for developing the disease. In Swedish individuals heritability was found to be 39%. In this group, if a first-degree family member was affected, a person has a four-fold greater risk of being affected.Investigations of genetic susceptibility yielded many candidate genes, but only few were confirmed by further investigations and no reliable genetic markers are known. Currently, the most interesting candidate gene is BTNL2; several HLA-DR risk alleles are also being investigated. In persistent sarcoidosis, the HLA haplotype HLA-B7-DR15 is either cooperating in disease or another gene between these two loci is associated. In nonpersistent disease, a strong genetic association exists with HLA DR3-DQ2. Cardiac sarcoid has been connected to tumor necrosis factor alpha (TNFA) variants.
Infectious agents
Several infectious agents appear to be significantly associated with sarcoidosis, but none of the known associations is specific enough to suggest a direct causative role. The major implicated infectious agents include: mycobacteria, fungi, borrelia, and rickettsia. A meta-analysis investigating the role of mycobacteria in sarcoidosis found it was present in 26.4% of cases, but they also detected a possible publication bias, so the results need further confirmation. Mycobacterium tuberculosis catalase-peroxidase has been identified as a possible antigen catalyst of sarcoidosis. The disease has also been reported by transmission via organ transplants. A large epidemiological study found little evidence that infectious diseases spanning years before sarcoidosis diagnosis could confer measurable risks for sarcoidosis diagnosis in the future.
Autoimmune
Association of autoimmune disorders has been frequently observed. The exact mechanism of this relation is not known, but some evidence supports the hypothesis that this is a consequence of Th1 lymphokine prevalence. Tests of delayed cutaneous hypersensitivity have been used to measure progression.
Pathophysiology
Granulomatous inflammation is characterized primarily by the accumulation of macrophages and activated T-lymphocytes, with increased production of key inflammatory mediators, tumor necrosis factor alpha (TNF), interferon gamma, interleukin 2 (IL-2), IL-8, IL-10, IL-12, IL-18, IL-23 and transforming growth factor beta (TGF-β), indicative of a T helper cell-mediated immune response.
Sarcoidosis has paradoxical effects on inflammatory processes; it is characterized by increased macrophage and CD4 helper T-cell activation, resulting in accelerated inflammation, but immune response to antigen challenges such as tuberculin is suppressed. This paradoxic state of simultaneous hyper- and hypoactivity is suggestive of a state of anergy. The anergy may also be responsible for the increased risk of infections and cancer. The regulatory T-lymphocytes in the periphery of sarcoid granulomas appear to suppress IL-2 secretion, which is hypothesized to cause the state of anergy by preventing antigen-specific memory responses.While TNF is widely believed to play an important role in the formation of granulomas (this is further supported by the finding that in animal models of mycobacterial granuloma formation inhibition of either TNF or IFN-γ production inhibits granuloma formation), sarcoidosis can and does still develop in those being treated with TNF antagonists like etanercept.
B cells also likely play a role in the pathophysiology of sarcoidosis. Serum levels of soluble human leukocyte antigen (HLA) class I antigens and angiotensin converting enzyme (ACE) are higher in people with sarcoidosis. Likewise the ratio of CD4/CD8 T cells in bronchoalveolar lavage is usually higher in people with pulmonary sarcoidosis (usually >3.5), although it can be normal or even abnormally low in some cases. Serum ACE levels have been found to usually correlate with total granuloma load.Cases of sarcoidosis have also been reported as part of the immune reconstitution syndrome of HIV, that is, when people receive treatment for HIV, their immune system rebounds and the result is that it starts to attack the antigens of opportunistic infections caught prior to said rebound and the resulting immune response starts to damage healthy tissue.
Histopathology
Sarcoidosis is characterized by the formation of non-necrotizing ("non-caseating") granulomas in various organs and tissues. Giant cells, specifically Langhans giant cells, are often seen in sarcoidosis. Schaumann bodies seen in sarcoidosis are calcium and protein inclusions inside of giant cells as part of a granuloma. Asteroid bodies can be seen in sarcoidosis. Hamazaki–Wesenberg bodies can be seen in lymph nodes and more rarely in lung biopsies with sarcoidosis and are inclusion bodies of lysosomes with protein, glycoprotein and iron.
Diagnosis
Diagnosis of sarcoidosis is a matter of exclusion, as there is no specific test for the condition. To exclude sarcoidosis in a case presenting with pulmonary symptoms might involve a chest radiograph, CT scan of chest, PET scan, CT-guided biopsy, mediastinoscopy, open lung biopsy, bronchoscopy with biopsy, endobronchial ultrasound, and endoscopic ultrasound with fine-needle aspiration of mediastinal lymph nodes (EBUS FNA). Tissue from biopsy of lymph nodes is subjected to both flow cytometry to rule out cancer and special stains (acid fast bacilli stain and Gömöri methenamine silver stain) to rule out microorganisms and fungi.Serum markers of sarcoidosis, include: serum amyloid A, soluble interleukin-2 receptor, lysozyme, angiotensin converting enzyme, and the glycoprotein KL-6. Angiotensin-converting enzyme blood levels are used in the monitoring of sarcoidosis. A bronchoalveolar lavage can show an elevated (of at least 3.5) CD4/CD8 T cell ratio, which is indicative (but not proof) of pulmonary sarcoidosis. In at least one study the induced sputum ratio of CD4/CD8 and level of TNF was correlated to those in the lavage fluid. A sarcoidosis-like lung disease called granulomatous–lymphocytic interstitial lung disease can be seen in patients with common variable immunodeficiency (CVID) and therefore serum antibody levels should be measured to exclude CVID.Differential diagnosis includes metastatic disease, lymphoma, septic emboli, rheumatoid nodules, granulomatosis with polyangiitis, varicella infection, tuberculosis, and atypical infections, such as Mycobacterium avium complex, cytomegalovirus, and cryptococcus. Sarcoidosis is confused most commonly with neoplastic diseases, such as lymphoma, or with disorders characterized also by a mononuclear cell granulomatous inflammatory process, such as the mycobacterial and fungal disorders.Chest radiograph changes are divided into four stages:
bihilar lymphadenopathy
bihilar lymphadenopathy and reticulonodular infiltrates
bilateral pulmonary infiltrates
fibrocystic sarcoidosis typically with upward hilar retraction, cystic and bullous changesAlthough people with stage 1 radiographs tend to have the acute or subacute, reversible form of the disease, those with stages 2 and 3 often have the chronic, progressive disease; these patterns do not represent consecutive "stages" of sarcoidosis. Thus, except for epidemiologic purposes, this categorization is mostly of historic interest.In sarcoidosis presenting in the Caucasian population, hilar adenopathy and erythema nodosum are the most common initial symptoms. In this population, a biopsy of the gastrocnemius muscle is a useful tool in correctly diagnosing the person. The presence of a noncaseating epithelioid granuloma in a gastrocnemius specimen is definitive evidence of sarcoidosis, as other tuberculoid and fungal diseases extremely rarely present histologically in this muscle.Cardiac magnetic resonance imaging (CMR) is one modality for diagnosing cardiac sarcoidosis. It has 78% specificity in diagnosing cardiac sarcoidosis. Its T2-weighted imaging can detect acute inflammation. Meanwhile, late gadolinium contrast (LGE) can detect fibrosis or scar. Lesions at the subpericardium and midwall enhancement of basal septum or inferolateral wall is strongly suggestive of sarcoidosis. MRI can also follow up on the treatment efficacy of corticosteroids and prognosis of cardiac sarcoidosis.PET scan is able to quantify disease activity which cannot be performed by CMR.
Classification
Sarcoidosis may be divided into the following types:
Treatment
Treatments for sarcoidosis vary greatly depending on the patient. At least half of patients require no systemic therapy. Most people (>75%) only require symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or aspirin. For those presenting with lung symptoms, unless the respiratory impairment is devastating, active pulmonary sarcoidosis is observed usually without therapy for two to three months; if the inflammation does not subside spontaneously, therapy is instituted.Major categories of drug interventions include glucocorticoids, antimetabolites, biologic agents especially monoclonal anti-tumor necrosis factor antibodies. Investigational treatments include specific antibiotic combinations and mesenchymal stem cells. If drug intervention is indicated, a step-wise approach is often used to explore alternatives in order of increasing side effects and to monitor potentially toxic effects.Corticosteroids, most commonly prednisone or prednisolone, have been the standard treatment for many years. In some people, this treatment can slow or reverse the course of the disease, but other people do not respond to steroid therapy. The use of corticosteroids in mild disease is controversial because in many cases the disease remits spontaneously.
Antimetabolites
Antimetabolites, also categorized as steroid-sparing agents, such as azathioprine, methotrexate, mycophenolic acid, and leflunomide are often used as alternatives to corticosteroids. Of these, methotrexate is most widely used and studied. Methotrexate is considered a first-line treatment in neurosarcoid |
Sarcoidosis | osis, often in conjunction with corticosteroids. Long-term treatment with methotrexate is associated with liver damage in about 10% of people and hence may be a significant concern in people with liver involvement and requires regular liver function test monitoring. Methotrexate can also lead to pulmonary toxicity (lung damage), although this is fairly uncommon and more commonly it can confound the leukopenia caused by sarcoidosis. Due to these safety concerns it is often recommended that methotrexate is combined with folic acid in order to prevent toxicity. Azathioprine treatment can also lead to liver damage. However, the risk of infection appears to be about 40% lower in those treated with methotrexate instead of azathioprine. Leflunomide is being used as a replacement for methotrexate, possibly due to its purportedly lower rate of pulmonary toxicity. Mycophenolic acid has been used successfully in uveal sarcoidosis, neurosarcoidosis (especially CNS sarcoidosis; minimally effective in sarcoidosis myopathy), and pulmonary sarcoidosis.
Immunosuppressants
As the granulomas are caused by collections of immune system cells, particularly T cells, there has been some success using immunosuppressants (like cyclophosphamide, cladribine, chlorambucil, and cyclosporine), immunomodulatory (pentoxifylline and thalidomide), and anti-tumor necrosis factor treatment (such as infliximab, etanercept, golimumab, and adalimumab).In a clinical trial cyclosporine added to prednisone treatment failed to demonstrate any significant benefit over prednisone alone in people with pulmonary sarcoidosis, although there was evidence of increased toxicity from the addition of cyclosporine to the steroid treatment including infections, malignancies (cancers), hypertension, and kidney dysfunction. Likewise chlorambucil and cyclophosphamide are seldom used in the treatment of sarcoidosis due to their high degree of toxicity, especially their potential for causing malignancies. Infliximab has been used successfully to treat pulmonary sarcoidosis in clinical trials in a number of cases. Etanercept, on the other hand, has failed to demonstrate any significant efficacy in people with uveal sarcoidosis in a couple of clinical trials. Likewise golimumab has failed to show any benefit in those with pulmonary sarcoidosis. One clinical trial of adalimumab found treatment response in about half of subjects, which is similar to that seen with infliximab, but as adalimumab has better tolerability profile it may be preferred over infliximab.
Specific organ treatments
Ursodeoxycholic acid has been used successfully as a treatment for cases with liver involvement. Thalidomide has also been tried successfully as a treatment for treatment-resistant lupus pernio in a clinical trial, which may stem from its anti-TNF activity, although it failed to exhibit any efficacy in a pulmonary sarcoidosis clinical trial. Cutaneous disease may be successfully managed with antimalarials (such as chloroquine and hydroxychloroquine) and the tetracycline antibiotic, minocycline. Antimalarials have also demonstrated efficacy in treating sarcoidosis-induced hypercalcemia and neurosarcoidosis. Long-term use of antimalarials is limited, however, by their potential to cause irreversible blindness and hence the need for regular ophthalmologic screening. This toxicity is usually less of a problem with hydroxychloroquine than with chloroquine, although hydroxychloroquine can disturb the glucose homeostasis.Recently selective phosphodiesterase 4 (PDE4) inhibitors like apremilast (a thalidomide derivative), roflumilast, and the less subtype-selective PDE4 inhibitor, pentoxifylline, have been tried as a treatment for sarcoidosis, with successful results being obtained with apremilast in cutaneous sarcoidosis in a small open-label study. Pentoxifylline has been used successfully to treat acute disease although its use is greatly limited by its gastrointestinal toxicity (mostly nausea, vomiting, and diarrhea). Case reports have supported the efficacy of rituximab, an anti-CD20 monoclonal antibody and a clinical trial investigating atorvastatin as a treatment for sarcoidosis is under-way. ACE inhibitors have been reported to cause remission in cutaneous sarcoidosis and improvement in pulmonary sarcoidosis, including improvement in pulmonary function, remodeling of lung parenchyma and prevention of pulmonary fibrosis in separate case series. Nicotine patches have been found to possess anti-inflammatory effects in sarcoidosis patients, although whether they had disease-modifying effects requires further investigation. Antimycobacterial treatment (drugs that kill off mycobacteria, the causative agents behind tuberculosis and leprosy) has also proven itself effective in treating chronic cutaneous (that is, it affects the skin) sarcoidosis in one clinical trial. Quercetin has also been tried as a treatment for pulmonary sarcoidosis with some early success in one small trial.Because of its uncommon nature, the treatment of male reproductive tract sarcoidosis is controversial. Since the differential diagnosis includes testicular cancer, some recommend orchiectomy, even if evidence of sarcoidosis in other organs is present. In the newer approach, testicular, epididymal biopsy and resection of the largest lesion has been proposed.
Symptoms
People with sarcoidosis may have a range of symptoms that do not correspond with objective physical evidence of disease but that still decrease quality of life.Physical therapy, rehabilitation, and counseling can help avoid deconditioning,: 733 and improve social participation, psychological well-being, and activity levels. Key aspects are avoiding exercise intolerance and muscle weakness.: 734 Low or moderate-intensity physical training has been shown to improve fatigue, psychological health, and physical functioning in people sarcoidosis without adverse effects. Inspiratory muscle training has also decreased severe fatigue perception in subjects with early stages of sarcoidosis, as well as improving functional and maximal exercise capacity and respiratory muscle strength. The duration, frequency, and physical intensity of exercise needs to accommodate impairments such as joint pain, muscle pain, and fatigue.: 734 Neurostimulants such as methylphenidate and modafinil have shown some effectiveness as an adjunct for treatment of sarcoidosis fatigue.: 733 Treatments for symptomatic neuropathic pain in sarcoidosis patients is similar to that for other causes, and include antidepressants, anticonvulsants and prolonged-release opioids, however, only 30 to 60% of patients experience limited pain relief.: 733
Prognosis
The disease can remit spontaneously or become chronic, with exacerbations and remissions. In some cases, it can progress to pulmonary fibrosis and death. In benign cases, remission can occur in 24 to 36 months without treatment but regular follow ups are required. Some cases, however, may persist several decades. Two-thirds of people with the condition achieve a remission within 10 years of the diagnosis. When the heart is involved, the prognosis is generally less favourable, though corticosteroids appear effective in improving AV conduction. The prognosis tends to be less favourable in African Americans than in white Americans. In a Swedish population-based analysis, the majority of cases who did not have severe disease at diagnosis had comparable mortality to the general population. The risk for premature death was markedly (2.3-fold) increased compared to the general population for a smaller group of cases with severe disease at diagnosis. Serious infections, sometimes multiple during the course of disease, and heart failure might contribute to the higher risk of early death in some patients with sarcoidosis.Some 1990s studies indicated that people with sarcoidosis appear to be at significantly increased risk for cancer, in particular lung cancer, lymphomas, and cancer in other organs known to be affected in sarcoidosis. In sarcoidosis-lymphoma syndrome, sarcoidosis is followed by the development of a lymphoproliferative disorder such as non-Hodgkin lymphoma. This may be attributed to the underlying immunological abnormalities that occur during the sarcoidosis disease process. Sarcoidosis can also follow cancer or occur concurrently with cancer. There have been reports of hairy cell leukemia, acute myeloid leukemia, and acute myeloblastic leukemia associated with sarcoidosis. Sometimes, sarcoidosis, even untreated, can be complicated by opportunistic infections although these are rare.
Epidemiology
Sarcoidosis most commonly affects young adults of both sexes, although studies have reported more cases in females. Incidence is highest for individuals younger than 40 and peaks in the age-group from 20 to 29 years; a second peak is observed for women over 50.Sarcoidosis occurs throughout the world in all races with an average incidence of 16.5 per 100,000 in men and 19 per 100,000 in women. The disease is most common in Northern European countries and the highest annual incidence of 60 per 100,000 is found in Sweden and Iceland. In the United Kingdom the prevalence is 16 in 100,000. In the United States, sarcoidosis is more common in people of African descent than Caucasians, with annual incidence reported as 35.5 and 10.9 per 100,000, respectively. Sarcoidosis is less commonly reported in South America, Spain, India, Canada, and the Philippines. There may be a higher susceptibility to sarcoidosis in those with celiac disease. An association between the two disorders has been suggested.There also has been a seasonal clustering observed in sarcoidosis-affected individuals. In Greece about 70% of diagnoses occur between March and May every year, in Spain about 50% of diagnoses occur between April and June, and in Japan it is mostly diagnosed during June and July.The differing incidence across the world may be at least partially attributable to the lack of screening programs in certain regions of the world, and the overshadowing presence of other granulomatous diseases, such as tuberculosis, that may interfere with the diagnosis of sarcoidosis where they are prevalent. There may also be differences in the severity of the disease between people of different ethnicities. Several studies suggest the presentation in people of African origin may be more severe and disseminated than for Caucasians, who are more likely to have asymptomatic disease. Manifestation appears to be slightly different according to race and sex. Erythema nodosum is far more common in men than in women and in Caucasians than in other races. In Japanese people, ophthalmologic and cardiac involvement are more common than in other races.It is more common in certain occupations, namely firefighters, educators, military personnel, those who work in industries where pesticides are used, law enforcement, and healthcare personnel. In the year after the September 11 attacks, the rate of sarcoidosis incidence went up four-fold (to 86 cases per 100,000).
History
It was first described in 1877 by Dr. Jonathan Hutchinson, a dermatologist as a condition causing red, raised rashes on the face, arms, and hands. In 1889 the term lupus pernio was coined by Dr. Ernest Besnier, another dermatologist. Later in 1892 lupus pernios histology was defined. In 1902 bone involvement was first described by a group of three doctors. Between 1909 and 1910 uveitis in sarcoidosis was first described, and later in 1915 it was emphasised, by Dr. Jörgen Nielsen Schaumann, that it was a systemic condition. This same year lung involvement was also described. In 1937 uveoparotid fever was first described and likewise in 1941 Löfgren syndrome was first described. In 1958 the first international conference on sarcoidosis was called in London, likewise the first USA sarcoidosis conference occurred in Washington, D.C., in the year 1961. It has also been called Besnier–Boeck disease or Besnier–Boeck–Schaumann disease.
Etymology
The word "sarcoidosis" comes from Greek [σάρκο-] sarco- meaning "flesh", the suffix -(e)ido (from the Greek εἶδος -eidos [usually omitting the initial e in English as the diphthong epsilon-iota in Classic Greek stands for a long "i" = English ee]) meaning "type", " resembles" or "like", and -sis, a common suffix in Greek meaning "condition". Thus the whole word means "a condition that resembles crude flesh". The first cases of sarcoïdosis, which were recognised as a new pathological entity, in Scandinavia, at the end of the 19th century exhibited skin nodules resembling cutaneous sarcomas, hence the name initially given.
Society and culture
The World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) is an organisation of physicians involved in the diagnosis and treatment of sarcoidosis and related conditions. WASOG publishes the journal Sarcoidosis, Vasculitis and Diffuse Lung Diseases. Additionally, the Foundation for Sarcoidosis Research (FSR) is devoted to supporting research into sarcoidosis and its possible treatments.There have been concerns that World Trade Center rescue workers are at a heightened risk for sarcoidosis.Comedian and actor Bernie Mac had sarcoidosis. In 2005, he mentioned that the disease was in remission. His death on 9 August 2008 was caused by complications from pneumonia, though Macs agent states the sarcoidosis was not related to his fatal pneumonia.Karen "Duff" Duffy, MTV personality and actress, was diagnosed with neurosarcoidosis in 1995.American football player Reggie White died in 2004, with pulmonary and cardiac sarcoidosis being contributing factors to his fatal heart arrhythmia.Singer Sean Levert died in 2008 of sarcoidosis complications.Joseph Rago, Pulitzer Prize-winning writer known for his work at The Wall Street Journal, died of sarcoidosis complications in 2017.Several historical figures are suspected of having sarcoidosis. In a 2014 letter to the British medical journal The Lancet, it was suggested that the French Revolution leader Maximilien Robespierre may have had sarcoidosis, causing him impairment during his time as head of the Reign of Terror. The symptoms associated with Ludwig van Beethovens 1827 death have been described as possibly consistent with sarcoidosis. Author Robert Louis Stevenson (1850–1894) had a history of chronic coughs and chest complaints, and sarcoidosis has been suggested as a diagnosis.
Pregnancy
Sarcoidosis generally does not prevent successful pregnancy and delivery; the increase in estrogen levels during pregnancy may even have a slightly beneficial immunomodulatory effect. In most cases, the course of the disease is unaffected by pregnancy, with improvement in a few cases and worsening of symptoms in very few cases, although it is worth noting that a number of the immunosuppressants (such as methotrexate, cyclophosphamide) used in corticosteroid-refractory sarcoidosis are known teratogens. Increased risks associated with sarcoidosis ranging from 30 to 70% have been reported for preeclampsia/eclampsia, cesarian or preterm delivery as well as (non-cardiac) birth defects in first singleton pregnancies. In absolute numbers, birth defects and other complications such as maternal death, cardiac arrest, placental abruption or venous thromboembolism are extremely rare in sarcoidosis pregnancies.
References
External links
Sarcoidosis UK Information Hub
Iannuzzi, M. C.; Sah, B. P. (March 2008). Sarcoidosis: Interstitial Lung Diseases. The Merck Manual Home Edition. Merck Sharp & Dohme Corp. Retrieved 19 February 2014. |
Glossitis | Glossitis can mean soreness of the tongue, or more usually inflammation with depapillation of the dorsal surface of the tongue (loss of the lingual papillae), leaving a smooth and erythematous (reddened) surface, (sometimes specifically termed atrophic glossitis). In a wider sense, glossitis can mean inflammation of the tongue generally. Glossitis is often caused by nutritional deficiencies and may be painless or cause discomfort. Glossitis usually responds well to treatment if the cause is identified and corrected. Tongue soreness caused by glossitis is differentiated from burning mouth syndrome, where there is no identifiable change in the appearance of the tongue, and there are no identifiable causes.
Symptoms
Depending upon what exact meaning of the word glossitis is implied, signs and symptoms might include:
Smooth, shiny appearance of the tongue, caused by loss of lingual papillae.
Tongue color changes, usually to a darker red color than the normal white-pink color of a healthy tongue.
Tongue swelling.
Difficulty with chewing, swallowing, or speaking (either because of tongue soreness or tongue swelling).
Burning sensation. Some use the term secondary burning mouth syndrome in cases where a detectable cause, such as glossitis, for an oral burning sensation.Depending upon the underlying cause, there may be additional signs and symptoms such as pallor, oral ulceration and angular cheilitis.
Causes
Anemias
Iron-deficiency anemia is mainly caused by blood loss, such as may occur during menses or gastrointestinal hemorrhage. This often results in a depapilled, atrophic glossitis, giving the tongue a bald and shiny appearance, along with pallor (paleness) of the lips and other mucous membranes a tendency towards recurrent oral ulceration, and cheilosis (swelling of the lips). The appearance of the tongue in iron deficiency anemia has been described as diffuse or patchy atrophy with tenderness or burning. One cause of iron deficiency anemia is sideropenic dysphagia (Plummer–Vinson or Paterson–Brown–Kelly syndrome) which is also characterized by esophageal webbing and dysphagia.Pernicious anemia is usually caused by autoimmune destruction of gastric parietal cells. Parietal cells secrete intrinsic factor which is required for the absorption of vitamin B12. Vitamin B12 deficiency results in megaloblastic anemia and may present as glossitis. The appearance of the tongue in vitamin B12 deficiency is described as "beefy"
or "fiery red and sore". There may be linear or patchy red lesions.
Vitamin B deficiencies
Vitamin B1 deficiency (thiamine deficiency) can cause glossitis. Vitamin B2 deficiency (ariboflavinosis) can cause glossitis, along with angular cheilitis, cheilosis, peripheral neuropathy and other signs and symptoms. The glossitis in vitamin B2 deficiency is described as magenta. Vitamin B3 deficiency (pellagra) can cause glossitis. Vitamin B6 deficiency (pyridoxine deficiency) can cause glossitis, along with angular cheilitis, cheilosis, peripheral neuropathy and seborrheic dermatitis. Folate deficiency (vitamin B9 deficiency) can cause glossitis, along with macrocytic anemia, thrombocytopenia, leukopenia, diarrhea, fatigue and possibly neurological signs. Apart from pernicious anemia discussed above, any other cause of vitamin B12 deficiency can cause glossitis, which tends to be painful, smooth and shiny.
Infections
Bacterial, viral or fungal infections can cause glossitis. Chronic Candida infections of the tongue can cause an atrophic glossitis known as median rhomboid glossitis.Syphilis is now relatively rare, but the tertiary stage can cause diffuse glossitis and atrophy of lingual papillae, termed "syphilitic glossitis", "luetic glossitis" or "atrophic glossitis of tertiary syphilis". It is caused by Treponema pallidum and is a sexually transmitted infection.
Other causes
Many conditions can cause glossitis via malnutrition or malabsorption, which creates the nutritional deficiencies described above, although other mechanisms may be involved in some of those conditions listed.
Alcoholism
Sprue (celiac disease, or tropical sprue), secondary to nutritional deficiencies
Crohn’s disease
Whipple disease
Glucagonoma syndrome
Cowden disease
Acquired immunodeficiency syndrome (AIDS)
Carcinoid syndrome
Kwashiorkor amyloidosis
Veganism and other specialized diets, without B12 supplementation.
Poor hydration and low saliva in the mouth, which allows bacteria to grow more readily
Mechanical irritation or injury from burns, rough edges of teeth or dental appliances, or other trauma
Tongue piercing Glossitis can be caused by the constant irritation by the ornament and by colonization of Candida albicans in site and on the ornament
Exposure to irritants such as tobacco, alcohol, hot foods, or spices
Allergic reaction to toothpaste, mouthwash, breath fresheners, dyes in confectionery, plastic in dentures or retainers, or certain blood-pressure medications (ACE inhibitors)
Administration of ganglion blockers (e.g., Tubocurarine, Mecamylamine).
Oral lichen planus, erythema multiforme, aphthous ulcer, pemphigus vulgaris
Heredity
Albuterol (bronchodilator medicine)A painful tongue may be an indication of an underlying serious medical condition and nearly always merits assessment by a physician or dental surgeon.
Diagnosis
Classification
Glossitis could be classified as a group of tongue diseases or gastrointestinal diseases. It may be primary, where there is no underlying cause, or secondary where it is a sign or symptom of another condition. It can be acute or chronic. Generally speaking, there are several clinical patterns of glossitis, some more common than others.
Atrophic glossitis
Atrophic glossitis, also known as bald tongue, smooth tongue, Hunter glossitis, Moeller glossitis, or Möller-Hunter glossitis, is a condition characterized by a smooth glossy tongue that is often tender/painful, caused by complete atrophy of the lingual papillae (depapillation). The dorsal tongue surface may be affected totally, or in patches, and may be associated with a burning sensation, pain and/or erythema. Atrophic glossitis is a non-specific finding, and has a great many causes, usually related to iron-deficiency anemia, pernicious anemia, B vitamin complex deficiencies, unrecognized and untreated celiac disease (which often presents without gastrointestinal symptoms), or other factors such as xerostomia (dry mouth). Although the terms Möller and Hunter glossitis were originally used to refer to specifically the glossitis that occurs in vitamin B12 deficiency secondary to pernicious anemia, they are now used as synonyms for atrophic glossitis generally. In this article, the term glossitis, unless otherwise specified, refers to atrophic glossitis.
Candidiasis may be a concurrent finding or an alternative cause of erythema, burning, and atrophy.
Median rhomboid glossitis
This condition is characterized by a persistent erythematous, rhomboidal depapillated lesion in the central area of the dorsum of the tongue, just in front of the circumvallate papillae. Median rhomboid glossitis is a type of oral candidiasis, and rarely causes any symptoms. It is treated with antifungal medication. Predisposing factors include use of corticosteroid sprays or inhalers or immunosuppression.
Benign migratory glossitis
Geographic tongue, also termed benign migratory glossitis, is a common condition which usually affects the dorsal surface of the tongue. It is characterized by patches of depapillation and erythema bordered by a whitish peripheral zone. These patches give the tongue the appearance of a map, hence the name. Unlike glossitis due to nutritional deficiencies and anemia, the lesions of geographic tongue move around the tongue over time. This is because in geographic tongue, new areas of the tongue become involved with the condition whilst previously affected areas heal, giving the appearance of a moving lesion. The cause is unknown, and there is no curative treatment. Rarely are there any symptoms associated with the lesions, but occasionally a burning sensation may be present, which is exacerbated by eating hot, spicy or acidic foodstuffs. Some consider geographic tongue to be an early stage of fissured tongue, since the two conditions often occur in combination.
Geometric glossitis
Geometric glossitis, also termed herpetic geometric glossitis, is a term used by some to refer to a chronic lesion associated with herpes simplex virus (HSV) type I infection, in which there is a deep fissure in the midline of the tongue, which gives off multiple branches. The lesion is usually very painful, and there may be erosions present in the depths of the fissures. Similar fissured lesions which are not associated with HSV, as may occur in fissured tongue, do not tend to be painful. The name comes from the geometric pattern of the fissures which are longitudinal, crossed or branched. It is described as occurring in immunocompromized persons, e.g. who have leukemia. However, the association between herpes simplex and geometric glossitis is disputed by some due to a lack of gold standard techniques for diagnosis of intraoral herpetic lesions, and the high prevalence of asymptomatic viral shedding in immunocompromized individuals. Treatment is with systemic aciclovir.
Strawberry tongue
Strawberry tongue, or raspberry tongue, is glossitis which manifests with hyperplastic (enlarged) fungiform papillae, giving the appearance of a strawberry. White strawberry tongue is where there is a white coating on the tongue through which the hyperplastic fungiform papillae protrude. Red strawberry tongue is where the white coating is lost and a dark red, erythematous surface is revealed, interspaced with the hyperplastic fungiform papillae. White strawberry tongue is seen in early scarlet fever (a systemic infection of group A β- hemolytic streptococci), and red strawberry tongue occurs later, after 4–5 days. Strawberry tongue is also seen in Kawasaki disease (a vasculitic disorder primarily occurring in children under 5), and toxic shock syndrome. It may mimic other types of glossitis or Vitamin B12 deficiency.
Treatment
The goal of treatment is to reduce inflammation. Treatment usually does not require hospitalization unless tongue swelling is severe. Good oral hygiene is necessary, including thorough tooth brushing at least twice a day, and flossing at least daily. Corticosteroids such as prednisone may be given to reduce the inflammation of glossitis. For mild cases, topical applications (such as a prednisone mouth rinse that is not swallowed) may be recommended to avoid the side effects of swallowed or injected corticosteroids. Antibiotics, antifungal medications, or other antimicrobials may be prescribed if the cause of glossitis is an infection. Anemia and nutritional deficiencies (such as a deficiency in niacin, riboflavin, iron, or Vitamin E) must be treated, often by dietary changes or other supplements. Avoiding irritants (such as hot or spicy foods, alcohol, and tobacco) may minimize the discomfort.
In some cases, tongue swelling may threaten the airway, a medical emergency that needs immediate attention.
Epidemiology
One review reported overall prevalence ranges of 0.1–14.3% for geographic tongue, 1.3–9.0% for "atrophy tongue" (atrophic glossitis), and 0.0–3.35% for median rhomboid glossitis.
References
== External links == |
Placental site trophoblastic tumor | Placental site trophoblastic tumor is a form of gestational trophoblastic disease, which is thought to arise from intermediate trophoblast.The tumor may secrete human placental lactogen, and result in a false-positive pregnancy test.A placental site trophoblastic tumor is a monophasic neoplasm of the implantation site intermediate trophoblast, and usually a benign lesion, which comprises less than 2% of all gestational trophoblastic proliferations. Preceding conditions include molar pregnancy (5%). Compared to choriocarcinoma or invasive mole, hemorrhage is less conspicuous and serum β-HCG level is low, making early diagnosis difficult.
Immunohistochemistry: Often stains with hPL, keratin, Mel-CAM, EGFR.
Treatment
Because chemotherapy is ineffective; the patient should undergo hysterectomy.
Prognosis
10–20% of cases metastasize leading to death.
References
== External links == |
Ureterovaginal fistula | A ureterovaginal fistula is an abnormal passageway existing between the ureter and the vagina. It presents as urinary incontinence. Its impact on women is to reduce the "quality of life dramatically."
Cause
A ureterovaginal fistula is a result of trauma, infection, pelvic surgery, radiation treatment and therapy, malignancy, or inflammatory bowel disease. Symptoms can be troubling for women especially since some clinicians delay treatment until inflammation is reduced and stronger tissue has formed. The fistula may develop as a maternal birth injury from a long and protracted labor, long dilation time and expulsion period. Difficult deliveries can create pressure necrosis in the tissue that is being pushed between the head of the infant and the softer tissues of the vagina, ureters, and bladder.Radiographic imaging can assist clinicians in identifying the abnormality. A Ureterovaginal fistula is always indicative of an obstructed kidney necessitating emergency intervention followed later by an elective surgical repair of the fistula.
Treatment
Many women delay treatment for decades. Surgeons often will correct the fistula through major gynecological surgery. Newer treatments can include the placement of a stent and is usually successful. In 0.5-2.5% of major pelvic surgeries a ureterovaginal fistula will form, usually weeks later. If the fistula cannot be repaired, the clinician may create a permanent diversion of urine or urostomy. Risks associated with the repair of the fistula are also associated with most other surgical procedures and include the risk of adhesions, disorders of wound healing, infection, ileus, and immobilization. There is a recurrence rate of 5%–15% in the surgical operation done to correct the fistula.
Epidemiology
Birth injuries that result in the formation of fistulas and urinary and fecal incontinence have been found to be strongly associated with economic and cultural factors. Teenagers and women who sustain injuries that develop into ureterovaginal fistulas during childbirth suffer significant social stigma. Ureterovaginal fistulas related to prolonged, obstructed labor are rare in developed nations but are more common in countries where access to emergent obstetrical care is limited.
References
Bibliography
Abele, H (2014). Atlas of gynecologic surgery. Stuttgart: Thieme. ISBN 978-3-13-650704-9.
== External links == |
Tardive dyskinesia | Tardive dyskinesia (TD) is a disorder that results in involuntary, repetitive body movements, which may include grimacing, sticking out the tongue, or smacking the lips. Additionally, there may be rapid jerking movements or slow writhing movements. In about 20% of people with TD, the disorder interferes with daily functioning.Tardive dyskinesia occurs in some people as a result of long-term use of dopamine-receptor-blocking medications such as antipsychotics and metoclopramide. These medications are usually used for mental illness but may also be given for gastrointestinal or neurological problems. The condition typically develops only after months to years of use. The diagnosis is based on the symptoms after ruling out other potential causes.Efforts to prevent the condition include either using the lowest possible dose or discontinuing use of neuroleptics. Treatment includes stopping the neuroleptic medication if possible or switching to clozapine. Other medications such as valbenazine, tetrabenazine, or botulinum toxin may be used to lessen the symptoms. With treatment, some see a resolution of symptoms, while others do not.Rates in those on atypical antipsychotics are about 20%, while those on typical antipsychotics have rates of about 30%. The risk of acquiring the condition is greater in older people, for women, as well as patients with mood disorders and/or medical diagnoses receiving antipsychotic medications. The term "tardive dyskinesia" first came into use in 1964.
Signs and symptoms
Tardive dyskinesia is characterized by repetitive, involuntary movements. Some examples of these types of involuntary movements include:
Grimacing
Tongue movements
Lip smacking
Lip puckering
Pursing of the lips
Excessive eye blinking
Rapid, involuntary movements of the limbs, torso, and fingers may also occur.In some cases, an individuals legs can be so affected that walking becomes difficult or impossible. These symptoms are the opposite of people who are diagnosed with Parkinsons disease. People with Parkinsons have difficulty moving, whereas people with tardive dyskinesia have difficulty not moving.Respiratory irregularity, such as grunting and difficulty breathing, is another symptom associated with tardive dyskinesia, although studies have shown that the rate of people affected is relatively low.Tardive dyskinesia is often misdiagnosed as a mental illness rather than a neurological disorder, and as a result, people are prescribed neuroleptic drugs, which increase the probability that the person will develop a severe and disabling case, and shortening the typical survival period.Other closely related neurological disorders have been recognized as variants of tardive dyskinesia. Tardive dystonia is similar to standard dystonia but permanent. Tardive akathisia involves painful feelings of inner tension and anxiety and a compulsive drive to move the body. In some extreme cases, afflicted individuals experience so much internal tension that they lose their ability to sit still. Tardive tourettism is a tic disorder featuring the same symptoms as Tourette syndrome. The two disorders are extremely close in nature and often can only be differentiated by the details of their respective onsets. Tardive myoclonus, a rare disorder, presents as brief jerks of muscles in the face, neck, trunk, and extremities."AIMS Examination": This test is used when psychotropic medications have been prescribed because people sometimes develop tardive dyskinesia due to prolonged use of antipsychotic medications. The Abnormal Involuntary Movement Scale (AIMS) examination is a test used to identify the symptoms of tardive dyskinesia (TD). The test is not meant to tell whether there is an absence or presence of tardive dyskinesia. It just scales to the level of symptoms indicated by the actions observed. The levels range from none to severe. The AIMS examination was constructed in the 1970s to measure involuntary facial, trunk, and limb movements. It is best to do this test before and after the administration of the psychotropic drugs. Taking the AIMS consistently can help to track severity of TD over time.
Causes
Tardive dyskinesia was first described in the 1950s shortly after the introduction of chlorpromazine and other antipsychotic drugs. However, the exact mechanism of the disorder remains largely uncertain. The most compelling line of evidence suggests that tardive dyskinesia may result primarily from neuroleptic-induced dopamine supersensitivity in the nigrostriatal pathway, with the D2 dopamine receptor being most affected. Neuroleptics act primarily on this dopamine system, and older neuroleptics, which have greater affinity for the D2 binding site, are associated with high risk for tardive dyskinesia. The D2 hypersensitivity hypothesis is also supported by evidence of a dose–response relationship, withdrawal effects, studies on D2 agonists and antagonists, animal studies, and genetic polymorphism research.Given similar doses of the same neuroleptic, differences among individuals still exist in the likelihood of developing tardive dyskinesia. Such individual differences may be due to genetic polymorphisms, which code for D2 receptor binding site affinity, or prior exposure to environmental toxins. Decreased functional reserve or cognitive dysfunction, associated with aging, intellectual disability, alcohol and drug use, or traumatic head injuries, has also been shown to increase risk of developing the disorder among those treated with neuroleptics. Antipsychotic drugs can sometimes camouflage the signs of tardive dyskinesia from occurring in the early stages; this can happen from the individual having an increased dose of an antipsychotic drug. Often the symptoms of tardive dyskinesia are not apparent until the individual comes off of the antipsychotic drugs; however, when tardive dyskinesia worsens, the signs become visible.Other dopamine antagonists and antiemetics can cause tardive dyskinesia, such as metoclopramide and promethazine, used to treat gastrointestinal disorders. Atypical antipsychotics are considered lower-risk for causing TD than their typical counterparts with their relative rates of TD of 13.1% and 32.4% respectively in short-term trials with haloperidol being the main typical antipsychotic utilised in said trials. Quetiapine and clozapine are considered the lowest risk agents for precipitating TD. From 2008, there have been reported cases of the anti-psychotic medication aripiprazole, a partial agonist at D2 receptors, leading to tardive dyskinesia.
As of 2013, reports of tardive dyskinesia in aripiprazole have grown in number.
The available research seems to suggest that the concurrent prophylactic use of a neuroleptic and an antiparkinsonian drug is useless to avoid early extrapyramidal side-effects and may render the person more sensitive to tardive dyskinesia. Since 1973 the use of these drugs has been found to be associated with the development of tardive dyskinesia.
Risk factors
An increased risk of tardive dyskinesia has been associated with smoking in some studies, although a negative study does exist. There seems to be a cigarette smoke-exposure-dependent risk for TD in people who are antipsychotic-treated . Elderly people are also at a heightened risk for developing TD, as are females and those with organic brain injuries or diabetes mellitus and those with the negative symptoms of schizophrenia. TD is also more common in those that experience acute neurological side effects from antipsychotic drug treatment. Racial discrepancies in TD rate also exist, with Africans and African Americans having higher rates of TD after exposure to antipsychotics. Certain genetic risk factors for TD have been identified including polymorphisms in the genes encoding the D3, 5-HT2A and 5-HT2C receptors.
Diagnosis
Prevention
Prevention of tardive dyskinesia is achieved by using the lowest effective dose of a neuroleptic for the shortest time. However, with diseases of chronic psychosis such as schizophrenia, this strategy must be balanced with the fact that increased dosages of neuroleptics are more beneficial in preventing recurrence of psychosis. If tardive dyskinesia is diagnosed, the causative drug should be discontinued. Tardive dyskinesia may persist after withdrawal of the drug for months, years or even permanently. Some studies suggest that practitioners should consider using atypical antipsychotics as a substitute to typical antipsychotics for people requiring medication. These agents are associated with fewer neuromotor side effects and a lower risk of developing tardive dyskinesia.Studies have tested the use of melatonin, high dosage vitamins, and different antioxidants in concurrence with antipsychotic drugs (often used to treat schizophrenia) as a way of preventing and treating tardive dyskinesia. Although further research is needed, studies reported a much lower percentage of individuals developing tardive dyskinesia than the current rate of people for those taking antipsychotic drugs. Tentative evidence supports the use of vitamin E for prevention.
Treatment
Valbenazine was approved by the FDA for tardive dyskinesia in April 2017. Tetrabenazine, which is a dopamine depleting drug, is sometimes used to treat tardive dyskinesia and other movement disorders (e.g. Huntingtons chorea). Deutetrabenazine, an isotopic isomer of tetrabenazine, was approved by the FDA for tardive dyskinesia in August 2017. Vitamin B6 has been reported to be an effective treatment for TD in two randomised double-blind placebo-controlled trials, but the overall evidence for its effectiveness is considered "weak." Clonidine may also be useful in the treatment of TD, although dose-limiting hypotension and sedation may hinder its usage. Botox injections are used for minor focal dystonia, but not in more advanced tardive dyskinesia. As of 2018 evidence is insufficient to support the use of benzodiazepines, baclofen, progabide, sodium valproate, gaboxadol, or calcium channel blockers (e.g. diltiazem).
Epidemiology
Tardive dyskinesia most commonly occurs in people with psychiatric conditions who are treated with antipsychotic medications for many years. The average rate of people affected has been estimated to be around 30% for individuals taking antipsychotic medication, such as that used to treat schizophrenia. A study being conducted at the Yale University School of Medicine has estimated that "32% of people develop persistent tics after 5 years on major tranquilizers, 57% by 15 years, and 68% by 25 years." More drastic data was found during a longitudinal study conducted on individuals 45 years of age and older who were taking antipsychotic drugs. According to this research study, 26% of people developed tardive dyskinesia after just one year on the medication. Another 60% of this at-risk group developed the disorder after 3 years, and 23% developed severe cases of tardive dyskinesia within 3 years. According to these estimates, the majority of people will eventually develop the disorder if they remain on the drugs long enough.Elderly people are more prone to develop tardive dyskinesia, and elderly women are more at-risk than elderly men. The risk is much lower for younger men and women, and also more equal across the sexes. People who have undergone electroconvulsive therapy or have a history of diabetes or heavy alcohol use also have a higher risk of developing tardive dyskinesia.Several studies have recently been conducted comparing the number of people affected of tardive dyskinesia with second generation, or more modern, antipsychotic drugs to that of first generation drugs. The newer antipsychotics appear to have a substantially reduced potential for causing tardive dyskinesia. However, some studies express concern that the number of people affected has decreased far less than expected, cautioning against the overestimation of the safety of modern antipsychotics.A practitioner can evaluate and diagnose a person with tardive dyskinesia by conducting a systematic examination. The practitioner should ask the person to relax, and look for symptoms like facial grimacing, eye or lip movements, tics, respiratory irregularities, and tongue movements. In some cases, people experience nutritional problems, so a practitioner can also look for a gain or loss in weight.Apart from the underlying psychiatric disorder, tardive dyskinesia may cause afflicted people to become socially isolated. It also increases the risk of body dysmorphic disorder (BDD) and can even lead to suicide. Emotional or physical stress can increase the severity of dyskinetic movements, whereas relaxation and sedation have the opposite effect.
References
== External links == |
Acute necrotizing ulcerative gingivitis | Acute necrotizing ulcerative gingivitis (ANUG) is a common, non-contagious infection of the gums with sudden onset. The main features are painful, bleeding gums, and ulceration of inter-dental papillae (the sections of gum between adjacent teeth). This disease, along with necrotizing (ulcerative) periodontitis (NP or NUP) is classified as a necrotizing periodontal disease, one of the seven general types of gum disease caused by inflammation of the gums (periodontitis).
The often severe gum pain that characterizes ANUG distinguishes it from the more common chronic periodontitis which is rarely painful. If ANUG is improperly treated or neglected, it may become chronic and/or recurrent. The causative organisms are mostly anaerobic bacteria, particularly Fusobacteriota and spirochete species.
Predisposing factors include poor oral hygiene, smoking, poor nutrition, psychological stress, and a weakened immune system. When the attachments of the teeth to the bone are involved, the term NUP is used. Treatment of ANUG is by removal of dead gum tissue and antibiotics (usually metronidazole) in the acute phase, and improving oral hygiene to prevent recurrence. Although the condition has a rapid onset and is debilitating, it usually resolves quickly and does no serious harm. The informal name trench mouth arose during World War I as many soldiers developed the disease, probably because of the poor conditions and extreme psychological stress.
Signs and symptoms
In the early stages some affected people may complain of a feeling of tightness around the teeth. Three signs/symptoms must be present to diagnose this condition:
Severe gum pain.
Profuse gum bleeding that requires little or no provocation.
Interdental papillae are ulcerated with dead tissue. The papillary necrosis of NUG has been described as "punched out".Other signs and symptoms may be present, but not always.
Foul breath.
Bad taste (metallic taste).Malaise, fever and/or cervical lymph node enlargement are rare (unlike the typical features of herpetic stomatitis). Pain is fairly well localized to the affected areas. Systemic reactions may be more pronounced in children. Cancrum oris (noma) is a very rare complication, usually in debilitated children. Similar features but with more intense pain may be seen in necrotizing periodontitis in HIV/AIDS.
Causes
Necrotizing periodontal disease is caused by a mixed bacterial infection that includes anaerobes such as P. intermedia and Fusobacterium as well as spirochetes, such as Treponema.ANUG may also be associated with diseases in which the immune system is compromised, including HIV/AIDS.
ANUG is an opportunistic infection that occurs on a background of impaired local or systemic host defenses. The predisposing factors for ANUG are smoking, psychological stress, malnutrition, and immunosuppression.
The following zones of infection have been described (superficial to deep): the bacterial zone, the neutrophil rich zone, the necrotic zone and the spirochetal zone.
Diagnosis
Diagnosis is usually clinical. Smear for fusospirochaetal bacteria and leukocytes; blood picture occasionally. The important differentiation is with acute leukemia or herpetic stomatitis.
Classification
Necrotizing gingivitis is part of a spectrum of disease termed necrotizing periodontal diseases. It is the most minor form of this spectrum, with more advanced stages being termed necrotizing periodontitis, necrotizing stomatitis, and the most extreme, cancrum oris. Acute necrotizing ulcerative gingivitis (ANUG) refers to the clinical onset of NUG. The word acute is used because usually the onset is sudden. Other forms of NUG may be chronic or recurrent.
Necrotizing ulcerative periodontitis (NUP) is where the infection leads to attachment loss, and involves only the gingiva, periodontal ligament and alveolar ligament. Progression of the disease into tissue beyond the mucogingival junction characterizes necrotizing stomatitis.
Treatment
Treatment includes irrigation and debridement of necrotic areas (areas of dead and/or dying gum tissue), oral hygiene instruction and the uses of mouth rinses and pain medication. If there is systemic involvement, then oral antibiotics may be given, such as metronidazole. As these diseases are often associated with systemic medical issues, proper management of the systemic disorders is appropriate.
Prognosis
Untreated, the infection may lead to rapid destruction of the periodontium and can spread, as necrotizing stomatitis or noma, into neighbouring tissues in the cheeks, lips or the bones of the jaw. As stated, the condition can occur and be especially dangerous in people with weakened immune systems. This progression to noma is possible in malnourished susceptible individuals, with severe disfigurement possible.
Epidemiology
In developed countries, this disease occurs mostly in young adults. In developing countries, NUG may occur in children of low socioeconomic status, usually occurring with malnutrition (especially inadequate protein intake) and shortly after the onset of viral infections (e.g. measles).Predisposing factors include smoking, viral respiratory infections and immune defects, such as in HIV/AIDS. Uncommon, except in lower socioeconomic classes, this typically affects adolescents and young adults, especially in institutions, armed forces, etc., or people with HIV/AIDS. The disease has occurred in epidemic-like patterns, but it is not contagious.
History
Necrotizing ulcerative gingivitis has been observed for centuries. Xenophon observes sore mouth and foul smelling breath in Greek soldiers in the 4th century BC. Hunter describes the clinical features of ANUG in 1778, differentiating it from scurvy (avitaminosis C) and chronic periodontitis. Jean Hyacinthe Vincent, a French physician working at the Paris Pasteur Institute describes a fusospirochetal infection of the pharynx and palatine tonsils, causing "ulcero-membranous pharyngitis and tonsillitis", which later became known as Vincents angina. Later in 1904, Vincent describes the same pathogenic organisms in "ulceronecrotic gingivitis". Vincents angina is sometimes confused with NUG, however the former is tonsillitis and pharyngitis, and the latter involves the gums, and usually the two conditions occur in isolation from each other.
The term trench mouth evolved because the disease was observed in front line soldiers during World War I, thought to be a result at least partly because of extreme psychologic stress they were exposed to. The same condition was appearing in civilians during periods of bombing raids, who were away from the front line, and who had relatively good diets during wartime due to rationing, so it is assumed that psychologic stress was the significant causative factor. It has also been associated with high tobacco use in the army.
Many other historical names for this condition (and Vincents angina) have occurred, including: "acute membranous gingivitis", "fusospirillary gingivitis", " fusospirillosis", "fusospirochetal gingivitis", "phagedenic gingivitis", "Vincent stomatitis", "Vincent gingivitis", and "Vincent infection".In the late 1980s-early 1990s, it was originally thought that some necrotizing periodontal diseases seen in severely affected AIDS patients were strictly a sequela of HIV, and it was even called HIV-associated periodontitis. It is now understood that its association with HIV/AIDS was due to the immunocompromised status of such patients; it also occurs with higher prevalence in association with other diseases in which the immune system is compromised.
See also
Canker sore
Mouth ulcer
References
== External links == |
Posthitis | Posthitis (pronounced pos-THI-tis) is the inflammation of the foreskin (prepuce) of the penis. It is characterised by swelling and redness on the skin and it may be accompanied by a smelly discharge.
The term posthitis comes from the Greek "posthe", meaning foreskin, and "-itis", meaning inflammation.
Causes
Posthitis can have infectious causes such as bacteria or fungi, or non-infectious causes such as contact dermatitis or psoriasis. The inflammation may be caused by irritants in the environment. Common causative organisms include candida, chlamydia, and gonorrhea. The cause must be properly diagnosed before a treatment can be prescribed. A common risk factor is diabetes.
Posthitis can lead to phimosis, the tightening of the foreskin which makes it difficult to retract over the glans. Posthitis can also lead to superficial ulcerations and diseases of the inguinal lymph nodes.
Prevention
Hygiene, in particular the regular cleaning of the glans, is generally considered sufficient to prevent infection and inflammation of the foreskin. Full retraction of the foreskin may not be possible in boys younger than about ten years and some may not be able to fully retract their foreskin for cleaning until their late teens.
Treatment
If contact dermatitis is suspected, soaps and other external irritants should be discontinued and a latex allergy should be investigated.
The treatment depends on identification of the cause. Irritants in the environment should be removed. Antibiotics and antifungals can be used to treat the infection, but good hygiene such as keeping the area dry is essential to stop recurrence, however excessive washing with soap can cause contact dermatitis.If infection is sexually transmitted, sexual partners should be notified and treated.
Posthitis and balanitis (inflammation of the glans penis) usually occur together as balanoposthitis. Circumcision can prevent balanoposthitis, though balanitis can still occur separately.
== References == |
Epidural hematoma | Epidural hematoma is when bleeding occurs between the tough outer membrane covering the brain (dura mater) and the skull. Often there is loss of consciousness following a head injury, a brief regaining of consciousness, and then loss of consciousness again. Other symptoms may include headache, confusion, vomiting, and an inability to move parts of the body. Complications may include seizures.The cause is typically head injury that results in a break of the temporal bone and bleeding from the middle meningeal artery. Occasionally it can occur as a result of a bleeding disorder or blood vessel malformation. Diagnosis is typically by a CT scan or MRI. When this condition occurs in the spine it is known as a spinal epidural hematoma.Treatment is generally by urgent surgery in the form of a craniotomy or burr hole. Without treatment, death typically results. The condition occurs in one to four percent of head injuries. Typically it occurs in young adults. Males are more often affected than females.
Signs and symptoms
Many people with epidural hematomas experience a lucid period immediately following the injury, with a delay before symptoms become evident. Because of this initial period of lucidity, it has been called "Talk and Die" syndrome. As blood accumulates, it starts to compress intracranial structures, which may impinge on the third cranial nerve, causing a fixed and dilated pupil on the side of the injury. The eye will be positioned down and out due to unopposed innervation of the fourth and sixth cranial nerves.Other symptoms include severe headache; weakness of the extremities on the opposite side from the lesion due to compression of the crossed pyramid pathways; and vision loss, also on the opposite side, due to compression of the posterior cerebral artery. In rare cases, small hematomas may be asymptomatic.If not treated promptly, epidural hematomas can cause tonsillar herniation, resulting in respiratory arrest. The trigeminal nerve may be involved late in the process as the pons is compressed, but this is not an important presentation, because the person may already be dead by the time it occurs. In the case of epidural hematoma in the posterior cranial fossa, tonsillar herniation causes Cushings triad: hypertension, bradycardia, and irregular breathing.
Causes
The most common cause of intracranial epidural hematoma is head injury, although spontaneous hemorrhages have been known to occur. Epidural hematomas occur in about 10% of traumatic brain injuries, mostly due to car accidents, assaults, or falls. They are often caused by acceleration-deceleration trauma and transverse forces.Epidural hematoma commonly results from a blow to the side (temporal bone) of the head. The pterion region, which overlies the middle meningeal artery, is relatively weak and prone to injury. Only 20 to 30% of epidural hematomas occur outside the region of the temporal bone. The brain may be injured by prominences on the inside of the skull as it scrapes past them. Epidural hematoma is usually found on the same side of the brain which was impacted by the blow, but on very rare occasions it can be due to a contrecoup injury.A "heat hematoma" is an epidural hematoma caused by severe thermal burn, causing contraction and exfoliation of the dura mater and exfoliate from the skull, in turn causing exudation of blood from the venous sinuses. The hematoma can be seen on autopsy as brick red, or as radiolucent on CT scan, because of heat-induced coagulation of the hematoma.
Pathophysiology
The break of the temporal bone causes bleeding from the middle meningeal artery, hence epidural bleeding is often rapid as arteries are high-pressure flow. In 10% of cases, however, it comes from veins and can progress more slowly. A venous hematoma may be acute (occurring within a day of the injury and appearing as a swirling mass of blood without a clot), subacute (occurring in 2–4 days and appearing solid), or chronic (occurring in 7–20 days and appearing mixed or lucent).In adults, the temporal region accounts for 75% of cases. In children, however, they occur with similar frequency in the occipital, frontal, and posterior fossa regions. Epidural bleeds from arteries can grow until they reach their peak size 6–8 hours post-injury, spilling 25–75 cubic centimeters of blood into the intracranial space. As the hematoma expands, it strips the dura from the inside of the skull, causing an intense headache. It also increases intracranial pressure, causing the brain to shift, lose blood supply, be crushed against the skull, or herniate. Larger hematomas cause more damage. Epidural bleeds can quickly compress the brainstem, causing unconsciousness, abnormal posturing, and abnormal pupil responses to light.
Diagnosis
Diagnosis is typically by CT scan or MRI. MRIs have greater sensitivity and should be used if there is a high suspicion of epidural hematoma and a negative CT scan. Differential diagnoses include a transient ischemic attack, intracranial mass, or brain abscess.Epidural hematomas usually appear convex in shape because their expansion stops at the skulls sutures, where the dura mater is tightly attached to the skull. Thus, they expand inward toward the brain rather than along the inside of the skull, as occurs in subdural hematomas. Most people also have a skull fracture.Epidural hematomas may occur in combination with subdural hematomas, or either may occur alone. CT scans reveal subdural or epidural hematomas in 20% of unconscious people. In the hallmark of epidural hematoma, people may regain consciousness and appear completely normal during what is called a lucid interval, only to descend suddenly and rapidly into unconsciousness later. This lucid interval, which depends on the extent of the injury, is a key to diagnosing an epidural hematoma.
Treatment
Epidural hematoma is a surgical emergency. Delayed surgery can result in permanent brain damage or death. Without surgery, death usually follows, due to enlargement of the hematoma, causing a brain herniation. As with other types of intracranial hematomas, the blood almost always must be removed surgically to reduce the pressure on the brain. The hematoma is evacuated through a burr hole or craniotomy. If transfer to a facility with neurosurgery is unavailable, prolonged trephination (drilling a hole into the skull) may be performed in the emergency department. Large hematomas and blood clots may require an open craniotomy.Medications may be given after surgery. They may include antiseizure medications and hyperosmotic agents to reduce brain swelling and intracranial pressure.It is extremely rare to not require surgery. If the volume of the epidural hematoma is less than 30 mL, the clot diameter less than 15 mm, a Glasgow Coma Score above 8, and no visible neurological symptoms, then it may be possible to treat it conservatively. A CT scan should be performed, and watchful waiting should be done, as the hematoma may suddenly expand.
Prognosis
The prognosis is better if there was a lucid interval than if the person was comatose from the time of injury. Arterial epidural hematomas usually progress rapidly. However, venous epidural hematomas, caused by a dural sinus tear, are slower.Outcomes are worse if there is more than 50 mL of blood in the hematoma before surgery. Age, pupil abnormalities, and Glasgow Coma Scale score on arrival to the emergency department also influence the prognosis. In contrast to most forms of traumatic brain injury, people with epidural hematoma and a Glasgow Coma Score of 15 (the highest score, indicating the best prognosis) usually have a good outcome if they receive surgery quickly.
Epidemiology
About 2 percent of head injuries and 15 percent of fatal head injuries involve an epidural hematoma. The condition is more common in teenagers and young adults than in older people, because the dura mater sticks more to the skull as a person ages, reducing the probability of a hematoma forming. Males are affected more than females.
References
External links
MedPix: Epidural hematoma
Epidural hematoma | Radiology Case | Radiopaedia.org |
Palmar erythema | Palmar erythema is reddening of the palms at the thenar and hypothenar eminences.: 139
Causes
It is associated with various physiological as well as pathological changes, or may be a normal finding:
Portal hypertension
Chronic liver disease (including chronic hepatitis)
Pregnancy
Polycythemia
Thyrotoxicosis
Rheumatoid arthritis (especially in patients with polycythaemia)
Eczema and psoriasis
Deep telangiectasias
Coxsackievirus A infection (Hand, foot and mouth disease)
Rocky Mountain spotted fever
Secondary syphilis
Kawasaki disease
Adverse drug reaction: palmoplantar erythrodysesthesia (acral erythema)Because circulating levels of estrogen increase in both cirrhosis and pregnancy, estrogen was thought to be the main cause for the increased vascularity. More recently, nitric oxide has also been implicated in the pathogenesis of palmar erythema.
Diagnosis
Palmar erythema has no specific treatment. Management is based on the underlying cause. When its cause is treated then patients get relief. If it is attributable to a particular drug then the drug should be withdrawn.
See also
Toxic erythema
List of cutaneous conditions
References
== External links == |
Myotonic dystrophy | Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness. In DM, muscles are often unable to relax after contraction. Other manifestations may include cataracts, intellectual disability and heart conduction problems. In men, there may be early balding and an inability to have children. While myotonic dystrophy can occur at any age, onset is typically in the 20s and 30s.Myotonic dystrophy is caused by a genetic mutation in one of two genes. Mutation of the DMPK gene causes myotonic dystrophy type 1 (DM1). Mutation of CNBP gene causes type 2 (DM2). DM is typically inherited from a persons parents, following an autosomal dominant inheritance pattern, and it generally worsens with each generation. A type of DM1 may be apparent at birth. DM2 is generally milder. Diagnosis is confirmed by genetic testing.There is no cure. Treatments may include braces or wheelchairs, pacemakers and non-invasive positive pressure ventilation. The medications mexiletine or carbamazepine can help relax muscles. Pain, if it occurs, may be treated with tricyclic antidepressants and nonsteroidal anti-inflammatory drugs (NSAIDs).Myotonic dystrophy affects more than 1 in 8,000 people worldwide. It is the most common form of muscular dystrophy that begins in adulthood. It was first described in 1909, with the underlying cause of type 1 determined in 1992.
Signs and symptoms
DM causes muscle weakness, early onset of cataracts, and myotonia, which is delayed relaxation of muscles after contraction. Cataracts can be either a cortical cataract with a blue dot appearance, or a posterior subcapsular cataract. Other organs affected include the heart, lungs, gastrointestinal tract, skin, and brain. Insulin resistance can also occur. Signs and symptoms vary considerably by severity, unusual phenotype, and form (DM1/DM2). DM1 and DM2 differ in regards to the muscles they affect, age of onset, severity of disease, and extramuscular manifestations.
DM1
DM1 usually begins in the muscles of the hands, feet, neck, or face. One manifestation of facial weakness is drooping of the eyelid (ptosis). It slowly progresses to involve other muscle groups, including the heart. Myotonia tends to be more prominent in DM1 compared to DM2. Other DM1 manifestations include problems with executive function (e.g., organization, concentration, word-finding) and hypersomnia. Abnormalities in the electrical activity of the heart are common in DM1, manifesting as arrhythmias or conduction blocks. Sometimes, dilated cardiomyopathy occurs. Symptoms onset any time from birth to adulthood. The earlier the disease onset, the greater the variety of possible signs and symptoms. Thus, various diagnostic classifications based on the age of onset/severity of the disease have been proposed, although DM1 manifestations likely lie on a continuum.
Congenital DM1
When DM1 onsets at birth, it is called congenital DM1. Manifestations that can be present at birth include hypotonia, respiratory failure, feeding difficulty, and club foot (talipes equinovarus), any of which tend to resolve over several years. During childhood, intellectual impairment, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorders (ASD) can result. Gastrointestinal issues can result, which can be severe, manifestations including diarrhea, constipation, and fecal incontinence. The symptoms of adult DM often manifest during adolescence. Infantile DM1 can be distinguished as another disease category, or it can be grouped with congenital DM1 or childhood-onset DM1.
Childhood-onset DM1
Childhood-onset DM1 is defined as onset of symptoms between ages 1 and 10 years. Manifestations include the same intellectual and gastrointestinal symptoms seen in congenital DM1.
DM2
DM2 is generally milder than DM1, with generally fewer DM2 people requiring assistive devices than DM1 people.
DM2 preferentially affects muscles closer to or on the torso, including the neck flexors, hip flexors, and hip extensors. Muscle pain is prominent in DM2. Heart issues, while still potentially fatal, are less common and severe in DM2 than DM1. Symptoms onset in early to late adulthood. Severe congenital onset, which can occur in DM1, has not been observed in DM2.
Genetics
Myotonic dystrophy (DM) is a genetic condition that is inherited in an autosomal dominant pattern, meaning each child of an affected individual has a 50% chance of inheriting the disease. The mutation involves satellite DNA, which is tandemly repeated sequences of DNA that do not code for a protein. The repeats implicated in myotonic dystrophy are either 3 or 4 nucleotides in length, classified as microsatellites. Disease results from an abnormally increased number of these microsatellites, termed microsatellite expansion.
DM1
The microsatellite expansion responsible for DM1 is of cytosine-thymine-guanine (CTG) triplet repeats, termed trinucleotide repeat expansion and classifying DM1 as a one of several trinucleotide repeat disorders. This expansion occurs at the end of the DMPK gene, in the 3 untranslated region. DMPK is located on the long arm of chromosome 19. DMPK codes for myotonic dystrophy protein kinase, a protein expressed predominantly in skeletal muscle.Between 5 and 37 repeats is considered normal; between 38 and 49 repeats is considered pre-mutation, and although not producing symptoms, children can have further repeat expansion and symptomatic disease; greater than 50 repeats almost invariably is symptomatic, with some noted exceptions. Longer repeats are usually associated with earlier onset and more severe disease.DMPK alleles with greater than 37 repeats are unstable and additional trinucleotide repeats may be inserted during cell division in mitosis and meiosis. Consequently, the children of individuals with premutations or mutations inherit DMPK alleles which are longer than their parents and therefore are more likely to be affected or display an earlier onset and greater severity of the condition, a phenomenon known as anticipation. Repeat expansion is generally considered to be a consequence of the incorporation of additional bases as a result of strand slippage during either DNA replication or DNA repair synthesis. Misalignments occurring during homologous recombinational repair, double-strand break repair or during other DNA repair processes likely contribute to trinucleotide repeat expansions in DM1. Paternal transmission of the congenital form is uncommon (13%), possibly due to selection pressures against sperm with expanded repeats, but juvenile or adult-onset is equally transmitted from either parent. Anticipation tends to be less severe than in cases of maternal inheritance.The RNA from the expanded trinucleotide repeat region forms intranucleoplasmic hairpin loops due to the extensive hydrogen bonding between C-G base pairs, and it has been demonstrated that these sequester the splicing regulator MBNL1 to form distinctive foci.A severe form of DM1, congenital myotonic dystrophy, may appear in newborns of mothers who have DM. Congenital myotonic dystrophy can also be inherited via the paternal gene, although it is said to be relatively rare. Congenital means that the condition is present from birth.
DM2
The microsatellite expansion responsible for DM2 is of cytosine-cytosine-thymine-guanine (CCTG) repeats, classifying it as a tetranucleotide repeat disorder. This expansion occurs in the first intron CNBP gene on chromosome 3.The repeat expansion for DM2 is much larger than for DM1, ranging from 75 to over 11,000 repeats. Like DM1, the size of the microsatellite repeat array lengthens from generation to generation. Unlike DM1, anticipation does not result, as the degree of repeat expansion beyond 75 repeats does not affect the age of onset or disease severity.The repeat expansion produces an RNA transcript that binds to RNA-binding proteins such as MBNL1, as in DM1. Also, repeat expansion likely reduces expression of CNBP, loss of which causes muscle toxicity.
Pathophysiology
Molecular
Mutations of DM1 and DM2 cause production of RNA that sequesters RNA-binding proteins, causing dysregulated RNA splicing. This dysregulated RNA splicing is particularly toxic to skeletal, cardiac, and smooth muscle. One example in DM1 involves the chloride channel ClC-1. Mutated DMPK RNA binds to MBNL1, causing ClC-1 pre-mRNA to be spliced into the fetal form instead of the adult form. Functional loss of the chloride channel causes myotonia.
Histology
In DM1, there can be increased central nuclei, angular fibers, fiber atrophy, and pyknotic clumps. There can be selective atrophy of type 1 muscle fibers. Muscle fibers show signs of degeneration and regeneration. There is modest fibrosis of the endomysium.In DM2, there can be variation in the sizes of muscle fibers, although often there are no abnormalities. There is selective atrophy of type 2 muscle fibers. Again, there are central nuclei and nuclear clumps.
Diagnosis
The diagnosis of DM1 and DM2 can be difficult due to the large number of neuromuscular disorders, most of which are very rare. One study found that diagnosis is made an average of seven years after symptom onset for DM1, and fourteen years for DM2.As a result, people with multiple symptoms that may be explained by a complex disorder such as DM1 or DM2 will generally be referred by their primary care physician to a neurologist for diagnosis. Depending on the presentation of symptoms, people may be referred to a number of medical specialists including cardiologists, ophthalmologists, endocrinologists, and rheumatologists. In addition, the clinical presentation is obscured by the degree of severity or the presence of unusual phenotypes.
Though there is presently no cure for DM and management is currently symptom-based, a precise diagnosis is still necessary to anticipate multiple other problems that may develop over time (e.g. cataracts). An accurate diagnosis is important to assist with appropriate medical monitoring and management of symptoms. In addition, genetic counseling should be made available to all people because of the high risk of transmission. Potentially serious anesthetic risks are important to note, so the presence of this disorder should be brought to the attention of all medical providers.
Classification
There are two main types of myotonic dystrophy. Type 1 (DM1), also known as Steinert disease, has a severe congenital form and a milder childhood-onset form as well as an adult-onset form. This disease is most often in the facial muscles, levator palpebrae superioris, temporalis, sternocleidomastoids, distal muscles of the forearm, hand intrinsic muscles, and ankle dorsiflexors. Type 2 (DM2), also known as proximal myotonic myopathy (PROMM), is rarer and generally manifests with milder signs and symptoms than DM1.Other forms of myotonic dystrophy not associated with DM1 or DM2 genetic mutations have been described. One case which was proposed as a candidate for the "DM3" label, was later characterized as an unusual form of inclusion body myopathy associated with Pagets disease and frontotemporal dementia.
Genetic testing
Genetic tests, including prenatal testing, are available for both confirmed forms. Molecular testing is considered the gold standard of diagnosis.
Prenatal testing
Testing at pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a DMPK mutation. This can be done at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS) that involves removing a tiny piece of the placenta and analyzing DNA from its cells. It can also be done by amniocentesis after 14 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it and those who are interested in learning more should check with their doctor or genetic counselor.
There is also another procedure called preimplantation diagnosis that allows a couple to have a child that is unaffected by the genetic condition in their family. This procedure is experimental and not widely available. Those interested in learning more about this procedure should check with their doctor or genetic counselor.
Predictive testing
It is possible to test someone who is at risk for developing DM1 before they are showing symptoms to see whether they inherited an expanded trinucleotide repeat. This is called predictive testing. Predictive testing cannot determine the age of onset that someone will begin to have symptoms or the course of the disease. If the child is not having symptoms, the testing is not possible with an exception of emancipated minors as a policy.
Auxiliary testing
Electrodiagnostic testing (EMG and NCS) can detect the electrical signs of myotonia before myotonia becomes noticeable to the affected individual.Muscle biopsy can reveal damage of the muscle, but findings are generally nonspecific and do not greatly aid in diagnosis.
Management
There is currently no cure for or treatment specific to myotonic dystrophy. Management is focused on the complications of the disease, particularly those related to the lungs and heart, which are life-threatening. Complications relating to the cardiopulmonary system account for 70% of deaths due to DM1. Compromised lung function can, in turn, contribute to life-threatening complications during anesthesia and pregnancy.Lung complications are the leading cause of death in DM1, warranting lung function monitoring with pulmonary function tests every 6 months. Central sleep apnea or obstructive sleep apnea may cause excessive daytime sleepiness, and these individuals should undergo a sleep study. Non-invasive ventilation may be offered if there is an abnormality. Otherwise, there is evidence for the use of modafinil as a central nervous system stimulant, although a Cochrane review has described the evidence thus far as inconclusive.Cardiac complications are the second leading cause of death in DM1, and commonly no symptoms are present prior to adverse events. All affected individuals are advised to have an annual or biennial ECG. Pacemaker insertion may be required for individuals with cardiac conduction abnormalities. Improving the quality of life which can be measured using specific questionnaires is also a main objective of the medical care.
Physical activity
There is a lack of high-quality evidence to determine the effectiveness and the safety of physical activities for people who have myotonic dystrophy. Further research is required to determine if combined strength and aerobic training at moderate intensity is safe for people who have neuromuscular diseases, however the combination of aerobic and strength exercises may increase muscle strength. Aerobic exercise via stationary bicycle with an ergometer may be safe and effective in improving fitness in people with DM1. Cardiovascular impairments and myotonic sensitivities to exercise and temperature necessitate close monitoring of people and educating people in self-monitoring during exercise via the Borg scale, heart rate monitors, and other physical exertion measurements.
Orthotics
Muscular weakness of dorsiflexors (dorsiflexion) hinders the ability to clear the floor during the swing phase of gait and people may adopt a steppage gait pattern or ankle-foot-orthotics may be indicated. Factors such as hand function, skin integrity, and comfort must be assessed prior to prescription. Neck braces can also be prescribed for neck muscle weakness.
Mobility aids and adaptive equipment
Upper and lower limb weakness, visual impairments and myotonia may lead to the need for mobility aids and functional adaptive equipment such as buttonhooks and handled sponges for optimal hand function. If assistive devices and home adaptations are needed, physical therapists may refer on to occupational therapist(s) for further assessment.
Prognosis
Life expectancy in non-congenital late-onset or adult onset DM1 is in the early 50s, with pulmonary complications being the leading cause of death, followed by cardiac complications. DM2 life expectancy has yet to be studied.
Epidemiology
The prevalence of DM1 ranges from 5 to 20 per 100,000 (1:20,000–1:5000). Up to 48 per 100,000 (1:2100) of individuals tested positive for the mutation of DM1 in New York, although not all of these individuals would have become symptomatic. Again in New York, premutations for DM1 were found in 191 per 100,000 (1:525). DM2 prevalence is not known, but genetic studies estimate it to be as high as 1:1830. DM affects males and females approximately equally. About 30,000 people in the United States are affected. In most populations, DM1 appears to be more common than DM2. However, recent studies suggest that type 2 may be as common as type 1 among people in Germany and Finland.DM1 is the most common form of myotonic muscular dystrophy diagnosed in children, with a prevalence ranging from 1 per 100,000 in Japan to 3–15 per 100,000 in Europe. The prevalence may be as high as 1 in 500 in regions such as Quebec, possibly due to the founder effect. The incidence of congenital myotonic dystrophy is thought to be about 1:20,000.
History
Myotonic dystrophy was first described by a German physician, Hans Gustav Wilhelm Steinert, who first published a series of 6 cases of the condition in 1909. Isolated case reports of myotonia had been published previously, including reports by Frederick Eustace Batten and Hans Curschmann, and type 1 myotonic dystrophy is therefore sometimes known as Curschmann-Batten-Steinert syndrome. The underlying cause of type 1 myotonic dystrophy was determined in 1992.
Research directions
Altered splicing of the muscle-specific chloride channel 1 (ClC-1) has been shown to cause the myotonic phenotype of DM1 and is reversible in mouse models using Morpholino antisense to modify splicing of ClC-1 mRNA.Some small studies have suggested that imipramine, clomipramine and taurine may be useful in the treatment of myotonia. However, due to the weak evidence and potential side effects such as cardiac arrhythmias, these treatments are rarely used. A recent study in December 2015 showed that a common FDA approved antibiotic, Erythromycin reduced myotonia in mice. Human studies are planned for erythromycin. Erythromycin has been used successfully in patients with gastric issues.
References
External links
Myotonic dystrophy at Curlie |
Monofixation syndrome | Monofixation syndrome (MFS) (also: microtropia or microstrabismus) is an eye condition defined by less-than-perfect binocular vision. It is defined by a small angle deviation with suppression of the deviated eye and the presence of binocular peripheral fusion. That is, MFS implies peripheral fusion without central fusion.
Aside the manifest small-angle deviation ("tropia"), subjects with MFS often also have a large-angle latent deviation (phoria). Their stereoacuity is often in the range of 3000 to 70 arcsecond, and a small central suppression scotoma of 2 to 5 deg.A rare condition, MFS is estimated to affect only 1% of the general population. There are three distinguishable forms of this condition: primary constant, primary decompensating and consecutive MFS. It is believed that primary MFS is a result of a primary sensorial defect, predisposing to anomalous retinal correspondence.Secondary MFS is a frequent outcome of surgical treatment of congenital esotropia. A study of 1981 showed MFS to result in the vast majority of cases if surgical alignment is reached before the age of 24 months and only in a minority of cases if it is reached later.MFS was first described by Marshall Parks.
References
== External links == |
Toxic and nutritional optic neuropathy | Toxic and nutritional optic neuropathy is a group of medical disorders defined by visual impairment due to optic nerve damage secondary to a toxic substance and/or nutritional deficiency. The causes of these disorders are various, but they are linked by shared signs and symptoms, which this article will describe. In several of these disorders, both toxic and nutritional factors play a role, acting synergistically.
Signs and symptoms
Vision loss in toxic and nutritional optic neuropathy is bilateral, symmetric, painless, gradual, and progressive. Dyschromatopsia, a change in color vision, is often the first symptom. Some patients notice that certain colors, particularly red, are less bright or vivid; others have a general loss of color perception. Loss of visual acuity may start with a blur or haze at the point of fixation, followed by a progressive decline. The degree of vision loss can extend to total blindness, but a loss beyond 20/400 is rare, except in the case of methanol ingestion. Peripheral vision is usually spared since the pattern of loss typically involves a central or cecocentral scotoma, a visual field defect at or surrounding the point of fixation. This pattern can be revealed via visual field testing.
Upon examination, the pupils usually demonstrate a normal response to light and near stimulation. In those who are practically blind, the pupils will be dilated with a weak or absent response to light. The optic disc may appear normal, swollen, or hyperemic in early stages. With hyperemia, disc hemorrhages may also be present. Continued damage to the optic nerve results in the development of optic atrophy, classically seen as temporal pallor of the optic disc.
Cause
Toxic optic neuropathy
There are several causes of toxic optic neuropathy. Among these are: ingestion of methanol (wood alcohol), ethylene glycol (automotive antifreeze), disulfiram (used to treat chronic alcoholism), halogenated hydroquinolones (amebicidal medications), ethambutol and isoniazid (tuberculosis treatment), and antibiotics such as linezolid and chloramphenicol as well as chloroquine and the related hydroxychloroquine (for lupus and rheumatoid arthritis) where it is known as chloroquine retinopathy. Tobacco is also a major cause of toxic optic neuropathy.
Nutritional optic neuropathy
The predominant cause of nutritional optic neuropathy is thought to be deficiency of B-complex vitamins, particularly thiamine (vitamin B1), cyanocobalamin (vitamin B12) and recently copper. Deficiency of pyridoxine (vitamin B6), niacin (vitamin B3), riboflavin (vitamin B2), and/or folic acid also seems to play a role. Those individuals who consume excessive amounts of alcohol and use tobacco are at greater risk because they tend to be malnourished. Those with pernicious anemia are also at risk due to an impaired ability to absorb vitamin B12 from the intestinal tract.
Pathophysiology
All of the above risk factors impact mitochondrial oxidative phosphorylation. Thus, the toxic and nutritional optic neuropathies are actually acquired mitochondrial optic neuropathies. The clinical picture that they produce is akin to that of the congenital mitochondrial optic neuropathies, e.g., Lebers hereditary optic neuropathy and Kjers optic neuropathy.
Diagnosis
The diagnosis of toxic or nutritional optic neuropathy is usually established by a detailed medical history and careful eye examination. If the medical history clearly points to a cause, neuroimaging to rule out a compressive or infiltrative lesion is optional. However, if the medical history is atypical or does not clearly point to a cause, neuroimaging is required to rule out other causes and confirm the diagnosis. In most cases of suspected toxic or nutritional optic neuropathy that require neuroimaging, an MRI scan is obtained. Further testing, guided by the medical history and physical examination, can be performed to elucidate a specific toxin or nutritional deficiency as a cause of the optic neuropathy. Examples include blood testing for methanol levels or vitamin B12 levels.
Treatment
Treatment of toxic and nutritional optic neuropathy is dictated by the cause of the disorder.
Toxic optic neuropathy is treated by identification and removal of the offending agent. Depending upon the individual affected, the nature of the agent, total exposure prior to removal, and degree of vision loss at the time of diagnosis, the prognosis is variable.
Nutritional optic neuropathy is treated with improved nutrition. A well-balanced diet with plenty of protein and green leafy vegetables, vitamin supplementation (thiamine, vitamin B12, folic acid, multivitamins), and reduction of smoking and/or drinking are the mainstay of treatment. Again, prognosis is variable and dependent upon the affected individual, treatment compliance, and degree of vision loss at diagnosis.In both toxic and nutritional neuropathy, vision generally recovers to normal over several days to weeks, though it may take months for full restoration and there is always the risk of permanent vision loss. Visual acuity usually recovers before color vision.
Epidemiology
In industrialized nations, toxic and nutritional optic neuropathy is relatively uncommon and is primarily associated with specific medications, occupational exposures, or tobacco and alcohol use disorder. However, in developing nations, nutritional optic neuropathy is much more common, especially in regions afflicted by famine. All genders and all races are equally affected, and all ages are susceptible.
References
Further reading
Glaser, JS (1999). "Nutritional and toxic optic neuropathies". In Glaser, JS (ed.). Neuro-ophthalmology (3rd ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 181–6.
Lessell, S (2000). "Nutritional deficiency and toxic optic neuropathies". In Albert, DM; Jakobiec, FA (eds.). Principles and Practice of Ophthalmology (2nd ed.). Philadelphia: W.B. Saunders Company. pp. 4169–76.
Sadun, A. A (2002). "Mitochondrial optic neuropathies". Journal of Neurology, Neurosurgery, and Psychiatry. 72 (4): 423–5. doi:10.1136/jnnp.72.4.423. PMC 1737836. PMID 11909893.
External links
eMedicine article |
Microspherophakia | Microspherophakia is a rare congenital autosomal recessive condition where the lens of the eye is smaller than normal and spherically shaped. This condition may be associated with a number of disorders including Peters anomaly, Marfan syndrome, and Weill–Marchesani syndrome. The spherical shape is caused by an underdeveloped zonule of Zinn, which doesnt exert enough force on the lens to make it form the usual oval shape. It is a result of a homozygous mutation to the LTBP2 gene.
See also
Ectopia lentis
References
Further reading
Microspherophakia at Online Mendelian Inheritance in Man
== External links == |
Syphilis | Syphilis (/ˈsɪfɪlɪs/) is a sexually transmitted infection caused by the bacterium Treponema pallidum subspecies pallidum. The signs and symptoms of syphilis vary depending in which of the four stages it presents (primary, secondary, latent, and tertiary). The primary stage classically presents with a single chancre (a firm, painless, non-itchy skin ulceration usually between 1 cm and 2 cm in diameter) though there may be multiple sores. In secondary syphilis, a diffuse rash occurs, which frequently involves the palms of the hands and soles of the feet. There may also be sores in the mouth or vagina. In latent syphilis, which can last for years, there are few or no symptoms. In tertiary syphilis, there are gummas (soft, non-cancerous growths), neurological problems, or heart symptoms. Syphilis has been known as "the great imitator" as it may cause symptoms similar to many other diseases.Syphilis is most commonly spread through sexual activity. It may also be transmitted from mother to baby during pregnancy or at birth, resulting in congenital syphilis. Other diseases caused by Treponema bacteria include yaws (T. pallidum subspecies pertenue), pinta (T. carateum), and nonvenereal endemic syphilis (T. pallidum subspecies endemicum). These three diseases are not typically sexually transmitted. Diagnosis is usually made by using blood tests; the bacteria can also be detected using dark field microscopy. The Centers for Disease Control and Prevention (U.S.) recommend all pregnant women be tested.The risk of sexual transmission of syphilis can be reduced by using a latex or polyurethane condom. Syphilis can be effectively treated with antibiotics. The preferred antibiotic for most cases is benzathine benzylpenicillin injected into a muscle. In those who have a severe penicillin allergy, doxycycline or tetracycline may be used. In those with neurosyphilis, intravenous benzylpenicillin or ceftriaxone is recommended. During treatment people may develop fever, headache, and muscle pains, a reaction known as Jarisch–Herxheimer.In 2015, about 45.4 million people had syphilis infections, of which six million were new cases. During 2015, it caused about 107,000 deaths, down from 202,000 in 1990. After decreasing dramatically with the availability of penicillin in the 1940s, rates of infection have increased since the turn of the millennium in many countries, often in combination with human immunodeficiency virus (HIV). This is believed to be partly due to increased promiscuity, prostitution, decreasing use of condoms and unsafe sexual practices among men who have sex with men.
Signs and symptoms
Syphilis can present in one of four different stages: primary, secondary, latent, and tertiary, and may also occur congenitally. It was referred to as "the great imitator" by Sir William Osler due to its varied presentations.
Primary
Primary syphilis is typically acquired by direct sexual contact with the infectious lesions of another person. Approximately 2–6 weeks after contact (with a range of 10–90 days) a skin lesion, called a chancre, appears at the site and this contains infectious spirochetes. This is classically (40% of the time) a single, firm, painless, non-itchy skin ulceration with a clean base and sharp borders approximately 0.3–3.0 cm in size. The lesion may take on almost any form. In the classic form, it evolves from a macule to a papule and finally to an erosion or ulcer. Occasionally, multiple lesions may be present (~40%), with multiple lesions being more common when coinfected with HIV. Lesions may be painful or tender (30%), and they may occur in places other than the genitals (2–7%). The most common location in women is the cervix (44%), the penis in heterosexual men (99%), and anally and rectally in men who have sex with men (34%). Lymph node enlargement frequently (80%) occurs around the area of infection, occurring seven to 10 days after chancre formation. The lesion may persist for three to six weeks if left untreated.
Secondary
Secondary syphilis occurs approximately four to ten weeks after the primary infection. While secondary disease is known for the many different ways it can manifest, symptoms most commonly involve the skin, mucous membranes, and lymph nodes. There may be a symmetrical, reddish-pink, non-itchy rash on the trunk and extremities, including the palms and soles. The rash may become maculopapular or pustular. It may form flat, broad, whitish, wart-like lesions on mucous membranes, known as condyloma latum. All of these lesions harbor bacteria and are infectious. Other symptoms may include fever, sore throat, malaise, weight loss, hair loss, and headache. Rare manifestations include liver inflammation, kidney disease, joint inflammation, periostitis, inflammation of the optic nerve, uveitis, and interstitial keratitis. The acute symptoms usually resolve after three to six weeks; about 25% of people may present with a recurrence of secondary symptoms. Many people who present with secondary syphilis (40–85% of women, 20–65% of men) do not report previously having had the classical chancre of primary syphilis.
Latent
Latent syphilis is defined as having serologic proof of infection without symptoms of disease. It develops after secondary syphilis and is divided into early latent and late latent stages. Early latent syphilis is defined by the World Health Organization as less than 2 years after original infection. Early latent syphilis is infectious as up to 25% of people can develop a recurrent secondary infection (during which spirochetes are actively replicating and are infectious). Two years after the original infection the person will enter late latent syphilis and is not as infectious as the early phase. The latent phase of syphilis can last many years after which, without treatment, approximately 15-40% of people can develop tertiary syphilis.
Tertiary
Tertiary syphilis may occur approximately 3 to 15 years after the initial infection, and may be divided into three different forms: gummatous syphilis (15%), late neurosyphilis (6.5%), and cardiovascular syphilis (10%). Without treatment, a third of infected people develop tertiary disease. People with tertiary syphilis are not infectious.Gummatous syphilis or late benign syphilis usually occurs 1 to 46 years after the initial infection, with an average of 15 years. This stage is characterized by the formation of chronic gummas, which are soft, tumor-like balls of inflammation which may vary considerably in size. They typically affect the skin, bone, and liver, but can occur anywhere.Cardiovascular syphilis usually occurs 10–30 years after the initial infection. The most common complication is syphilitic aortitis, which may result in aortic aneurysm formation.Neurosyphilis refers to an infection involving the central nervous system. Involvement of the central nervous system in syphilis (either asymptomatic or symptomatic) can occur at any stage of the infection. It may occur early, being either asymptomatic or in the form of syphilitic meningitis, or late as meningovascular syphilis, general paresis, or tabes dorsalis.Meningovascular syphilis involves inflammation of the small and medium arteries of the central nervous system. It can present between 1–10 years after the initial infection. Meningovascular syphilis is characterized by stroke, cranial nerve palsies and spinal cord inflammation. Late symptomatic neurosyphilis can develop decades after the original infection and includes 2 types; general paresis and tabes dorsalis. General paresis presents with dementia, personality changes, delusions, seizures, psychosis and depression. Tabes dorsalis is characterized by gait instability, sharp pains in the trunk and limbs, impaired positional sensation of the limbs as well as having a positive Rombergs sign. Both tabes dorsalis and general paresis may present with Argyll Robertson pupil which are pupils that constrict when the person focuses on near objects (accommodation reflex) but do not constrict when exposed to bright light (pupillary reflex).
Congenital
Congenital syphilis is that which is transmitted during pregnancy or during birth. Two-thirds of syphilitic infants are born without symptoms. Common symptoms that develop over the first couple of years of life include enlargement of the liver and spleen (70%), rash (70%), fever (40%), neurosyphilis (20%), and lung inflammation (20%). If untreated, late congenital syphilis may occur in 40%, including saddle nose deformation, Higouménakis sign, saber shin, or Cluttons joints among others. Infection during pregnancy is also associated with miscarriage. The three main dental defects in congenital syphilis are Hutchinsons incisors (screwdriver shaped incisors), Moons molars or bud molars, and Fourniers molars or mulberry molars (molars with abnormal occlusal anatomy resembling a mulberry).
Cause
Bacteriology
Treponema pallidum subspecies pallidum is a spiral-shaped, Gram-negative, highly mobile bacterium. Three other human diseases are caused by related Treponema pallidum subspecies, including yaws (subspecies pertenue), pinta (subspecies carateum) and bejel (subspecies endemicum). Unlike subspecies pallidum, they do not cause neurological disease. Humans are the only known natural reservoir for subspecies pallidum. It is unable to survive more than a few days without a host. This is due to its small genome (1.14Mbp) failing to encode the metabolic pathways necessary to make most of its macronutrients. It has a slow doubling time of greater than 30 hours. The bacterium is known for its ability to evade the immune system and its invasiveness.
Transmission
Syphilis is transmitted primarily by sexual contact or during pregnancy from a mother to her baby; the spirochete is able to pass through intact mucous membranes or compromised skin. It is thus transmissible by kissing near a lesion, as well as oral, vaginal, and anal sex. Approximately 30% to 60% of those exposed to primary or secondary syphilis will get the disease. Its infectivity is exemplified by the fact that an individual inoculated with only 57 organisms has a 50% chance of being infected. Most new cases in the United States (60%) occur in men who have sex with men; and in this population 20% of syphilis cases were due to oral sex alone. Syphilis can be transmitted by blood products, but the risk is low due to screening of donated blood in many countries. The risk of transmission from sharing needles appears to be limited.It is not generally possible to contract syphilis through toilet seats, daily activities, hot tubs, or sharing eating utensils or clothing. This is mainly because the bacteria die very quickly outside of the body, making transmission by objects extremely difficult.
Diagnosis
Syphilis is difficult to diagnose clinically during early infection. Confirmation is either via blood tests or direct visual inspection using dark field microscopy. Blood tests are more commonly used, as they are easier to perform. Diagnostic tests are unable to distinguish between the stages of the disease.
Blood tests
Blood tests are divided into nontreponemal and treponemal tests.Nontreponemal tests are used initially, and include venereal disease research laboratory (VDRL) and rapid plasma reagin (RPR) tests. False positives on the nontreponemal tests can occur with some viral infections, such as varicella (chickenpox) and measles. False positives can also occur with lymphoma, tuberculosis, malaria, endocarditis, connective tissue disease, and pregnancy.Because of the possibility of false positives with nontreponemal tests, confirmation is required with a treponemal test, such as treponemal pallidum particle agglutination (TPHA) or fluorescent treponemal antibody absorption test (FTA-Abs). Treponemal antibody tests usually become positive two to five weeks after the initial infection. Neurosyphilis is diagnosed by finding high numbers of leukocytes (predominately lymphocytes) and high protein levels in the cerebrospinal fluid in the setting of a known syphilis infection.
Direct testing
Dark field microscopy of serous fluid from a chancre may be used to make an immediate diagnosis. Hospitals do not always have equipment or experienced staff members, and testing must be done within 10 minutes of acquiring the sample. Two other tests can be carried out on a sample from the chancre: direct fluorescent antibody (DFA) and polymerase chain reaction (PCR) tests. DFA uses antibodies tagged with fluorescein, which attach to specific syphilis proteins, while PCR uses techniques to detect the presence of specific syphilis genes. These tests are not as time-sensitive, as they do not require living bacteria to make the diagnosis.
Prevention
Vaccine
As of 2018, there is no vaccine effective for prevention. Several vaccines based on treponemal proteins reduce lesion development in an animal model but research continues.
Sex
Condom use reduces the likelihood of transmission during sex, but does not eliminate the risk. The Centers for Disease Control and Prevention (CDC) states, "Correct and consistent use of latex condoms can reduce the risk of syphilis only when the infected area or site of potential exposure is protected. However, a syphilis sore outside of the area covered by a latex condom can still allow transmission, so caution should be exercised even when using a condom."Abstinence from intimate physical contact with an infected person is effective at reducing the transmission of syphilis. The CDC states, "The surest way to avoid transmission of sexually transmitted diseases, including syphilis, is to abstain from sexual contact or to be in a long-term mutually monogamous relationship with a partner who has been tested and is known to be uninfected."
Congenital disease
Congenital syphilis in the newborn can be prevented by screening mothers during early pregnancy and treating those who are infected. The United States Preventive Services Task Force (USPSTF) strongly recommends universal screening of all pregnant women, while the World Health Organization (WHO) recommends all women be tested at their first antenatal visit and again in the third trimester. If they are positive, it is recommended their partners also be treated. Congenital syphilis is still common in the developing world, as many women do not receive antenatal care at all, and the antenatal care others receive does not include screening. It still occasionally occurs in the developed world, as those most likely to acquire syphilis are least likely to receive care during pregnancy. Several measures to increase access to testing appear effective at reducing rates of congenital syphilis in low- to middle-income countries. Point-of-care testing to detect syphilis appeared to be reliable although more research is needed to assess its effectiveness and into improving outcomes in mothers and babies.
Screening
The CDC recommends that sexually active men who have sex with men be tested at least yearly. The USPSTF also recommends screening among those at high risk.Syphilis is a notifiable disease in many countries, including Canada, the European Union, and the United States. This means health care providers are required to notify public health authorities, which will then ideally provide partner notification to the persons partners. Physicians may also encourage patients to send their partners to seek care. Several strategies have been found to improve follow-up for STI testing, including email and text messaging of reminders for appointments.
Treatment
As a form of chemotherapy, elemental mercury was frequently used to treat syphilis in Europe very early on in the epidemic, and in this respect was rather effective. Mercury is highly anti-microbial, and in the early stages of infection was sometimes sufficient in halting development of the disease when applied to cankers or other wounds. Once the bacterium gained a strong foothold, however, the amounts and forms of mercury necessary to control its development exceeded the human ability to endure this extremely toxic metal, and the treatment became worse and more lethal than the disease. Medically directed mercury poisoning also became widespread, and thousands died in desperate attempts to rid themselves of the excruciating, disfiguring, and humiliating illness.
Early infections
The first-line treatment for uncomplicated syphilis (primary or secondary stages) remains a single dose of intramuscular benzathine benzylpenicillin. Doxycycline and tetracycline are alternative choices for those allergic to penicillin; due to the risk of birth defects, these are not recommended for pregnant women. Resistance to macrolides, rifampicin, and clindamycin is often present. Ceftriaxone, a third-generation cephalosporin antibiotic, may be as effective as penicillin-based treatment. It is recommended that a treated person avoid sex until the sores are healed.
Late infections
For neurosyphilis, due to the poor penetration of benzathine penicillin into the central nervous system, those affected are given large doses of intravenous penicillin G for a minimum of 10 days. If a person is allergic to penicillin, ceftriaxone may be used or penicillin desensitization attempted. Other late presentations may be treated with once-weekly intramuscular benzathine penicillin for three weeks. Treatment at this stage solely limits further progression of the disease and has a limited effect on damage which has already occurred. Serologic cure can be measured when the non-treponemal titers decline by a factor of 4 or more in 6–12 months in early syphilis or 12–24 months in late syphilis.
Jarisch–Herxheimer reaction
One of the potential side effects of treatment is the Jarisch–Herxheimer reaction. It frequently starts within one hour and lasts for 24 hours, with symptoms of fever, muscle pains, headache, and a fast heart rate. It is caused by cytokines released by the immune system in response to lipoproteins released from rupturing syphilis bacteria.
Pregnancy
Penicillin is an effective treatment for syphilis in pregnancy but there is no agreement on which dose or route of delivery is most effective.
Epidemiology
In 2012, about 0.5% of adults were infected with syphilis, with 6 million new cases. In 1999, it is believed to have infected 12 million additional people, with greater than 90% of cases in the developing world. It affects between 700,000 and 1.6 million pregnancies a year, resulting in spontaneous abortions, stillbirths, and congenital syphilis. During 2015, it caused about 107,000 deaths, down from 202,000 in 1990. In sub-Saharan Africa, syphilis contributes to approximately 20% of perinatal deaths. Rates are proportionally higher among intravenous drug users, those who are infected with HIV, and men who have sex with men. In the United States about 55,400 people are newly infected each year. In the United States as of 2020, rates of syphilis have increased by more than threefold; in 2018 approximately 86% of all cases of syphilis in the United States were in men. African Americans accounted for almost half of all cases in 2010. As of 2014, syphilis infections continue to increase in the United States.Syphilis was very common in Europe during the 18th and 19th centuries. Flaubert found it universal among nineteenth-century Egyptian prostitutes. In the developed world during the early 20th century, infections declined rapidly with the widespread use of antibiotics, until the 1980s and 1990s. Since 2000, rates of syphilis have been increasing in the US, Canada, the UK, Australia and Europe, primarily among men who have sex with men. Rates of syphilis among US women have remained stable during this time, while rates among UK women have increased, but at a rate less than that of men. Increased rates among heterosexuals have occurred in China and Russia since the 1990s. This has been attributed to unsafe sexual practices, such as sexual promiscuity, prostitution, and decreasing use of barrier protection.Left untreated, it has a mortality rate of 8% to 58%, with a greater death rate among males. The symptoms of syphilis have become less severe over the 19th and 20th centuries, in part due to widespread availability of effective treatment, and partly due to virulence of the bacteria. With early treatment, few complications result. Syphilis increases the risk of HIV transmission by two to five times, and coinfection is common (30–60% in some urban centers). In 2015, Cuba became the first country to eliminate mother-to-child transmission of syphilis.
History
The origin of syphilis is disputed. Syphilis was present in the Americas before European contact, and it may have been carried from the Americas to Europe by the returning crewmen from Christopher Columbuss voyage to the Americas, or it may have existed in Europe previously but gone unrecognized until shortly after Columbuss return. These are the Columbian and pre-Columbian hypotheses, respectively. The Columbian hypothesis is better supported by the evidence and findings from phylogenetic science suggest that it is, in fact, a New World disease.The timing of the arrival of syphilis in Europe certainly supports the above theory, Columbus having journeyed in 1492. The first written records of an outbreak of syphilis in Europe occurred in 1494 or 1495 in Naples, Italy, during a French invasion (Italian War of 1494–98). Since it was claimed to have been spread by French troops, it was initially called the "French disease" by the people of Naples. The disease reached London in 1497 and was recorded at St Batholomews Hospital as infected 10 out of the 20 patients. In 1530, the pastoral name "syphilis" (the name of a character) was first used by the Italian physician and poet Girolamo Fracastoro as the title of his Latin poem in dactylic hexameter Syphilis sive morbus gallicus (Syphilis or The French Disease) describing the ravages of the disease in Italy. In Great Britain it was also called the "Great Pox".In the 16th through 19th centuries, syphilis was one of the largest public health burdens in prevalence, symptoms, and disability,: 208–209 although records of its true prevalence were generally not kept because of the fearsome and sordid status of sexually transmitted infections in those centuries.: 208–209 According to a 2020 study, more than 20% of individuals in the age range 15–34 years in late 18th century London were treated for syphilis. At the time the causative agent was unknown but it was well known that it was spread sexually and also often from mother to child. Its association with sex, especially sexual promiscuity and prostitution, made it an object of fear and revulsion and a taboo. The magnitude of its morbidity and mortality in those centuries reflected that, unlike today, there was no adequate understanding of its pathogenesis and no truly effective treatments. Its damage was caused not so much by great sickness or death early in the course of the disease but rather by its gruesome effects decades after infection as it progressed to neurosyphilis with tabes dorsalis. Mercury compounds and isolation were commonly used, with treatments often worse than the disease.There is some evidence to suggest that syphilis was a common childhood skin disease in the Old World, and did not originate in the New World. According to this hypothesis, syphilis was a mostly benign infection like chicken pox which for thousands of years had been common among the young who transmitted the disease among themselves—and as adults, they gained immunity and could not be reinfected. Once living conditions in Europe began to change and certain social classes began to practice greater hygiene, syphilis was driven out of the age group in which it was harmless. It then began to appear in adults who were unable to fend off the infection because they had never been exposed as children, and they readily spread it via sexual contact to other adults who also had limited or no resistance, causing deformity and death where before it had been only been a temporary childhood ailment. This transition is reported to have coincided temporally with the return of the Columbus expedition from the New World. The most compelling evidence for its validity is the presence of syphilitic-like damage to bones in a number of adult skeletons found in the British city of Hull who were buried over a century before Columbus made his journey to the Americas.More recent analysis of that research, however, concluded in 2012 that syphilis almost certainly had a New World origin.The causative organism, Treponema pallidum, was first identified by Fritz Schaudinn and Erich Hoffmann, in 1905. The first effective treatment for syphilis was arsphenamine, discovered by Sahachiro Hata in 1909, during a survey of hundreds of newly synthesized organic arsenical compounds led by Paul Ehrlich. It was manufactured and marketed from 1910 under the trade name Salvarsan by Hoechst AG. This organoarsenic compound was the first modern chemotherapeutic agent.
During the 20th century, as both microbiology and pharmacology advanced greatly, syphilis, like many other infectious diseases, became more of a manageable burden than a scary and disfiguring mystery, at least in developed countries among those people who could afford to pay for timely diagnosis and treatment. Penicillin was discovered in 1928, and effectiveness of treatment with penicillin was confirmed in trials in 1943, at which time it became the main treatment.Many famous historical figures, including Franz Schubert, Arthur Schopenhauer, Édouard Manet, Charles Baudelaire, and Guy de Maupassant are believed to have had the disease. Friedrich Nietzsche was long believed to have gone mad as a result of tertiary syphilis, but that diagnosis has recently come into question.
Arts and literature
The earliest known depiction of an individual with syphilis is Albrecht Dürers Syphilitic Man, a woodcut believed to represent a Landsknecht, a Northern European mercenary. The myth of the femme fatale or "poison women" of the 19th century is believed to be partly derived from the devastation of syphilis, with classic examples in literature including John Keats "La Belle Dame sans Merci".The Flemish artist Stradanus designed a print called Preparation and Use of Guayaco for Treating Syphilis, a scene of a wealthy man receiving treatment for syphilis with the tropical wood guaiacum sometime around 1590.
Tuskegee and Guatemala studies
The "Tuskegee Study of Untreated Syphilis in the Negro Male" was an infamous, unethical and racist clinical study conducted between 1932 and 1972 by the U.S. Public Health Service. Whereas the purpose of this study was to observe the natural history of untreated syphilis; the African-American men in the study were told they were receiving free treatment for "bad blood" from the United States government.The Public Health Service started working on this study in 1932 in collaboration with Tuskegee University, a historically black college in Alabama. Researchers enrolled 600 poor, African-American sharecroppers from Macon County, Alabama in the study. Of these men, 399 had contracted syphilis before the study began, and 201 did not have the disease. Medical care, hot meals and free burial insurance were given to those who participated. The men were told that the study would last six months, but in the end it continued for 40 years. After funding |
Syphilis | for treatment was lost, the study was continued without informing the men that they were only being studied and would not be treated. Facing insufficient participation, the Macon County Health Department nevertheless wrote to subjects to offer them a "last chance" to get a special "treatment", which was not a treatment at all, but a spinal tap administered exclusively for diagnostic purposes. None of the men infected were ever told that they had the disease, and none were treated with penicillin even after the antibiotic had been proven to successfully treat syphilis. According to the Centers for Disease Control, the men were told they were being treated for "bad blood"—a colloquialism describing various conditions such as fatigue, anemia and syphilis—which was a leading cause of death among southern African-American men.The 40-year study became a textbook example of poor medical ethics because researchers had knowingly withheld treatment with penicillin and because the subjects had been misled concerning the purposes of the study. The revelation in 1972 of these study failures by a whistleblower, Peter Buxtun, led to major changes in U.S. law and regulation on the protection of participants in clinical studies. Now studies require informed consent, communication of diagnosis, and accurate reporting of test results.
Similar experiments were carried out in Guatemala from 1946 to 1948. It was done during the administration of American President Harry S. Truman and Guatemalan President Juan José Arévalo with the cooperation of some Guatemalan health ministries and officials. Doctors infected soldiers, prostitutes, prisoners and mental patients with syphilis and other sexually transmitted infections, without the informed consent of the subjects, and treated most subjects with antibiotics. The experiment resulted in at least 83 deaths. In October 2010, the U.S. formally apologized to Guatemala for the ethical violations that took place. Secretary of State Hillary Clinton and Health and Human Services Secretary Kathleen Sebelius stated "Although these events occurred more than 64 years ago, we are outraged that such reprehensible research could have occurred under the guise of public health. We deeply regret that it happened, and we apologize to all the individuals who were affected by such abhorrent research practices." The experiments were led by physician John Charles Cutler who also participated in the late stages of the Tuskegee syphilis experiment.
Names
It was first called grande verole or the "great pox" by the French. Other historical names have included "button scurvy", sibbens, frenga and dichuchwa, among others. Since it was a disgraceful disease, the disease was known in several countries by the name of their neighbouring country. The English, the Germans, and the Italians called it "the French disease", while the French referred to it as the "Neapolitan disease". The Dutch called it the "Spanish/Castilian disease". To the Turks it was known as the "Christian disease", whilst in India, the Hindus and Muslims named the disease after each other.
References
Further reading
Ghanem KG, Ram S, Rice PA (February 2020). "The Modern Epidemic of Syphilis". N. Engl. J. Med. 382 (9): 845–54. doi:10.1056/NEJMra1901593. PMID 32101666. S2CID 211537893.
Ropper AH (October 2019). "Neurosyphilis". N. Engl. J. Med. 381 (14): 1358–63. doi:10.1056/NEJMra1906228. PMID 31577877. S2CID 242487360.
External links
"Syphilis - CDC Fact Sheet" Centers for Disease Control and Prevention (CDC)
UCSF HIV InSite Knowledge Base Chapter: Syphilis and HIV Archived 20 January 2013 at the Wayback Machine
Recommendations for Public Health Surveillance of Syphilis in the United States
Pastuszczak, M.; Wojas-Pelc, A. (2013). "Current standards for diagnosis and treatment of syphilis: Selection of some practical issues, based on the European (IUSTI) and U.S. (CDC) guidelines". Advances in Dermatology and Allergology. 30 (4): 203–210. doi:10.5114/pdia.2013.37029. PMC 3834708. PMID 24278076. |
Lymphomatoid granulomatosis | Lymphomatoid granulomatosis (LYG or LG) is a very rare lymphoproliferative disorder first characterized in 1972. Lymphomatoid means lymphoma-like and granulomatosis denotes the microscopic characteristic of the presence of granulomas with polymorphic lymphoid infiltrates and focal necrosis within it.
LG most commonly affects middle aged people, but has occasionally been observed in young people. Males are found to be affected twice as often as females.
Causes
Lymphomatoid granulomatosis involves malignant B cells and reactive, non-malignant T cells and is almost always associated with infection of the malignant B cells by the Epstein-Barr virus; it is therefore considered to be a form of the Epstein-Barr virus-associated lymphoproliferative diseases. The disease is believed to be induced by a combination of Epstein Barr virus infection and immunosuppression through immunosuppressive drugs (with case reports of methotrexate and azathioprine), infections such as HIV or chronic viral hepatitis or endogenous T cell defects.
Pathophysiology
The onset of the disease results in proliferation of EBV-infected malignant B-cells and a cytotoxic T-cell response which in turn leads to organ infiltration and dysfunction of the affected organs. The disease typically always relapse after successful treatment due to inability of the immune system and current viral drugs to eliminate an EBV-infection. If the onset of the disease can be linked to use of immunosuppressive drugs then discontinuation of these drugs may hinder a relapse. Organs usually affected are the skin, lungs, central nervous system while liver and kidney are affected to lesser extent. The pulmonary complications are usually what leads to death, however, CNS involvement that affects up to one third of the patients can be very severe with mental status changes, ataxia, hemiparesis, seizures, unconsciousness and death, typically followed in that order.The disease has been seen to transform to diffuse large B-cell lymphoma and while LG is graded I-III based on the number of large EBV-positive B-cells, grade II and III can be considered as a variant of T-cell rich diffuse large B-cell lymphoma.
Treatment
Treatment depends on the grade (I-III) but typically consist of cortisone, rituximab and chemotherapy (etoposide, vincristine, cyclophosphamide, doxorubicin). Methotrexate has been seen to induce LG. Interferon alpha has been used by the US National Cancer Institute with varying results. In recent years hematopoietic stem cell transplantation has been performed on LG-patients with relative good success; a 2013 study identifying 10 cases found that 8 patients survived the treatment and were disease free several years later. Two of the disease free patients later died, one from suicide and one from graft versus host disease after a second transplantation 4 years later. The remaining two patients died from sepsis after the transplantation.
Prognosis
The current mortality is over 60% after 5 years. However, due to hematopoietic stem cell transplantation being performed only in recent years, this number could potentially be lowered in the future. In people with CNS involvement, treatment with Interferon alpha at the US National Cancer Institute resulted in complete remission in 90% of patients.
See also
List of cutaneous conditions
References
== External links == |
Acute interstitial pneumonitis | Acute interstitial pneumonitis is a rare, severe lung disease that usually affects otherwise healthy individuals. There is no known cause or cure.
Acute interstitial pneumonitis is often categorized as both an interstitial lung disease and a form of acute respiratory distress syndrome (ARDS) but it is distinguished from the chronic forms of interstitial pneumonia such as idiopathic pulmonary fibrosis.
Symptoms and signs
The most common symptoms of acute interstitial pneumonitis are highly productive cough with expectoration of thick mucus, fever, and difficulties breathing. These often occur over a period of one to two weeks before medical attention is sought. The presence of fluid means the person experiences a feeling similar to drowning. Difficulties breathing can quickly progress to an inability to breathe without support (respiratory failure).Acute interstitial pneumonitis typically progresses rapidly, with hospitalization and mechanical ventilation often required only days to weeks after initial symptoms of cough, fever, and difficulties breathing develop.
Diagnosis
Rapid progression from initial symptoms to respiratory failure is a key feature. An X-ray that shows ARDS is necessary for diagnosis (fluid in the small air sacs (alveoli) in both lungs). In addition, a biopsy of the lung that shows organizing diffuse alveolar damage is required for diagnosis. This type of alveolar damage can be attributed to nonconcentrated and nonlocalized alveoli damage, marked alveolar septal edema with inflammatory cell infiltration, fibroblast proliferation, occasional hyaline membranes, and thickening of the alveolar walls. The septa are lined with atypical, hyperplastic type II pneumocytes, thus leading to the collapse of airspaces. Other diagnostic tests are useful in excluding other similar conditions, but history, X-ray, and biopsy are essential. These other tests may include basic blood work, blood cultures, and bronchoalveolar lavage.
The clinical picture is similar to ARDS, but AIP differs from ARDS in that the cause for AIP is not known.
Treatment
Treatment is primarily supportive. Management in an intensive care unit is required and the need for mechanical ventilation is common. Therapy with corticosteroids is generally attempted, though their usefulness has not been established. The only treatment that has met with success to date is a lung transplant.
Prognosis
Sixty percent of people with acute interstitial pneumonitis will die in the first six months of illness. The median survival is 1+1⁄2 months. However, most people who have one episode do not have a second. People who survive often recover lung function completely.
Epidemiology
Acute interstitial pneumonitis occurs most frequently among people older than forty years old. It affects men and women equally. There are no known risk factors; in particular, smoking is not associated with increased risk.
History
Acute interstitial pneumonitis was first described in 1935 by Louis Hamman and Arnold Rich, and given the name Hamman–Rich syndrome.
References
External links
synd/3010 at Who Named It?
00181 at CHORUS |
Exophoria | Exophoria is a form of heterophoria in which there is a tendency of the eyes to deviate outward. During examination, when the eyes are dissociated, the visual axes will appear to diverge away from one another.The axis deviation in exophoria is usually mild compared with that of exotropia.
Cause
Exophoria can be caused by several factors, which include:
Refractive errors - distance and near deviation approximately equal.
Divergence excess - exodeviation is more than 15 dioptres greater for distance than near deviation.
Convergence insufficiency - near exodeviation greater than distance deviation.These can be due to nerve, muscle, or congenital problems, or due to mechanical anomalies. Unlike exotropia, fusion is possible in this condition, causing diplopia to be uncommon.
Diagnosis
Prevalence
Exophoria is particularly common in infancy and childhood, and increases with age.
References
== External links == |
Genetics of obesity | Like many other medical conditions, obesity is the result of an interplay between environmental and genetic factors. Studies have identified variants in several genes that may contribute to weight gain and body fat distribution; although, only in a few cases are genes the primary cause of obesity.Polymorphisms in various genes controlling appetite and metabolism predispose to obesity under certain dietary conditions. The percentage of obesity that can be attributed to genetics varies widely, depending on the population examined, from 6% to 85%, with the typical estimate at 50%. It is likely that in each person a number of genes contribute to the likelihood of developing obesity in small part, with each gene increasing or decreasing the odds marginally, and together determining how an individual responds to the environmental factors. As of 2006, more than 41 sites on the human genome have been linked to the development of obesity when a favorable environment is present. Some of these obesogenic or leptogenic genes may influence the obese individuals response to weight loss or weight management.
Genes
Although genetic deficiencies are currently considered rare, variations in these genes may predispose to common obesity. Many candidate genes are highly expressed in the central nervous system.Several additional loci have been identified. Also, several quantitative trait loci for BMI have been identified.
Confirmed and hypothesized associations include:
Some studies have focused upon inheritance patterns without focusing upon specific genes. One study found that 80% of the offspring of two obese parents were obese, in contrast to less than 10% of the offspring of two parents who were of normal weight.The thrifty gene hypothesis postulates that due to dietary scarcity during human evolution people are prone to obesity. Their ability to take advantage of rare periods of abundance by storing energy as fat would be advantageous during times of varying food availability, and individuals with greater adipose reserves would more likely survive famine. This tendency to store fat, however, would be maladaptive in societies with stable food supplies. This is the presumed reason that Pima Native Americans, who evolved in a desert ecosystem, developed some of the highest rates of obesity when exposed to a Western lifestyle.Numerous studies of laboratory rodents provide strong evidence that genetics play an important role in obesity.The risk of obesity is determined by not only specific genotypes but also gene-gene interactions. However, there are still challenges associated with detecting gene-gene interactions for obesity.
Genes protective against obesity
There are also genes that can be protective against obesity. For instance, in GPR75 variants were identified as such alleles in ~640,000 sequenced exomes which may be relevant to e.g. therapeutic strategies against obesity. Other candidate anti-obesity-related genes include ALK, TBC1D1, and SRA1.
Genetic syndromes
The term "non-syndromic obesity" is sometimes used to exclude these conditions. In people with early-onset severe obesity (defined by an onset before 10 years of age and body mass index over three standard deviations above normal), 7% harbor a single locus mutation.
See also
New World Syndrome
Nutritional genomicsRelated:
Human genetic variation
== References == |
Pulmonary capillary hemangiomatosis | Pulmonary capillary hemangiomatosis (PCH) is a disease affecting the blood vessels of the lungs, where abnormal capillary proliferation and venous fibrous intimal thickening result in progressive increase in vascular resistance. It is a rare cause of pulmonary hypertension, and occurs predominantly in young adults. Together with pulmonary veno-occlusive disease, PCH comprises WHO Group I causes for pulmonary hypertension. Indeed, there is some evidence to suggest that PCH and pulmonary veno-occlusive disease are different forms of a similar disease process.
Presentation
These are non specific. Typical symptoms include dyspnea, cough, chest pain and fatigue.
Genetics
At least some cases appear to be due to mutations in the eukaryotic translation initiation factor 2-alpha kinase 4 (EIF2AK4) gene.
Diagnosis
Lung biopsy is essential to make this diagnosis. This can be difficult if the pulmonary pressure is high.
Investigations
Chest X ray may show enlargement of the heart and ill-defined patchy lesions in the lung fields.
CT chest typically shows wide spread ill-defined centrilobular nodules of ground glass opacity. This is a nonspecific finding and may be seen in a number of pulmonary diseases.
CT pulmonary angiography usually shows enlargement of the main pulmonary artery.
When measured by echocardiography or pulmonary angiography, the pulmonary arterial pressure is typically elevated.
Differential diagnosis
Pulmonary veno-occlusive disease
Associations
This condition has been reported in patients with Ehlers Danlos syndrome, CREST syndrome and scimitar syndrome.
Treatment
The only definitive treatment for this condition currently is lung transplantation.
Median survival without treatment is 3 years.Imatinib may be of use.Epoprostenol does not appear to be of use.
Epidemiology
The prevalence of this disease is estimated to be < 1/million.The usual age at presentation is between 20 and 40 but it has been reported in the newborn.
History
This condition was first described in 1978.
Animals
This condition has been reported in cats. and dogs.
References
== External links == |
Ocular rosacea | Ocular rosacea is a manifestation of rosacea that affects the eyes and eyelids. Signs and symptoms generally consist of redness, irritation or burning of the eyes. Affected individuals may also feel that there is something, such as an eyelash, in the eye and frequently have redness of the nose and cheeks as well.
Those who have ocular rosacea may be treated with warm compresses, artificial tears and washing the area around the eye with warm water, including the eyelids, to help relieve symptoms. Additionally, oral antibiotics, typically doxycycline, may be prescribed. Some people with ocular rosacea feel that dietary restrictions of caffeine, spicy foods, and alcoholic beverages may reduce or eliminate symptoms.
Ocular rosacea may be caused by an overproliferation of the Demodex mites D. folliculorum and D. brevis, both frequently referred to as "eyelash mites".
Notes
Kunimoto, Derek Y, et al. The Wills Eye Manual, 4th ed. Lippincott, Philadelphia.2004.
References
External links
emedicine |
Claudes syndrome | Claudes syndrome is a form of brainstem stroke syndrome characterized by the presence of an ipsilateral oculomotor nerve palsy, contralateral hemiparesis, contralateral ataxia, and contralateral hemiplegia of the lower face, tongue, and shoulder.
Claudes syndrome affects oculomotor nerve, red nucleus and brachium conjunctivum.
Cause
Claudes syndrome is caused by midbrain infarction as a result of occlusion of a branch of the posterior cerebral artery. This lesion is usually a unilateral infarction of the red nucleus and cerebellar peduncle, affecting several structures in the midbrain including:
It is very similar to Benedikts syndrome.
Other causes
It has been reported that posterior cerebral artery stenosis can also precipitate Claudes syndrome.
Diagnosis
History
It carries the name of Henri Charles Jules Claude, a French psychiatrist and neurologist, who described the condition in 1912.
See also
Wallenbergs syndrome
Moritz Benedikt
References
== External links == |
Plasma cell dyscrasias | Plasma cell dyscrasias (also termed plasma cell disorders and plasma cell proliferative diseases) are a spectrum of progressively more severe monoclonal gammopathies in which a clone or multiple clones of pre-malignant or malignant plasma cells (sometimes in association with lymphoplasmacytoid cells or B lymphocytes) over-produce and secrete into the blood stream a myeloma protein, i.e. an abnormal monoclonal antibody or portion thereof. The exception to this rule is the disorder termed non-secretory multiple myeloma; this disorder is a form of plasma cell dyscrasia in which no myeloma protein is detected in serum or urine (at least as determined by conventional laboratory methods) of individuals who have clear evidence of an increase in clonal bone marrow plasma cells and/or evidence of clonal plasma cell-mediated tissue injury (e.g. plasmacytoma tumors). Here, a clone of plasma cells refers to group of plasma cells that are abnormal in that they have an identical genetic identity and therefore are descendants of a single genetically distinct ancestor cell.
At one end of this spectrum of hematological disorders, detection of one of these myeloma proteins in an individuals blood or urine is due to a common and clinically silent disorder termed MGUS, i.e. monoclonal gammopathy of undetermined significance. At the other end of this spectrum, detection of the myeloid protein is due to a hematological malignancy, i.e. multiple myeloma, Waldenström macroglobulinemia, or other B cell-associated neoplasm, that has developed, often in a stepwise manner, from their MGUS precursors.The clinical importance of understanding this spectrum of diseases is that it can be used to: a) advise individuals on the likelihood of their condition progressing to a malignant phase; b) monitor individuals for the many complications that may occur at any stage of the dyscrasias so that they can be treated to avoid or reduce their clinical impacts; and c) monitor patients for transitions to malignancy so that the malignancy can be treated at an early stage when treatment results are best. Unless otherwise noted, the advice and monitoring given here are those recommended by the International Myeloma Working Group in 2014 and updated in 2016.
Clonal plasma cells
Plasma cells are key effector elements of the adaptive immune system. They contribute to immunity by making antibodies that bind with and thereby initiate the process of neutralizing specific antigens that usually are found on the surface of invading pathogens and foreign substances. Plasma cells develop from B lymphocytes (i.e. B cells) which are stimulated to undergo this maturational development by T lymphocytes during the latter cells processing of these antigens. As they are stimulated to become plasma cells, B cells refashion parts of their genome in efforts to create a new gene that encodes a functional antibody. In humans, antibodies are composed of two identical heavy chains which are of the gamma (γ), alpha (α), epsilon (ε), delta (δ), or mu (μ) subtypes and two identical light chains which are of the kappa (κ) or lambda (λ) subtypes. Antibodies are classified as IgG, IgA, IgE, IgD, and IgM based on their being made up of γ, α, ε, δ, or μ heavy chains, respectively. Formation of the genes that make these antibodies requires B cells and/or their descendent plasma cells to mutate, break, and recombine various genes at the immunoglobulin heavy chain antigen-binding locus on the long (i.e. "q") arm of human chromosome 14 at position 32.33 (notated as 14q32.33) and the immunoglobulin light chain antigen binding locus on the q arm of chromosome 22 at position 11.2 (i.e. 22 q11.2) by processes termed V(D)J recombination, somatic hypermutation, and immunoglobulin class switching. These genomic changes can go awry by placing a gene that controls cell growth an/or survival adjacent to a normally highly active antibody gene promoter and/or by causing the formation of extra chromosomes (see trisomy) or chromosomes with large deletions that result in the overexpression or under-expression, respectively, of genes that control cell growth and/or survival. In consequence of these "primary genomic changes", an expanding clone of cells develops; overproduces and secretes a monoclonal IgM, IgG, IgA, IgE, or IgD antibody, a κ or λ light chain, an α, γ, or μ heavy chain, or, very rarely, fragments of these proteins; and may accumulate "secondary genomic changes" that cause them to become malignant. The overproduced monoclonal proteins, termed myeloma proteins, commonly circulate in blood, may accumulate in urine, and are the hallmarks of plasma cell dyscrasias including their most malignant forms viz., multiple myeloma, light chain multiple myeloma, and plasma cell leukemia. IgG-secretory, IgA-secretory, and light-chain secretory multiple myeloma represent 52%, 21%, and 16%, respectively, of all multiple myeloma cases; these myelomas are associated with various types of chromosomal aberrancies and mutations. IgD-secretory multiple myeloma occurs in only 1% to 2% of multiple myeloma cases and is commonly associated with somatic mutations in the gene encoding the gV (i.e. variable) region of the monoclonal antibody. IgE-secretory multiple myeloma has been reported in <50 cases as of 2013 and is characteristically associated with translocations between the q arms of chromosome 11 and 14, i.e. t(11;14)(q13;q32) translocations.In other cases, plasma cells and/or lymphoplasmacytoid cells (a type of B cell resembling, and possible precursor to, plasma cells) suffer other kinds of mutations that lead to the production of an IgM myeloma protein. Overproduction of this myeloma protein may progress to a different form of plasma cell/lymphoplasmacytoid cell malignancy, Waldenström macroglobulinaemia. Genetic mutations thought to be involved in the development and/or progression of the latter disease include the L265P mutation in the MYD88 gene found in >90% of Waldenström macroglobulinaemia patients as well as various mutations in the CXCR gene found in 27% to 40% of Waldenström macroglobulinaemia patients.The clonal plasma cells involved in plasma cell dyscrasias exhibit a high degree of genetic instability. For example, the clonal plasma cell population formed by initial genetic alterations that lead to multiple myeloma contains cells that develop further genetic changes that enhance their survival, proliferation, tissue-injuring, and metastatic capacities. This allows the new cell clones to crowd out older cell clones and thereby establish a more malignant disease. Repetition of such genetic changes underlie the evolution of a clinically silent plasma cell dyscrasia to an overt malignancy. The progressive genetic changes in clonal plasma cells include accumulating numerous single nucleotide polymorphisms, increases and decreases in gene and chromosome copy numbers, and chromosomal translocations. Genes affected include those regulating genome stability itself (e.g. KIF2B) as well as cellular activation, proliferation, and apoptosis (e.g. CIDEC, TP52, ATM, KRAS, NRAS, Wnt, and NF-κB). In the most malignant form of plasma cell dyscrasias, primary plasma cell leukemia, the plasma cell population contains >1900 distinct DNA alterations in >600 genes.In general, the plasma cell dyscrasias are defined by 1) the presence of these genetically unstable clonal plasma cells, lymphoplasmacytoid cells, or B cells infiltrating the bone marrow or forming distinct masses in bone, and/or other tissues as defined by biopsy of involved tissues and 2) the presence of these cells myeloma proteins (i.e. intact monoclonal antibody, free light chain, free heavy chain, shortened version of these proteins, or any combination of these proteins) in blood and/or urine as defined by various types of gel electrophoresis. Obviously, the latter criterion does not apply to the rare cases of true non-secretory myeloma.
Myeloma protein toxicity
Myeloma proteins form as a result of gene mutations rather than physiological gene remodeling responses to an instigating foreign antigen: typically these proteins are non-functional. However, they sometimes cause serious tissue damage with the kidney being a particularly vulnerable target. The toxic effects of monoclonal proteins may occur at early stages in the plasma cell dyscrasia spectrum and require treatment independently of the mass or tissue-destructive effects of the myeloma protein-producing cells. Myeloma protein toxicities include:
Monoclonal free light chains, free heavy chains, or a mixture of these chains can deposit in the kidney and other organs to cause systemic monoclonal immunoglobulin deposition disease; free κ or λ light chains can deposit selectively in the kidneys proximal tubule to cause light chain proximal tubulopathy or in the kidneys distal tubule to cause light chain myeloma cast nephropathy; and various myeloma proteins can deposit selectively in the kidneys glomeruli to cause various forms of organized deposit and non-organized deposit glomerulonephritis diseases.
Free κ or λ light chains can aggregate with each other to cause extracellular amyloid deposits and a disease termed amyloidosis in which the deposits injure and ultimately lead to the failure of such organs as the kidney, heart, liver, stomach, and intestines; these deposits can also cause peripheral and autonomic neuropathies.
IgM myeloma proteins or in rare cases other myeloma proteins such as IgA, free κ light chains, or free λ light chains may increase blood viscosity, deposit in peripheral blood vessels, and thereby cause vascular occlusion and gangrene of the extremities in the syndrome termed cryoglobulinemia.
Monoclonal IgM myeloma proteins operating through their effects on increasing blood hyperviscosity can reduce blood flow to the central nervous system to cause blurred vision, headaches, vertigo, ataxia, and cold-induced hemolytic anemia.
IgM, IgG, and to lesser extents κ and λ free light chain myeloma proteins can cause Immune thrombocytopenic purpura with extensive bleeding tendencies.
Stages
MGUS stage
Monoclonal gammopathy of undetermined significance (MGUS), is defined as the presence in the blood or urine of a monoclonal antibody, antibody heavy chain, or antibody light chain in a person lacking symptoms or signs of a more serious plasma cell dyscrasia. The condition is typically discovered as an incidental finding when serum protein electrophoresis is done for various reasons unrelated to plasma cell dyscrasias. Protein electrophoresis generally detects one of the following patterns of monoclonal myeloma protein spikes representing: a) intact IgG, IgA, IgE, IgE, or IgM; b) intact IgG, IgA, IgE, IgD, or IgM plus high concentrations of a free (i.e. not bound to a heavy chain) κ or λ light chain; c) a free κ chain in great excess of a λ chain or a free λ chain in great excess of a κ chain; and d) free γ, δ, or μ heavy chains unbound to a light chain (free α and ε heavy chain myeloma protein spikes have not been reported). Among MGUS cases expressing an intact antibody, 70%, 15%, 12%, and 3% express either IgG, IgM, IgA, or two of these M proteins, respectively, with or without excessive levels of a light chain; these cases represent ~80% of all MGUS. About 20% of MGUS cases express either κ or λ light chains. As a group, these MGUS findings occur more commonly in men and are ~2-fold more common in individuals of African descent than Caucasians. MGUS cases expressing free γ, δ, or μ heavy chains are extremely rare. MGUS is categorized into the following sub-types based upon the identity and levels of the myeloma proteins detected as well as the prognoses for progressive disease indicated by these myeloma protein findings.
Non-IgM MGUS
Non-IgM MGUS, commonly termed MGUS, is diagnosed in individuals who exhibit a serum IgG, IgD, IgA, or IgE monoclonal protein with or without increased levels of blood and/or urine free κ or λ light chains. These patients typically also show small increases in bone marrow plasma cells. Further requirements for the diagnosis of non-IgM MGUS are: a) bone marrow clonal plasma cells <10% of total nucleated cells; b) absence of any of the four CRAB criteria (CRAB criteria are C = Calcium serum levels >1 milligram/deciliter above normal values and/or a serum level >11 milligram/deciliter; R = Renal insufficiency as defined by a glomerular filtration rate <40 milliliter/minute and/or a serum creatinine >2 gram/deciliter due to myeloma protein-induced kidney damaged; A = Anemia, as defined by a blood hemoglobin level >2 gram/deciliter below normal and/or <10 gram/deciliter due to the plasma cell dyscrasia rather than e.g. iron deficiency or blood loss; B = Bone lesions, i.e. ≥1 lytic (i.e. bone re-adsorbing) bone lesion due to a plasmacytoma as detected by skeletal radiography, computed tomography, or positron emission tomography-computed tomography); c) no evidence of a plasmacytoma in bone or soft tissues, of amyloidosis, or of another plasma cell disorder; d) a ratio of free serum light chains (i.e. free κ/λ or λ/κ light chain ratio) less than 100, providing that the higher light chain concentration is >100 milligram/liter; and e) a circulating blood plasma cell absolute count of <2x109 and/or <20% of total circulating nucleated cells. Presence of any one of the latter findings indicates that the plasma cell dyscrasia has progressed beyond the MGUS stage.Non-IgM MGUS is a relatively stable condition afflicting 3% of people aged 50 and 5% of people aged 70; on average, it progresses to multiple myeloma at a rate of 0.5-1% cases per year, as defined in studies following patients over a 25-year period. A study conducted by the Mayo Clinic found that MGUS associated with non-IgG myeloma proteins or with serum myeloma protein levels greater than 15 gram/liter had a greater risk per year of progression to multiple myeloma. A Spanish study group found that MGUS patients demonstrating aneuploidy (i.e. abnormal number of chromosomes) in bone marrow cells or >95% of resident bone marrow plasma cells that are clonal in nature also have a greater risk per year of progression to myeloma. In a more recent study, MGUS patients that had the presence of none, 1, 2, or 3 of the three following risk factors, serum M protein levels >15 gram/liter, a non-IgG isotype, and abnormal free light chain ratios, had 5, 32, 37, and 58% chances, respectively, of progressing to multiple myeloma within 20 years. In another study, MGUS patients with none, 1, or 2 of the following risk factors, >95% of bone marrow plasma cells that are clonal in nature and a 10% or greater rise in the levels of their monoclonal proteins within 3 years, had 2, 16, and 72% risks, respectively, of progression within 7 years. However, estimates on the risks of progression for some of these parameters are tentative and subject to change. For example, the IgA form of MGUS, while once considered to have a poorer prognosis than IgG MGUS, was found to have a prognosis similar to IgG MGUS in a more recent study.
IgM MGUS
While traditionally classified as such, it is not clear that IgM MGUS is a clonal plasma cell dyscrasia. IgM MGUS involves an increase in a B cell derivative with morphological features of both plasma cells and lymphocytes viz., lymphoplasmacytic cells. Studies indicate that both plasma cells and lymphoblastic cells infiltrate involved tissues and that one or perhaps both cell types harbor mutations in a) the MYD88 gene (~20% in IgM MGUS and >90% in IgM-related malignancies), almost all of which are L265P mutations (i.e. changing leucine to proline at the 265th amino acid position of the MYK88 protein thereby causing the protein to be continuously active in stimulating the same cell-activating pathways that Toll-like receptors activate intermittently and on a physiologically basis); b) the CXCR4 gene (8% in IgM MGUS, 25% in IgM-related malignancies); and c) increased gene copy number due to chromosomal rearrangements (36% in IgM MGUS, 82% in IgM-related malignancies). It is clear that each cell type contributes to different features of IgM malignancies but not clear that clonal plasma cells are critical to the development or progression of IgM MGUS. In all events, IgM MGUS is diagnosed in individuals who have serum IgM levels less than 30 gram/liter; have less than 10% of nucleated bone marrow cells with the lymphoplasmacytic morphology, and have no symptoms or findings of end organ dysfunction attributed to Waldenström macroglobulinemia such as anemia, decreases in any white blood cell count, cold agglutinin disease, hyperviscosity of blood, lymphadenopathy, hepatomegaly, splenomegaly, peripheral neuropathy, cryoglobulinemia, or constitutional symptoms.There may be a modest increase in the incidence of IgM MGUS in people of African descent. A study of 213 individuals diagnosed with IgM MGUS found that 10% at 5 years and 24% in 15 years progressed to more serious IgM-related diseases including non-Hodgkin lymphoma, Waldenstorms macroglobulinemia, systemic amyloidosis, and chronic lymphocytic leukemia. A second long-term study of 116 individuals with IgM MGUS found a 15-fold increased risk of progressing to a lymphoid malignancy, mostly to Waldenstorms macroglobulinemia. In general, progression to one of these malignant outcomes occurs at a rate of 2% to 3% per year. Individuals with higher serum IgM or lower serum albumin levels progress at faster rates than those with normal levels of these parameters.
Light chain MGUS
Individuals diagnosed with light chain MGUS typically do not express detectable levels of an IgG, IgA, IgD, IgE, or IgM intact myeloma protein in their blood. Rather, they overexpress a monoclonal, aberrant free κ (i.e. kappa) or λ (i.e., lambda) immunoglobulin light chain. For diagnosis, the κ and λ free light chains are quantified by immunological methods and the ratio of κ to λ light chains is used to detect unbalanced light chain synthesis that is indicative of a monoclonal light chain plasma cell dyscrasia. Light chain MGUS is defined as a disorder in which a serum κ to λ free light chain ratio falls outside the normal range of 0.26–1.65 (mean =0.9) provided that it is not associated with: a) any of the CRAB criteria, b) a bone marrow plasma cell count of 10 or a higher percentage of nucleated cells, c) evidence of amyloid deposition (see Light chain deposition disease), and d) an accumulation of 0.5 or more grams of the monoclonal light chain in the urine over a 24-hour period. As so defined, light chain MGUS comprises ~19% of all MGUS cases, occurs in ~0.8% of the general population, and progresses to light chain multiple myeloma at the very slow rate of 0.3 cases per 100 years.Some early studies have reported that a very rapid rate of progression occurs in light chain MGUS patients who have free light chain κ/λ or λ/κ ratios equal to or greater than 100 (i.e. and κ/λ ratio outside of 0.02 to 100). About 80% of individuals bearing these light chain ratios were found to progress to light chain multiple myeloma within 2 years. In consequence, these individuals were recommended for being diagnosed and treated as having light chain multiple myeloma. However, two more recent studies reported a 2-year progression rate for these patients of 64% and 30%. It is therefore suggested that the diagnosis of light chain multiple myeloma based solely on a free κ/λ light chain ratio of 0.02 to 100 may be premature.
Monoclonal gammopathy of renal significance
Monoclonal gammopathy of renal significance or MGRS designates any MGUS disorder that has a clinically significant impact on renal function. MGRS can be caused by the deposition of a monoclonal immunoglobulin in, and consequent injury to, the kidneys. The diagnosis of this form of MGRS is made based on the presence of: 1) a disorder meeting the criteria for MGUS; b) decreased kidney function as evidence by, e.g. a Glomerular filtration rate of <40; and c) biopsy confirmed or suspicion of cast nephropathy, glomerulonephritis, of other morphological expressions of clonal immunoglobulin-induced kidney injury. Increased excretion of a urinary monoclonal light chain (typically >0.5 gram/day), which suggests the presence of a particularly severe form of kidney injury (myeloma cast nephropathy), supports but is not a requirement for the diagnosis of MGRS. The disorder can also be caused by a monoclonal immunoglobulin that acts as an autoantibody that activates the blood complement system to cause complement-related kidney injury. This form of MGRS is usually associated with other syndromes like glomerulopathy associated with a monoclonal immunoglobulin or C4 dense deposit disease associated with a monoclonal immunoglobulin. Diagnosis depends or identifying these other syndromes and the identification of complement components on kidney biopsy.
Regardless of the exact pathophysiology causing monoclonal immunoglobulin-induced kidney injury, MGRS has a greater morbidity and mortality than other forms of MGUS. Since renal dysfunction usually improves with therapy directed at the underlying plasma cell dyscrasia, MGRS may warrant treatment even when other parameters of plasma cell dyscrasia severity (e.g. low levels of serum monoclonal immunoglobulin and bone marrow plasma cells) suggest the presence of minimal, non-malignant disease.
Smoldering multiple myeloma stage
Smoldering multiple myeloma or SMM (also termed smoldering myeloma) is the next stage following MGUS in the spectrum of plasma cell dyscrasias. While still considered a pre-malignant condition, its chances of progressing to a malignant plasma cell dyscrasia are generally greater than that for MGUS. SMM consists of the following subtypes which represent progression of their corresponding MGUS subtypes.
Non-IgM SMM
Non-IgM SMM (also termed IgG and IgA SMM because of the rarity of IgD and IgE SMM) is diagnosed in asymptomatic individuals based on criteria identical to those listed above for Non-IgM MGUS except that: their intact IgG or IgA myeloma protein levels are equal to or greater than 30 grams/liter rather than 15 grams/liter; their bone marrow shows plasma cells comprise between 10% and <60% rather than <10% of nucleated cells; and/or their 24-hour urine contains 0.5 gram or greater levels of Bence Jones, i.e. light chain myeloma, proteins. individuals must also lack evidence of more recently established multiple myeloma-defining criteria viz., CRAB features, amyloidosis, more than one solitary plasmacytoma, and/or serum or urine free light chain κ to λ or λ to κ ratios of 100 or greater.Overall, the risk of Non-IgM SMM progressing to multiple myeloma is 10% per year for the first 5 years but falls off sharply to 3% per year for the next 5 years and thereafter to 1% per year.
Smoldering Waldenström macroglobulinemia
Smoldering Waldenström macroglobulinemia is diagnosed in asymptomatic individuals that have a serum IgM level 30 gram/liter and/or a bone marrow lymphoplasmacytoid cell infiltrate >10% of total nucleated cells. These cases should have no symptoms or findings of end organ dysfunction attributed to Waldenström macroglobulinemia such as anemia, decreases in any white blood cell count, cold agglutinin disease, hyperviscosity of blood, lymphadenopathy, hepatomegaly, splenomegaly, peripheral neuropathy, cryoglobulinemia, or constitutional symptoms.As determined by a Mayo Clinic study of 48 individuals, smoldering Waldenström macroglobulinemias risk of progression to Waldenström macroglobulinemia is estimated to be ~12% per year and then falling of sharply for at least the next 5 years to 2% per year. In this study the only factor predictive of a more rapid progress was a finding of anemia (hemoglobin level <115 grams/liter). During a 15-year follow-up, the Clinic subsequently reported that patients progressed to Waldenström macroglobulinemia, amyloidosis, or a related IgM-associated neoplasm at a rate of 6%, 39%, 59%, and 68% after the first, third, fifth, and tenth year, respectively. However, the Southwest Oncology Group in a study on 231 individuals reported that the smoldering disease progressed to overt Waldenström macroglobulinemia over 9 years in only 26% of cases.
Light chain SMM
Light chain smoldering multiple myeloma (light chain SMM) was previously termed idiopathic Bence Jones proteinuria. The condition is currently diagnosed in asymptomatic individuals who have a 24-hour urinary Bence Jones, i.e. light chain myeloma protein level, that is >0.5 grams and/or bone marrow plasma cells that are 10% to <60% of nucleated cells. These individuals must also; lack detectable IgG, IgA, IgD, IgE, or IgM myeloma proteins in sera; have a free κ/λ or λ/κ light chain ratio outside of 0.26 to 1.65 range but less than 100; and/or have no evidence for the presence of any one of the CRAB criteria, amyloidosis, or end organ damage attributable to the myeloma proteins or plasma cells.In a Mayo clinic study of 101 individuals with light chain SMM, the cumulative probability of progression to active multiple myeloma or light-chain amyloidosis in patients with light-chain SMM was 28%, 45%, and 56% after 5, 10, and 15 years, respectively. The major risk factors for progression were the level of urinary excretion of M protein, percentage of bone marrow plasma cells, and immunoparesis (i.e. reduced serum levels of intact immunoglobulins).
Paraneoplastic complications
Serious and potentially life-threatening paraneoplastic complications can occur in plasma cell dyscrasias regardless of tumor cell burden, myeloma protein levels, or the presence of other criteria suggesting the dyscrasia has entered a malignant phase. Many of these complications are caused by the tissue-destructive effects of the myeloma proteins, are predictive of a rapidly progressive disease, and require chemotherapeutic or other treatments directed at lowering the burden of the myeloma protein-producing cells. The serious par |
Plasma cell dyscrasias | aneoplasitic diseases that complicate the plasma cell dyscrasias and may require such treatments include the following.
Amyloidosis
Amyloidosis is a general term for a protein misfolding syndrome that involves the deposition of a low molecular weight beta-pleated sheet-containing protein in extracellular tissues. These proteins normally circulate in the blood but may undergo conformational changes that cause them to auto-aggregate along their beta-pleated sheets to become insoluble and form fibril deposits in and outside of the circulation. These deposits disrupt tissue architecture and, in the case of light chains, directly injure cells, thereby causing potentially cataclysmic organ failures. There are 31 types of circulating proteins that can become misfolded and lead to distinctly different types of amyloidosis; among these, myeloma proteins, particularly free light chains, are the predominant cause of the disease. Increases in the levels of free κ or λ light chains are a common feature of plasma cell dyscrasias. These increases occur in: 40% of IgM MGUS, IgM SMM, and Waldenstroms macroglbulonemia cases; 60% to 70% of non-secretory multiple myelom cases; 90% to 95% of intact immunoglobulin multiple myeloma cases; and, by definition, 100% of light chain multiple myeloma cases. There are two different types of plasma cell dyscrasia-associated amyloidosis syndromes: amyloid light chain amyloidosis (AL amyloidosis) in which amyloid deposits consist of free light chains and amyloid heavy chain amyloidosis (AH amyloidosis) in which amyloid deposits contain only free heavy chains. The deposits in a third type, AHL amyloidosis, consists of both free light chains and free heavy chains. AHL amyloidosis is here, as in some recent reports, grouped with AH amyloidosis.
AL Amyloidosis
AL amyloidosis can occur at any stage in the plasma cell dyscrasia spectrum. Typically, patients developing this type of amyloidosis have had excess κ or λ free light chains in their urine for years before diagnosis. At diagnosis, however, they typically have a relatively small plasma cell burden (bone marrow plasma cells <5% to 7% of total nucleated cells) and in only <5% to 10% of cases do other findings indicate the presence of a malignant condition (i.e. definitive signs of multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia associated with over-production of a clonal light chain). Nonetheless, these individuals often evidence serious involvement of the kidney (proteinuria, nephrotic syndrome) or heart (restrictive cardiomyopathy, arrhythmias) in 70% or 60% of cases, respectively, and of dysfunction in the peripheral nervous system (numbness, paresthesias) or autonomic nervous system (orthostatic hypotension) in 20% or 15% of cases, respectively. They may also exhibit evidence of liver involvement (liver failure, increases in circulating liver enzymes, bleeding due to factor X deficiency), gastrointestinal track deficiencies (malabsorption), and amyloid deposition in surface tissues (macroglossia, shoulder pad masses, cutaneous nodules). Arthritis in multiple joints, often manifested before diagnosis, is also a common feature of AL amyloidosis and has led to initial misdiagnoses of rheumatoid arthritis. Diagnosis of the disease requires evidence of increased levels of a κ or λ myeloma protein in blood and/or blood, presence of an amyloid-related organ-involvement syndrome, detection in tissues of amyloid deposition based on birefringence-staining with Congo red, and detection in tissues of κ or λ deposition based on electron microscopy or mass spectrometry. Reflecting the widespread systemic nature of the disease, patient median survival is only 8 months dating from the time of diagnosis. Treatment commonly improves this poor survival. In a Mayo Clinic study, for example, AL amyloidosis assigned stage 1, 2, 3, or 4 based on the presence of 0, 1, 2, or 3 prognostic signs (high blood levels of [cardiac troponin T]), blood levels of a marker for congestive heart failure (viz., NT-ProBNP), or free light chain ratios) had median survivals of 94.1, 40.3, 14, and 5.8 months respectively. Additional factors indicating a worse prognosis include the involvement of multiple organs, ≥ 10% bone marrow plasma cells, presence of a translocation between chromosomes 11 and 14 [i.e. t(11;14)], and chromosomal trisomy.
AH Amyloidosis
AH and AHL amyloidosis are extremely rare forms of systemic amyloidosis in which the amyloid deposit is a free heavy chain (AH amyloidosis) or a free heavy chain plus free light chain (AHL amyloidosis). Case reports have detected amyloid deposits containing a free γ, α, or μ heavy chain (or portions of one of these chains) accompanied in many cases by a free κ or λ light chain in primarily in the kidney but also the spleen and other tissues. AH plus AHL amyloidosis cases are ~17-fold less common than AL amyloidosis cases. The disease often presents late in its course with signs and/or symptoms of kidney failure such as those associated with the nephrotic syndrome and is therefore treated as a malignant condition. In a small study of 16 patients with renal amyloidosis, the 5 patients with AH amyloidosis and the 11 patients with AHL amyloidosis had less frequent concurrent cardiac involvement and better overall survival than 202 patients with renal AL amyloidosis. The hematological response to chemotherapy of the AH and AHL renal amyloidosis patients was comparable to those with renal AL amyloidosis.
POEMS syndrome
POEMS syndrome (also known as Crow–Fukase syndrome, Takatsuki disease, or PEP syndrome) is a rare and complex medical syndrome that involves a combination of syndrome-defining signs and symptoms due to the dysfunction of multiple organs. The syndrome is associated with a plasma cell dyscrasia in almost 100% of cases, pathological overexpression of certain cytokines in >95% of cases, and the lymphoproliferative disorder termed Castlemans disease in ~15% of cases. (Rare cases of POEMS have been associated with polyclonal rather than clonal plasma cells; these cases are not plasma cell dyscrasias but rather appear to be caused by the over-activity of non-malignant immune cell responses in chronic infections or autoimmune diseases.) POEMS is an acronym standing for the characteristic signs or symptoms of the syndrome: Polyneuropathy, Organomegaly, Endocrinopathy, Plasma cell disorder (typically, the plasma cell burden is low in POEMS patients), and Skin changes (e.g. hemangioma, hyperpigmentation). The syndrome is defined by the presence of; both of two major criteria, peripheral neuropathy and a clonal plasma cell dyscrasia (increased bone marrow plasma cells in ~67% of cases; ≥1 plasmacytoma in ~33% of cases); at least one other major criteria (Castlemans disease, sclerotic bone lesions, elevated serum levels of the cytokine VEGF); and at least one minor criterion (organomegaly, extravascular volume overload [e.g. ascites, edema, pleural effusion, and/or pericardial effusion], endocrinopathy [i.e. hypogonadism, defects in the hypothalamic–pituitary–adrenal axis], skin changes, papilledema, and/or hematological manifestations [i.e. thrombocytosis or polycythemia]). The monoclonal protein in POEMS patients is typically identified as IgA or IgG which in >95% of cases contains a λ chain that is restricted to either of two members of the V lambda 1 subfamily viz., IGLV1-40*01 and IGLV1-44*01 (there are 29 other members in the V lambda family). That is, the myeloma protein in POEMS is almost invariably a clonal λ light chain variant. Deletion of chromosome 13 and chromosomal translocations but not increases in chromosome number have also been reported to occur in POEMS patients.Patients with 1 or 2 isolated plasmacytomas have been successfully treated with targeted radiotherapy to obtain relief of symptoms and sometimes complete remission of disease. (Isolated plasmacytomas may regress spontaneously.) Patients with >2 plasmacytomas or symptomatic disseminated disease have been treated with chemotherapy often followed by autologous stem-cell transplantation; these treatments have been found to reduce symptoms of the disease and lead to long-term partial remissions of disease.
The overall survival of POEMS patients who have been treated for their disease is relatively good for a disease occurring in patients with an average age of 50 years; one estimate of median overall survival is 14 years. POEMS patients evaluated to be in low and intermediate risk groups had ≥>85% survival at 10 years; those in the high risk group had a 40% survival over this time period.
Cryoglobulinemia
Cryoglobulins are proteins, principally immunoglobulins, that circulate in the blood, precipitate at temperatures <37 °C (98.6 °F), and re-solubilize upon restoring physiological blood temperatures. They are made and secreted into the blood as a result of underlying pathological conditions viz., inflammation, infection, or malignancies. Rarely, cryoglobulinemia (i.e. essential cryoglobulinemia) occurs in patients without these or other identifiable conditions. Non-essential cryoglobulonemia is classified into three types. Type 1 cryoglobulinemia (10-25% of cases) involves a circulating myeloma protein, typically IgM or IgG but in rare case reports IgA. The condition is associated with Waldenström macroglobulinemia or multiple myeloma in ~40% of type I cases, the MGUS or smoldering predecessors to these diseases in ~44% of type I cases, and other B cell lymphoproliferative disorders in ~16% of type I cases. Type II cryglobulinemia (50-60% of cases) involves circulating IgM myeloma protein with rheumatoid factor activity and therefore bound to polyclonal IgG and protein components of the blood complement system; hepatitis C virus and, far more rarely, hepatitis B virus or human immunodeficiency virus infections are the major causes of this cryoglobulinemia. Type III cryoglobulinemia (15-30% of cases) involves circulating polyclonal IgM protein with rheumatoid factor activity bound to polyclonal IgG and blood complement components; autoimmune diseases and, less commonly, hepatitis virus C infection or lymphoproliferative disorders are the cause of this type of croglobulinemia. Only types I and II are defined as plasma cell dyscrasias.Patients suffering type 1 cryoglobulinemia present with symptoms due to cold temperature-induce blood hyperviscosity and consequential interruptions of blood flow, e.g. skin lesions (lower extremity purpuric spots and papules, acrocyanosis, necrosis skin ulcers, livedo reticularis urticaria), peripheral neuropathy, blurred vision, loss of vision, hearing loss, headaches, confusion, transient ischemic attacks, chest pain, heart failure, glomerulonephritis, kidney failure, oral bleeding, and nasal bleeding. Rarely, patients may present with catastrophic decreases in blood flow to vital tissues and require emergency treatment. Symptomatic patients typically exhibit levels of a myeloma protein >5 gram/liter and can be diagnosed by simple observing the temperature-induced, reversible induction of serum precipitate formation. Patients, particularly those with catastrophic presentations, are treated with plasma exchange and/or plasmapharesis to reduce the load of circulating myeloma proteins and relieve acute symptoms. Patients with an overt malignancy are treated with the chemotherapy regimens used for Waldenstroms macroglobulinemia or multiply myeloma; patients with MGUS precursors to these diseases appear less responsive to these chemotherapeutic regimens. These patients as well as patients with overt malignancy may be treated with rituximab (kills normal and malignant B cells that bear the CD20 antigen or the proteasome inhibitor, Bortezomib.Patients suffering type II (or type III) cryoglobulinemia present with many of the symptoms of type I disease plus those of inflammatory vasculitis. Their treatments are tailored to the underlying infectious, autoimmune, or malignant disease. Type II patients associated with a monoclonal antibody and clonal plasma cells or other types of clonal B cells, are typically treated with regimens used for Walsdenstorms macroglobulonemia or multiple myeloma.
Malignant stage
In the malignant stage of plasma cell dyscrasias, a clearly excessive tumor cell burden causes symptoms and findings predictive of rapid, life-threatening progression of disease. These dyscrasias fall into several distinct categories.
Solitary plasmacytoma
Solitary plasmacytoma is an early stage malignancy with a clinical course that lies between MGUS and multiple myeloma in the spectrum of plasma cell dyscrasias. Solitary plasmacytomas typically present with local symptoms due to the growing mass of plasma cells such as the bone pain or pathologic bone fractures occurring in solitary plasmacytomas of bone or the headache, focal neurological deficits, and cranial nerve palsies occurring in extramedullary plasmacytomas of sellar and parasellar compartments of the brain. Its diagnoses must meet all four of the following criteria: biopsy-proven tumor consisting of clonal plasma cells; no evidence of any other plasmacytomas based on bone survey and MRI (or in place of MRI, CT scan); normal bone marrow examination; and absence end organ damage, CRAB features, or other signs or symptoms of systemic disease attributable to a plasma cell dyscrasia. Blood or urine myeloma proteins are usually undetectable or low in solitary plasmacytomas. Solitary plasmacytoma is a rare disease with an incidence in the USA of <450 cases per year. In a review of 1,691 cases in the US, the median age at diagnosis was 63 with males representing ~60% of all cases. The most common site of plasmacytoma involvement was bone (~58%) followed by upper or lower airway tract (~16%), soft tissue or connective tissue (~5%), central nervous system (~3%), gastrointestinal tract (~3%), skin (~1%), and all other sites (~3%). Overall median survival was 8.12 years with survival decreasing with age from 12.4 years for patients <40 to 5.2 years for patients of 60 years or older. Risk of its recurrence or progression to overt multiple myeloma within 3 years is ~10%.A subset of solitary plasmacytomas, termed solitary plasmacytoma with minimal bone marrow involvement, has the same criteria for diagnosis as solitary plasmacytoma except that bone marrow examination shows an increase in plasma cells from a normal value of ~0% to 1.5% to >~1.6% but less than 10% of total nucleated cells. While its presentations and findings are similar to solitary plasmacytoma, solitary plasmacytoma with minimal bone marrow involvement is more likely to progress, i.e. it recurs or becomes overt multiple myeloma in 20% to 60% of cases within 3 years. Solitary plasmacytomas associated with 10% or more plasma cells are diagnosed as overt multiple myeloma.
Non-secretory multiple myeloma
Non-secretory multiple myeloma represents a class of plasma cell dyscrasias where no myeloma protein is detected in serum or urine of patients with evidence of increased clonal bone marrow plasma cells and/or multiple plasmacytomas, particularly of the bone but also of soft tissues. While a pre-malignant phase is likely, most new cases of non-secretory multiple myeloma are brought to attention not because of incidental M protein detection which by definition is absent but because of patient symptoms indicative of malignancy possibly of plasma cell origin. The condition has been diagnosed based on biopsy-proved clonal plasma cell tumors and/or the presence in bone marrow of plasma cells at ≥10% of nucleated cells in individuals who have evidence of end organ damage attributable to an underlying plasma cell disorder. These patients typically also show one or more CRAB signs and lack evidence of a myeloma protein as measured by protein electrophoresis and immunofixation. However, more sensitive methods of detecting urinary and serum light chain myeloma proteins using enzyme-linked immunosorbent assays indicate that >60% of cases initially diagnosed as non-secretory multiple myeloma had abnormal levels of either a clonal κ or λ light chain in their urine or serum and therefore were better diagnosed as having light chain multiple myeloma. Based on the latter definition, non-secretory multiple myeloma represents ~1% of all multiple myeloma cases with formerly diagnosed non-secretory myelomas considered to be cases primarily of light chain multiple myeloma but on occasion "false non-secretors", i.e. cases in which there is evidence of myeloma protein secretion such as renal myeloma protein deposits.A Mayo Clinic study of 124 patients initially diagnosed as having non-secretory multiple myeloma were later found to be composed of 65% free light chain secretors and 35% true non-secretors. As a group, these patients response to therapy, time to disease recurrence, and overall survival were similar to typical myeloma patients. However, in a subset of patients diagnosed after 2001 and therefore treated with more effective therapy that included autologous stem-cell transplantation, prognosis was significantly better in non-secretory multiple myeloma patients (median survival 8.3 years) compared to typical myeloma patients (median survival 5.4 years). In addition, non-secretory patients exhibited a better prognosis than light chain-secretory patients.
Plasma Cell Myeloma with concomitant chronic Lymphocytic Leukemia/monoclonal B-Cell Lymphocytosis
Multiple myeloma occurring concurrently with chronic Lymphocytic Leukemia or its pre-malignant precursor, monoclonal B-cell lymphocytosis, is an extremely rare condition in which patients evidence findings of the plasma cell dyscrasia plus either one of the cited clonal lymphocytic diseases. Patients are typically elderly (median age of 74, range 42–91 years old) males (51 of 66 case reports) and commonly present with a combination of symptoms related to chronic lymphocytic leukemia symptoms (fatigue, autoimmune hemolytic anemia, enlargements of liver and/or spleen and lymphadenopathy) plus symptoms of multiple myelomas. Patients exhibit two distinct populations of clonal cells in their bone marrow, blood, and/or other tissues: plasma cells, which may have an immature plasmablastic morphology and small lymphocytes, which have a morphology typical of chronic lymphocytic leukemia cells. Patients blood and/or urine evidences a plasma cell-derived myeloma proteins, either IgG, IgA, or free light chain in ~50%, 20%, and 20% of cases, respectively, but may also have a second myeloma protein made by the lymphocytic cells, either an IgM or IgG. Signs and symptoms of chronic lymphocytic leukemia commonly precede those of multiple myeloma, sometimes by years. The relationship between the two clones of cells in this combined disease has not been established although one study suggests that the clonal plasma cells and clonal lymphocytes arise from a common hematological stem cell. In general, patients with plasma cell myeloma with concomitant chronic Lymphocytic Leukemia/monoclonal B-cell Lymphocytosis have been treated with the same regimens used for multiple myeloma patients unless significant complications related to the lymphocytic component of their disease (e.g. autoimmune hemolytic anemia) require treatments used in chronic lymphocytic leukemia. Some patients who lack appreciable symptoms have been followed with no specific treatment of their disease.
Waldenström macroglobulinemia
According to the International Workshop on Waldenströms Macroglobulinemia, the disease is diagnosed in patients that have a serum IgM monoclonal protein and a bone marrow that contains ≥10% of its nucleated cells as lymphoplasmacytic cells. There is no requirement for symptomatic disease, a particular level of IgM protein, or presence of extramedullary (i.e. non-bone) lymphoplasmacytic cell infiltrates. The overall survival for this malignancy at 5 and 10 years among >5,000 patients is 62% and 39%, respectively, with newer treatment regimens anticipated to improve these survival rates in the future.
Multiple myeloma
Multiple myeloma is diagnosed in patients that (except for non-secretory multiple myeloma patients) have a clonal IgG, IgA, IgD, or IgE myeloma protein in their serum and/or a clonal κ or λ light chain in their serum or urine plus either one of two sets of criteria. In the first criteria set, patients must have ≥10% bone marrow clonal plasma cells plus ≥1 of the CRAB criteria; in the second criteria set, patients must have ≥10 bone marrow clonal plasma cells plus ≥1 of the following findings, ≥60% bone marrow clonal plasma cells, a free κ/λ or λ/κ light chain ratio in serum of ≥100 (the involved clonal light chain concentration must be ≥100 milligrams/liter), and/or >1 focal bone lesion on magnetic resonance imaging. The 5 year medium survival of patients with multiple myeloma treated with currently used treatment regiments is 48.5%.
Light chain multiple myeloma
Light chain multiple myeloma is diagnosed in patients who have: a) the criteria for diagnosis of multiple myeloma except having a serum free light chain ratio outside the normal range of 0.26 to 1.65 without evidence of an intact immunoglobulin or free heavy chain; or b) an extreme free light chain ratio, i.e. outside the range of 0.02 to 100 (with the light chain having the lower concentration being present at >10 milligrams/liter) regardless of the stage of their plasma cell dyscrasia. At the time of diagnosis, 30% to 50% of light chain multiple myeloma patients have severe renal dysfunction or kidney failure due to light chain myeloma cast nephropathy or the nephrotoxic effects of free light chains on renal tubular cells. Patients are treated similarly to patients suffering the counterparts those with multiple myeloma except that the focus is treating or preventing kidney damage using chemotherapy to reduce production of the monoclonal light chain and thereby stopping, reversing, or preventing kidney injury.
Plasma cell leukemia
Plasma cell leukemia is a form of multiple myeloma in which significant numbers of typically immature appearing plasma cells, i.e. plasmablasts, circulate in the blood. Very small numbers of plasma cells may reach the circulation in non-IgM multiple myeloma, non-IgM SMM, and, exceptionally, non-IgM MGUS. In these plasma cell dyscrasias, the presence of even very small numbers of circulating plasma cells is a poor prognostic indicator. In plasma cell leukemia, however, circulating plasma cells reach far higher numbers and at these circulating levels are associated with exceptionally poor survival rates. The International Myeloma Working Group has defined the diagnostic criteria for plasma cell leukemia as the presence in blood of >2x109 plasma cells per liter or, alternatively, >20% of nucleated blood cells being plasma cells. More recently, the Group has suggested that values of 0.5x109 or 5%, respectively, may be more appropriate from a therapeutic viewpoint and therefore should be studied as a definitive criterion for the disease. A recent study supported this suggestion in finding that multiple myeloma patients with >5% circulating plasma cells had a prognosis much worse than that for multiple myeloma and similar to that for plasma cell leukemia. Flow cytometry immunophenotyping of blood cells to detect clonal phenotypes of plasma cells seen in multiple myeloma (e.g. the CD138+, CD38+, CD19−, CD4+/- phenotype) may be a more sensitive method to enumerate circulating clonal plasma cells and diagnose plasma cell leukemia.There are two forms of plasma cell leukemia: Primary plasma cell leukemia in which patients without a history of multiple myeloma present with diagnostically high levels of circulating plasma cells and Secondary plasma cell leukemia in which patients with multiple myeloma suffer their dyscrasias progression by the expansion of large numbers of their malignant plasma cells into the circulation and distant tissues. Historically, primary plasma cell leukemia was more common than the secondary form but with the increased survival of multiple myeloma patients due to new treatment regiments, more cases of secondary plasma cell leukemia are occurring; currently, the two forms occur in approximately equal numbers. Patients with primary plasma cell leukemia present with clinical findings that are less commonly found in multiple myeloma, e.g. they often have hepatomegaly, splenomegaly, lymphadenopathy, nerve and central nervous system defects, bleeding tendencies secondary to thrombocytopenia, and pleural effusions. They are less likely than multiple myeloma patients to have lytic bone lesions. In several studies of patients with either form of plasma cell leukemia, the disease was associated with clonal IgG in 28% to 56% of cases, IgA in 4% to 7% of cases, and a light chain in 23% to 44% of cases; 0-12% of patients had no myeloma protein. Medium survival for primary and secondary plasma cell dyscrasias have been 7–13 months and 2–7 months, respectively, but appear to be improving with new treatment regimens.
Heavy chain disease
The four heavy chain diseases are exceedingly rare conditions associated with the production, circulation in blood, and often presence in urine of a free clonal heavy chain with no detected clonal light chains. The heavy chain is non-functional and altered by having deletions, insertions, and point mutations due to somatic mutations in their respective coding genes. Beyond this commonality, however, these diseases have very different clinical differences. Furthermore, each of the heavy chain diseases appears to be due to rare variants of lymphoma and therefore is sometimes regarded as a B cell dyscrasia However, heavy chain diseases are still often classified with plasma cell dyscrasias. The heavy chain diseases are classified as α, γ, and μ heavy chain diseases and are based respectively on >400, 130, and 30-40 case reports as reviewed in a 2014 publication.
α Heavy chain disease
α Heavy chain disease (also termed immunoproliferative small intestinal disease or IPSID, Mediterranean lymphoma, and Seligmann disease) afflicts primarily individuals of Mediterranean, North African, and Middle Eastern descent of lower economic status. Many cases are centered in the Middle East and associated with relatively unsanitary living conditions. The disease usually appears between the ages 10 and 30 and in some cases may be an aberrant immune response to a parasite or other microorganism. The disease commonly effects the gastrointestinal tract leading to signs and symptoms of a malabsorption syndrome or, far less commonly, the respiratory tract with signs and symptoms of respiratory dysfunction. Involved tissues usually include mucosa-associated lymphoid tissues and evidence a histology of lymphoplasmacytoid infiltrates accompanied by large numbers of plasma cells and small lymphocytes. The plasma cells therein express the monoclonal α chain and therefore are clonal in nature and the sole or contributing producer of the α chain myeloma protein. Some 57% to 66% of patients present with disseminated lymphoma, 17% to 36% of patients present with a localized lymphoma, and 9% to 17% of patients lack any evidence of a lymphoplasmacytic neoplasm. A majority of the latter patients have an autoimmune |
Plasma cell dyscrasias | disease or a chronic infection which may be responsible for, or contribute to, production of the α heavy chain. Studies indicated that a sub-set particularly of the digestive form of heavy chain disease is caused by infection. This is based on findings that the majority of α heavy chain disease patients are in the lower economic class living under unsanitary conditions, that gastrointestinal bacterial and parasitic infections have been documented in many of these patients, and that long-term (>6 months) appropriately selected antibiotic therapy has improved the condition in 33% to 71% of patients who are at an early stage of the disease and documented to be infected. However, these patients frequently relapse. Patients resistant to antibiotic trials have been treated with multiple drug chemotherapy to obtain complete remission rates of 64% and an overall 5 year survival of 67%.
γ heavy chain disease
γ Heavy chain disease (also termed Franklin disease or Franklins disease) presents in three patterns: a) aggressive lymphoma (57% to 66% of cases) associated with constitutional symptoms and in 50% of cases with enlargement of lymph nodes, spleen, and/or liver; b) localized lymphoma (~25% of cases) with lymphoma limited to the bone marrow or an extra-nodal site, usually the skin but sometimes the thyroid gland, parotid gland, oropharyngeal cavity, conjunctiva, or gastrointestinal tract; and c) no lymphoma (9% to 17% of cases) associated typically with a preexistent autoimmune disease but no evidence of lymphoma. Involved lymphoma-infiltrated tissues typically show a mixture of lymphoplamsmacytoid cells, plasma cells, lymphocytes, and sometimes variable numbers of eosinophils and hystiocytes. Treatment of the disease varies with its clinical severity. Patients with aggressive lymphoma have been treated with multiple drug chemotherapy, patients with limited lymphoma have been monitored for disease progression or treated locally (e.g. radiation therapy, surgical removal), and patients with no lymphoma have been monitored for progression in their diseases while being treated for any autoimmune disease that they bear. Spontaneous remissions in γ heavy chain disease have occurred. Regardless of presentation pattern, these patients may have an aggressive or indolent disease with courses ranging from the asymptomatic presence of a stable monoclonal heavy chain in the serum or urine (e.g. MGUS) to a rapid, downhill progression of a few weeks duration. γ Heavy chain disease survivorship ranged form 1 month to >20 years (medium survival 7.4 years) in a Mayo Clinic study.
μ Heavy chain disease
μ Heavy chain disease presents with a picture of a lymphoid neoplasm resembling either chronic lymphocytic leukemia or small lymphocytic lymphoma. This picture includes splenomegaly in virtually all cases, hepatomegaly in ~75% of cases, lymphadenopathy in ~40% of cases, and lytic bone lesions in ~20% of cases. Patients often have hypogammaglobulinemia, increases in urinary free light chains, and a bone marrow containing vacuolated plasma cells or lymphoid cells. Treatment of μ heavy chain disease had varied form observation only in asymptomatic patients to single drug or and multiple drug chemotherapy in symptomatic patients. Survival with this disease varies between <1 month to >10 years with a median survival rate of ~ 2years.
See also
Paraproteinemia
Gammaglobulins
References
== External links == |
Hemotympanum | Hemotympanum, or hematotympanum, refers to the presence of blood in the tympanic cavity of the middle ear. Hemotympanum is often the result of basilar skull fracture.Hemotympanum refers to the presence of blood in the middle ear, which is the area behind the eardrum. In most cases, the blood is trapped behind the eardrum, so no discharge is visible.
Treating hemotympanum depends on the underlying cause.
Presentation
The most common symptoms of hemotympanum are:
pain
sense of fullness in the ear
hearing loss
Causes
Skull fracture
A basal skull fracture is a fracture in one of the bones at the base of the skull. This is almost always caused by impact trauma such as a hard fall or a car crash. If the temporal bone is affected, one of the following may co-occur:
Auricular cerebrospinal fluid discharge
Dizziness
Bruises around the eyes or behind the ears
Facial weakness
Difficulty seeing, smelling, or hearing
Nasal packing
Following nasal surgery or frequent nosebleeds, gauze or cotton may be inserted into the nose to stop the bleeding. This process is called therapeutic nasal packing. Nasal packing sometimes causes blood to back up into the middle ear, causing hemotympanum. Removing the packing may allow the blood to drain from the ear. Antibiotics can prevent an ear infection.
Bleeding disorders
Bleeding disorders, such as hemophilia or idiopathic thrombocytopenia purpura, can also cause hemotympanum. These disorders prevent proper blood clotting. In that circumstance, a mild head injury or a strong sneeze can cause hemotympanum.
Anticoagulant medications
Anticoagulants, often called blood thinners, are medications that keep blood from clotting too easily. In rare cases, anticoagulants can cause hemotympanum with no underlying cause or injury. Experiencing a head injury while taking anticoagulants, increases the likelihood of hemotympanum.
Ear infections
Frequent ear infections, ongoing inflammation and fluid buildup can increase the risk of hemotympanum.
Treatment
Skull fractures usually heal on their own, but they can also cause several complications. Cerebrospinal fluid leaking out of the ear involves a higher risk of developing meningitis. Treatment may include corticosteroids, antibiotics, or surgery.
== References == |
Chondrodermatitis nodularis chronica helicis | Chondrodermatitis nodularis chronica helicis is a small, nodular, tender, chronic inflammatory lesion occurring on the helix of the ear, most often in men.: 610 it often presents as a benign painful erythematous nodule fixed to the cartilage of the helix or antihelix of the external ear. Although the exact cause of the condition is unknown, it has been linked to head pressure on the ear while sleeping. Treatment options include the use of pressure-relieving devices or, in cases where that is not an option, surgery.
See also
List of cutaneous conditions
== References == |
Phenylketonuria | Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also result in a musty smell and lighter skin. A baby born to a mother who has poorly treated PKU may have heart problems, a small head, and low birth weight.Phenylketonuria is a genetic disorder inherited from a persons parents. It is due to mutations in the PAH gene, which results in low levels of the enzyme phenylalanine hydroxylase. This results in the buildup of dietary phenylalanine to potentially toxic levels. It is autosomal recessive, meaning that both copies of the gene must be mutated for the condition to develop. There are two main types, classic PKU and variant PKU, depending on whether any enzyme function remains. Those with one copy of a mutated gene typically do not have symptoms. Many countries have newborn screening programs for the disease.Treatment is with a diet that (1) is low in foods that contain phenylalanine, and which (2) includes special supplements. Babies should use a special formula with a small amount of breast milk. The diet should begin as soon as possible after birth and be continued for life. People who are diagnosed early and maintain a strict diet can have normal health and a normal life span. Effectiveness is monitored through periodic blood tests. The medication sapropterin dihydrochloride may be useful in some.Phenylketonuria affects about 1 in 12,000 babies. Males and females are affected equally. The disease was discovered in 1934 by Ivar Asbjørn Følling, with the importance of diet determined in 1935. Gene therapy, while promising, requires a great deal more study as of 2014.
Signs and symptoms
Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also result in a musty smell and lighter skin. A baby born to a mother who has poorly treated PKU may have heart problems, a small head, and low birth weight.Because the mothers body is able to break down phenylalanine during pregnancy, infants with PKU are normal at birth. The disease is not detectable by physical examination at that time, because no damage has yet been done. Newborn screening is performed to detect the disease and initiate treatment before any damage is done. The blood sample is usually taken by a heel prick, typically performed 2–7 days after birth. This test can reveal elevated phenylalanine levels after one or two days of normal infant feeding.If a child is not diagnosed during the routine newborn screening test and a phenylalanine-restricted diet is not introduced, then phenylalanine levels in the blood will increase over time. Toxic levels of phenylalanine (and insufficient levels of tyrosine) can interfere with infant development in ways that have permanent effects. The disease may present clinically with seizures, hypopigmentation (excessively fair hair and skin), and a "musty odor" to the babys sweat and urine (due to phenylacetate, a carboxylic acid produced by the oxidation of phenylacetone). In most cases, a repeat test should be done at approximately two weeks of age to verify the initial test and uncover any phenylketonuria that was initially missed.Untreated children often fail to attain early developmental milestones, develop microcephaly, and demonstrate progressive impairment of cerebral function. Hyperactivity, EEG abnormalities, and seizures, and severe learning disabilities are major clinical problems later in life. A characteristic "musty or mousy" odor on the skin, as well as a predisposition for eczema, persist throughout life in the absence of treatment.The damage done to the brain if PKU is untreated during the first months of life is not reversible. It is critical to control the diet of infants with PKU very carefully so that the brain has an opportunity to develop normally. Affected children who are detected at birth and treated are much less likely to develop neurological problems or have seizures and intellectual disability (though such clinical disorders are still possible including asthma, eczema, anemia, weight gain, renal insufficiency, osteoporosis, gastritis, esophagus, and kidney deficiencies, kidney stones, and hypertension). Additionally, major depressive disorders occur 230% higher than controls; dizziness and giddiness occur 180% higher; chronic ischemic heart disease, asthma, diabetes, and gastroenteritis occur 170% higher; and stress and adjustment disorders occur 160% higher. In general, however, outcomes for people treated for PKU are good. Treated people may have no detectable physical, neurological, or developmental problems at all.
Genetics
PKU is an autosomal recessive metabolic genetic disorder. As an autosomal recessive disorder, two PKU alleles are required for an individual to experience symptoms of the disease. For a child to inherit PKU, both the mother and father must have and pass on the defective gene. If both parents are carriers for PKU, there is a 25% chance any child they have will be born with the disorder, a 50% chance the child will be a carrier and a 25% chance the child will neither develop nor be a carrier for the disease.PKU is characterized by homozygous or compound heterozygous mutations in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional.: 541 This enzyme is necessary to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine (Tyr). When PAH activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which can be detected in the urine.Carriers of a single PKU allele do not exhibit symptoms of the disease but appear to be protected to some extent against the fungal toxin ochratoxin A. This accounts for the persistence of the allele in certain populations in that it confers a selective advantage—in other words, being a heterozygote is advantageous.The PAH gene is located on chromosome 12 in the bands 12q22-q24.2. As of 2000, around 400 disease-causing mutations had been found in the PAH gene. This is an example of allelic genetic heterogeneity.
Pathophysiology
When phenylalanine (Phe) cannot be metabolized by the body, a typical diet that would be healthy for people without PKU causes abnormally high levels of Phe to accumulate in the blood, which is toxic to the brain. If left untreated (and often even in treatment), complications of PKU include severe intellectual disability, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioral problems such as attention deficit hyperactivity disorder, as well as physical symptoms such as a "musty" odor, eczema, and unusually light skin and hair coloration.
Classical PKU
Classical PKU, and its less severe forms "mild PKU" and "mild hyperphenylalaninemia" are caused by a mutated gene for the enzyme phenylalanine hydroxylase (PAH), which converts the amino acid phenylalanine ("Phe") to other essential compounds in the body, in particular tyrosine. Tyrosine is a conditionally essential amino acid for PKU patients because without PAH it cannot be produced in the body through the breakdown of phenylalanine. Tyrosine is necessary for the production of neurotransmitters like epinephrine, norepinephrine, and dopamine.PAH deficiency causes a spectrum of disorders, including classic phenylketonuria (PKU) and mild hyperphenylalaninemia (also known as "hyperphe" or "mild HPA"), a less severe accumulation of phenylalanine. Compared to classic PKU patients, patients with "hyperphe" have greater PAH enzyme activity and are able to tolerate larger amounts of phenylalanine in their diets. Without dietary intervention, mild HPA patients have blood Phe levels higher than those with normal PAH activity. There is currently no international consensus on the definition of mild HPA, however, it is most frequently diagnosed at blood Phe levels between 2–6 mg/dL.Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the blood–brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). If phenylalanine is in excess in the blood, it will saturate the transporter. Excessive levels of phenylalanine tend to decrease the levels of other LNAAs in the brain. As these amino acids are necessary for protein and neurotransmitter synthesis, Phe buildup hinders the development of the brain, causing intellectual disability.Recent research suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, bone pathology are slightly suboptimal even for patients who are treated and maintain their Phe levels in the target range, if their diet is not supplemented with other amino acids.Classic PKU affects myelination and white matter tracts in untreated infants; this may be one major cause of neurological problems associated with phenylketonuria. Differences in white matter development are observable with magnetic resonance imaging. Abnormalities in gray matter can also be detected, particularly in the motor and pre-motor cortex, thalamus and the hippocampus.It was recently suggested that PKU may resemble amyloid diseases, such as Alzheimers disease and Parkinsons disease, due to the formation of toxic amyloid-like assemblies of phenylalanine.
Tetrahydrobiopterin-deficient hyperphenylalaninemia
A rarer form of hyperphenylalaninemia is tetrahydrobiopterin deficiency, which occurs when the PAH enzyme is normal, and a defect is found in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH4). BH4 is necessary for proper activity of the enzyme PAH, and this coenzyme can be supplemented as treatment. Those with this form of hyperphenylalaninemia may have a deficiency of tyrosine (which is created from phenylalanine by PAH), in which case treatment is supplementation of tyrosine to account for this deficiency.Levels of dopamine can be used to distinguish between these two types. Tetrahydrobiopterin is required to convert Phe to Tyr and is required to convert Tyr to L-DOPA via the enzyme tyrosine hydroxylase. L-DOPA, in turn, is converted to dopamine. Low levels of dopamine lead to high levels of prolactin. By contrast, in classical PKU (without dihydrobiopterin involvement), prolactin levels would be relatively normal.As of 2020, tetrahydrobiopterin deficiency was known to result from defects in five genes.
Metabolic pathways
The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and phenethylamine. Elevated levels of phenylalanine in the blood and detection of phenylketones in the urine is diagnostic, however most patients are diagnosed via newborn screening.
Screening
PKU is commonly included in the newborn screening panel of many countries, with varied detection techniques. Most babies in developed countries are screened for PKU soon after birth. Screening for PKU is done with bacterial inhibition assay (Guthrie test), immunoassays using fluorometric or photometric detection, or amino acid measurement using tandem mass spectrometry (MS/MS). Measurements done using MS/MS determine the concentration of Phe and the ratio of Phe to tyrosine, the ratio will be elevated in PKU.
Treatment
PKU is not curable. However, if PKU is diagnosed early enough, an affected newborn can grow up with normal brain development by managing and controlling phenylalanine ("Phe") levels through diet, or a combination of diet and medication.
Diet
People who follow the prescribed dietary treatment from birth may (but not always) have no symptoms. Their PKU would be detectable only by a blood test. People must adhere to a special diet low in Phe for optimal brain development. Since Phe is necessary for the synthesis of many proteins, it is required for appropriate growth, but levels must be strictly controlled.
For people who do not have phenylketonuria, the U.S. Institute of Medicine set recommended at least 33 mg/kg body weight/day phenylalanine plus tyrosine for adults 19 years and older. For people with PKU, a recommendation for children up to age 10 years is 200 to 500 mg/d; for older children and adults below 600 mg/day . Where in the range depends on body weight and age, and on monitoring blood concentration.Optimal health ranges (or "target ranges") are between 120 and 360 μmol/L or equivalently 2 to 6 mg/dL. This is optimally to be achieved during at least the first 10 years, to allow the brain to develop normally.
The diet requires restricting or eliminating foods high in Phe, such as soybeans, egg whites, shrimp, chicken breast, spirulina, watercress, fish, nuts, crayfish, lobster, tuna, turkey, legumes, and lowfat cottage cheese. Starchy foods, such as potatoes and corn are generally acceptable in controlled amounts, but the quantity of Phe consumed from these foods must be monitored. A corn-free diet may be prescribed in some cases. A food diary is usually kept to record the amount of Phe consumed with each meal, snack, or drink. An "exchange" system can be used to calculate the amount of Phe in a portion of food from the protein content identified on a nutritional information label. Lower-protein "medical food" substitutes are often used in place of normal bread, pasta, and other grain-based foods, which contain a significant amount of Phe. Many fruits and vegetables are lower in Phe and can be eaten in larger quantities. Infants may still be breastfed to provide all of the benefits of breastmilk, but the quantity must also be monitored and supplementation for missing nutrients will be required. The sweetener aspartame, present in many diet foods and soft drinks, must also be avoided, as aspartame contains phenylalanine.Different people can tolerate different amounts of Phe in their diet. Regular blood tests are used to determine the effects of dietary Phe intake on blood Phe level.
Nutritional supplements
Supplementary "protein substitute" formulas are typically prescribed for people PKU (starting in infancy) to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low-phenylalanine diet. Tyrosine, which is normally derived from phenylalanine and which is necessary for normal brain function, is usually supplemented. Consumption of the protein substitute formulas can actually reduce phenylalanine levels, probably because it stops the process of protein catabolism from releasing Phe stored in the muscles and other tissues into the blood. Many PKU patients have their highest Phe levels after a period of fasting (such as overnight) because fasting triggers catabolism. A diet that is low in phenylalanine but does not include protein substitutes may also fail to lower blood Phe levels, since a nutritionally insufficient diet may also trigger catabolism. For all these reasons, the prescription formula is an important part of the treatment for patients with classic PKU.Evidence supports dietary supplementation with large neutral amino acids (LNAAs). The LNAAs (e.g. leu, tyr, trp, met, his, ile, val, thr) may compete with phe for specific carrier proteins that transport LNAAs across the intestinal mucosa into the blood and across the blood–brain barrier into the brain. Its use is limited in the US due to the cost but is available in most countries as part of a low protein / PHE diet to replace missing nutrients.
Another interesting treatment strategy is casein glycomacropeptide (CGMP), which is a milk peptide naturally free of Phe in its pure form CGMP can substitute for the main part of the free amino acids in the PKU diet and provides several beneficial nutritional effects compared to free amino acids. The fact that CGMP is a peptide ensures that the absorption rate of its amino acids is prolonged compared to free amino acids and thereby results in improved protein retention and increased satiety compared to free amino acids. Another important benefit of CGMP is that the taste is significantly improved when CGMP substitutes part of the free amino acids and this may help ensure improved compliance to the PKU diet.
Furthermore, CGMP contains a high amount of the Phe-lowering LNAAs, which constitutes about 41 g per 100 g protein and will therefore help maintain plasma phe levels in the target range.
Enzyme substitutes
In 2018, the FDA approved an enzyme substitute called pegvaliase which metabolizes phenylalanine. It is for adults who are poorly managed on other treatments.Tetrahydrobiopterin (BH4) (a cofactor for the oxidation of phenylalanine) when taken by mouth can reduce blood levels of this amino acid in some people.
Mothers
For women with PKU, it is important for the health of their children to maintain low Phe levels before and during pregnancy. Though the developing fetus may only be a carrier of the PKU gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta. The child may develop congenital heart disease, growth retardation, microcephaly and intellectual disability as a result. PKU-affected women themselves are not at risk of additional complications during pregnancy.In most countries, women with PKU who wish to have children are advised to lower their blood Phe levels (typically to between 2 and 6 mg/dL) before they become pregnant, and carefully control their levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, in general monitored on a day-to-day basis by a specialist metabolic dietitian. In many cases, as the fetus liver begins to develop and produce PAH normally, the mothers blood Phe levels will drop, requiring an increased intake to remain within the safe range of 2–6 mg/dL. The mothers daily Phe intake may double or even triple by the end of the pregnancy, as a result. When maternal blood Phe levels fall below 2 mg/dL, anecdotal reports indicate that the mothers may experience adverse effects, including headaches, nausea, hair loss, and general malaise. When low phenylalanine levels are maintained for the duration of pregnancy, there are no elevated levels of risk of birth defects compared with a baby born to a non-PKU mother.
Epidemiology
The average number of new cases of PKU varies in different human populations. United States Caucasians are affected at a rate of 1 in 10,000. Turkey has the highest documented rate in the world, with 1 in 2,600 births, while countries such as Finland and Japan have extremely low rates with fewer than one case of PKU in 100,000 births. A 1987 study from Slovakia reports a Roma population with an extremely high incidence of PKU (one case in 40 births) due to extensive inbreeding. It is the most common amino acid metabolic problem in the United Kingdom.
History
Before the causes of PKU were understood, PKU caused severe disability in most people who inherited the relevant mutations. Nobel and Pulitzer Prize winning author Pearl S. Buck had a daughter named Carol who lived with PKU before treatment was available, and wrote an account of its effects in a book called The Child Who Never Grew. Many untreated PKU patients born before widespread newborn screening are still alive, largely in dependent living homes/institutions.Phenylketonuria was discovered by the Norwegian physician Ivar Asbjørn Følling in 1934 when he noticed hyperphenylalaninemia (HPA) was associated with intellectual disability. In Norway, this disorder is known as Føllings disease, named after its discoverer. Følling was one of the first physicians to apply detailed chemical analysis to the study of disease.
In 1934 at Rikshospitalet, Følling saw a young woman named Borgny Egeland. She had two children, Liv and Dag, who had been normal at birth but subsequently developed intellectual disability. When Dag was about a year old, the mother noticed a strong smell to his urine. Følling obtained urine samples from the children and, after many tests, he found that the substance causing the odor in the urine was phenylpyruvic acid. The children, he concluded, had excess phenylpyruvic acid in the urine, the condition which came to be called phenylketonuria (PKU).His careful analysis of the urine of the two affected siblings led him to request many physicians near Oslo to test the urine of other affected patients. This led to the discovery of the same substance he had found in eight other patients. He conducted tests and found reactions that gave rise to benzaldehyde and benzoic acid, which led him to conclude that the compound contained a benzene ring. Further testing showed the melting point to be the same as phenylpyruvic acid, which indicated that the substance was in the urine.In 1954, Horst Bickel, Evelyn Hickmans and John Gerrard published a paper that described how they created a diet that was low in phenylalanine and the patient recovered. Bickel, Gerrard and Hickmans were awarded the John Scott Medal in 1962 for their discovery.PKU was the first disorder to be routinely diagnosed through widespread newborn screening. Robert Guthrie introduced the newborn screening test for PKU in the early 1960s. With the knowledge that PKU could be detected before symptoms were evident, and treatment initiated, screening was quickly adopted around the world. Ireland was the first country to introduce a national screening programme in February 1966, Austria also started screening in 1966 and England in 1968.In 2017 the European Guidelines were published. They were called for by the patient organizations such as the European Society for Phenylketonuria and Allied Disorders Treated as Phenylketonuria. They have received some critical reception.
Etymology and pronunciation
The word phenylketonuria uses combining forms of phenyl + ketone + -uria; it is pronounced .
Research
Other therapies are currently under investigation, including gene therapy.
Biomarin is currently conducting clinical trials to investigate PEG-PAL (PEGylated recombinant phenylalanine ammonia lyase or PAL) is an enzyme substitution therapy in which the missing PAH enzyme is replaced with an analogous enzyme that also breaks down Phe. PEG-PAL is now in Phase 2 clinical development.
See also
Hyperphenylalanemia
Lofenalac
Tetrahydrobiopterin deficiency
Flowers for Algernon, which features a character who has phenylketonuria
References
External links
Phenylketonuria at Curlie |
Folie à deux | Folie à deux (folly of two, or madness [shared] by two), also known as shared psychosis or shared delusional disorder (SDD), is a collection of rare psychiatric syndromes in which symptoms of a delusional belief, and sometimes hallucinations, are transmitted from one individual to another. The same syndrome shared by more than two people may be called folie à... trois (three) or quatre (four); and further, folie en famille (family madness) or even folie à plusieurs (madness of several).
The disorder, first conceptualized in 19th-century French psychiatry by Charles Lasègue and Jules Falret, and is also known as Lasègue–Falret syndrome.Recent psychiatric classifications refer to the syndrome as shared psychotic disorder (DSM-4 – 297.3) and induced delusional disorder (ICD-10 – F24), although the research literature largely uses the original name.
This disorder is not in the current, fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), which considers the criteria to be insufficient or inadequate. DSM-5 does not consider Shared Psychotic Disorder (Folie à Deux) as a separate entity; rather, the physician should classify it as "Delusional Disorder" or in the "Other Specified Schizophrenia Spectrum and Other Psychotic Disorder".
Signs and symptoms
This syndrome is most commonly diagnosed when the two or more individuals of concern live in proximity, may be socially or physically isolated, and have little interaction with other people.
Various sub-classifications of folie à deux have been proposed to describe how the delusional belief comes to be held by more than one person:
Folie imposée
Where a dominant person (known as the primary, inducer, or principal) initially forms a delusional belief during a psychotic episode and imposes it on another person or persons (the secondary, acceptor, or associate) with the assumption that the secondary person might not have become deluded if left to his or her own devices. If the parties are admitted to hospital separately, then the delusions in the person with the induced beliefs usually resolve without the need of medication.
Folie simultanée
Either the situation where two people considered to independently experience psychosis influence the content of each others delusions so they become identical or strikingly similar, or one in which two people "morbidly predisposed" to delusional psychosis mutually trigger symptoms in each other.Folie à deux and its more populous derivatives are psychiatric curiosities. The current Diagnostic and Statistical Manual of Mental Disorders states that a person cannot be diagnosed as being delusional if the belief in question is one "ordinarily accepted by other members of the persons culture or subculture." It is not clear at what point a belief considered to be delusional escapes from the folie à... diagnostic category and becomes legitimate because of the number of people holding it. When a large number of people may come to believe obviously false and potentially distressing things based purely on hearsay, these beliefs are not considered to be clinical delusions by the psychiatric profession, and are instead labelled as mass hysteria.
As with most psychological disorders, the extent and type of delusion varies, but the non-dominant persons delusional symptoms usually resemble those of the inducer. Prior to therapeutic interventions, the inducer typically does not realize that they are causing harm, but instead believe they are helping the second person to become aware of vital or otherwise notable information.
Type of delusions
Psychology Today magazine defines delusions as "fixed beliefs that do not change, even when a person is presented with conflicting evidence." Types of delusion include:
Bizarre delusions
Those which are clearly implausible and not understood by peers within the same culture, even those with psychological disorders; for example, if one thought that all of their organs had been taken out and replaced by someone elses while they were asleep without leaving any scar and without their waking up. It would be impossible to survive such a procedure, and even surgery involving transplantation of multiple organs would leave the person with severe pain, visible scars, etc.
Non-bizarre delusions
Common among those with personality disorders and are understood by people within the same culture. For example, unsubstantiated or unverifiable claims of being followed by the FBI in unmarked cars and watched via security cameras would be classified as a non-bizarre delusion; while it would be unlikely for the average person to experience such a predicament, it is possible, and therefore understood by those around them.
Mood-congruent delusions
These correspond to a persons emotions within a given timeframe, especially during an episode of mania or depression. For example, someone with this type of delusion may believe with certainty that they will win $1 million at the casino on a specific night, despite lacking any way to see the future or influence the probability of such an event. Similarly, someone in a depressive state may feel certain that their mother will get hit by lightning the next day, again in spite of having no means of predicting or controlling future events.
Mood-neutral delusions
These are unaffected by mood, and can be bizarre or non-bizarre; the formal definition provided by Mental Health Daily is "a false belief that isnt directly related to the persons emotional state." An example would be a person who is convinced that somebody has switched bodies with their neighbor, the belief persisting irrespective of changes in emotional status.
Biopsychosocial effects
As with many psychiatric disorders, shared delusional disorder can negatively impact the psychological and social aspects of a persons wellbeing. Unresolved stress resulting from a delusional disorder will eventually contribute to or increase the risk of other negative health outcomes, such as cardiovascular disease, diabetes, obesity, immunological problems, and others. These health risks increase with the severity of the disease, especially if an affected person does not receive or comply with adequate treatment.
Persons with a delusional disorder have a significantly high risk of developing psychiatric comorbidities such as depression and anxiety. This may be attributable to a genetic pattern shared by 55% of SDD patients.Shared delusional disorder can have a profoundly negative impact on a persons quality of life. Persons diagnosed with a mental health disorder commonly experience social isolation, which is detrimental to psychological health. This is especially problematic with SDD, as social isolation contributes to the onset of the disorder; in particular, relapse is likely if returning to an isolated living situation, in which shared delusions can be reinstated.
Causes
While the exact causes of SDD are unknown, the main two contributors are stress and social isolation.People who are socially isolated together tend to become dependent on those they are with, leading to an inducers influence on those around them. Additionally, people developing shared delusional disorder do not have others reminding them that their delusions are either impossible or unlikely. As a result, treatment for shared delusional disorder includes those affected be removed from the inducer.Stress is also a factor, as it is a common factor in mental illness developing or worsening. The majority of people that develop shared delusional disorder are genetically predisposed to mental illness, but this predisposition is not enough to develop a mental disorder. However, stress can increase the risk of this disorder. When stressed, an individuals adrenal gland releases the "stress hormone" cortisol into the body, increasing the brains level of dopamine; this change can be linked to the development of a mental illness, such as a shared delusional disorder.While there is no exact cause of shared psychosis, there are several factors that are contributors depending on different cultures and communities. Taking into consideration the individuals circumstance which entails their environmental changes and relationships.
Diagnosis
Shared delusional disorder is often difficult to diagnose. Usually, the person with the condition does not seek out treatment, as they do not realize that their delusion is abnormal, as it comes from someone in a dominant position who they trust. Furthermore, since their delusion comes on gradually and grows in strength over time, their doubt is slowly weakened during this time. Shared delusional disorder is diagnosed using the DSM-5, and according to this, the patient must meet three criteria:
They must have a delusion that develops in the context of a close relationship with an individual with an already established delusion.
The delusion must be very similar or even identical to the one already established one that the primary case has.
The delusion cannot be better explained by any other psychological disorder, mood disorder with psychological features, a direct result of physiological effects of substance abuse or any general medical condition.
Related phenomena
Reports have stated that a phenomenon similar to folie à deux was induced by the military incapacitating agent BZ in the late 1960s.
Prevalence
Shared delusional disorder is most commonly found in women with slightly above-average IQs, who are isolated from their family, and who are in relationships with a dominant person who has delusions. The majority of secondary cases (people who develop the shared delusion) also meet the criteria for Dependent Personality Disorder, which is characterized by a pervasive fear that leads them to need constant reassurance, support, and guidance. Additionally, 55% of secondary cases had a relative with a psychological disorder that included delusions and, as a result, the secondary cases are usually susceptible to mental illness.
Treatment
After a person has been diagnosed, the next step is to determine the proper course of treatment. The first step is to separate the formerly healthy person from the inducer, and see if the delusion goes away or lessens over time. If this is not enough to stop the delusions, there are two possible courses of action: medication or therapy. Therapy can be provided as both personal therapy and/or family therapy.
With treatment, the delusions, and therefore the disease, will eventually lessen so much so, that it will practically disappear in most cases. However, if left untreated, it can become chronic and lead to anxiety, depression, aggressive behavior, and further social isolation. Unfortunately, there are not many statistics about the prognosis of shared delusional disorder, as it is a rare disease, and it is expected that the majority of cases go unreported; however, with treatment, the prognosis is very good.
Medication
If the separation alone is not working, antipsychotics are often prescribed for a short time to prevent the delusions. Antipsychotics are medications that reduce or relieve symptoms of psychosis such as delusions or hallucinations (seeing or hearing something that is not there). Other uses of antipsychotics include stabilizing moods for people with mood swings and mood disorders ( i.e. in bipolar patients), reducing anxiety in anxiety disorders, and lessening tics in people with Tourettes. Antipsychotics do not cure psychosis, but they do help reduce symptoms; when paired with therapy, the person with the condition has the best chance of recovering. While antipsychotics are powerful, and often effective, they do have side effects, such as inducing involuntary movements. They should only be taken if absolutely required, and under the supervision of a psychiatrist.
Therapy
The two most common forms of therapy for people with shared delusional disorder are personal and family therapy.Personal therapy is one-on-one counseling that focuses on building a relationship between the counselor and the patient, and aims to create a positive environment where the patient feels that they can speak freely and truthfully. This is advantageous, as the counselor can usually get more information out of the patient to get a better idea of how to help them. Additionally, if the patient trusts what the counselor says, disproving the delusion will be easier.Family therapy is a technique in which the entire family comes into therapy together to work on their relationships, and to find ways to eliminate the delusion within the family dynamic. For example, if someones sister is the inducer, the family will have to get involved to ensure the two stay apart, and to sort out how the family dynamic will work around that. The more support a patient has, the more likely they are to recover, especially since SDD usually occurs due to social isolation.
Notable cases
In May 2008, in the case of twin sisters Ursula and Sabina Eriksson, Ursula ran into the path of an oncoming articulated lorry, sustaining severe injuries. Sabina then immediately duplicated her twins actions by stepping into the path of an oncoming car; both sisters survived the incident with severe but non-life-threatening injuries. It was later claimed that Sabina Eriksson was a secondary sufferer of folie à deux, influenced by the presence or perceived presence of her twin sister, Ursula—the primary. Sabina later told an officer at the police station, "We say in Sweden that an accident rarely comes alone. Usually at least one more follows—maybe two." However, upon her release from hospital, Sabina behaved erratically before stabbing a man to death.
Psychiatrist Reginald Medlicott published an article about the Parker–Hulme murder case, called "Paranoia of the Exalted Type in a Setting of Folie a Deux - A Study of Two Adolescent Homicides," arguing that the intense relationship and shared fantasy world of the two teenaged friends reinforced and exacerbated the mental illness that led to the murder: "each acted on the other as a resonator, increasing the pitch of their narcissism."
Psychologists H. OConnell and P.G. Doyle believe folie à plusieurs to have been at least a partial factor in the murder of Bridget Cleary. In 1895, Michael Cleary convinced several friends and relatives that his wife, Bridget Cleary, was a changeling who had been replaced by a fairy. They assisted him in physically abusing her to "cast the fairies" out, before he ultimately burned her to death shortly afterwards.
Christine and Léa Papin were two French sisters who, as live-in maids, were convicted of murdering their employers wife and daughter in Le Mans, France on February 2, 1933.
Born in Yemen in 1963 to Barbados immigrants, June and Jennifer Gibbons were known as "the Silent Twins" for speaking solely to each other in an idioglossia derived from an idiosyncratic, sped-up Bajan Creole dialect that qualified as an example of cryptophasia. The inseparable twins had a longstanding agreement that, if one died, the other must begin to speak and live a normal life, and it was during their 11-year admission to Broadmoor Hospital — where the twins had been indefinitely placed following a series of crimes (e.g. vandalism, petty theft and arson) in 1981 — that they began to believe that it was necessary for one of them to die. Jennifer agreed it should be her, and when the twins were transferred from Broadmoor to the more open Caswell Clinic in Bridgend, Wales in 1993, Jennifer could not be roused upon arrival. She was taken to the hospital where she died soon after of acute myocarditis, or inflammation of the heart. As no drugs or poison were found in her system, her death remains a mystery. Fulfilling their pact, June proceeded to live an otherwise-normal life.
The Burari Deaths, wherein a family of 11 members was found hanging in their home in Delhi, was ruled as a case of "Shared Psychosis," led by the youngest son of the matriarch.
In popular culture
In Folie à Deux (The X-Files) Season 5, Episode 19 (1998), Mulder is taken hostage by an employee who believes his boss is turning his coworkers into zombies.
Bug (2006) is a film that depicts a couple with a shared delusion that aphids are living under their skin.
In Season 2, Episode 3 of Criminal Minds, "The Perfect Storm" (2006), Dr. Reid mentions that the rapists had this condition.
Folie à Deux (2008) is an album by American rock band Fall Out Boy
The independent film Apart (2011) depicts two lovers affected and diagnosed with induced delusional disorder, trying to uncover a mysterious and tragic past they share. In a 2011 interview, director Aaron Rottinghaus stated the film was based on research from actual case studies.
Nine Perfect Strangers shows a couple who lost one of their two children. The couple and the surviving child have shared hallucinations of the dead child.
Any Porth in a Storm: The Long-Distance Walk that Goes South (2021), a travelogue by Oscar Burton, has a chapter with the title Folie à deux, referencing meeting another person dressed identically and with the same equipment who was also walking the 1000 km South West Coast Path in England. It is suggestive of the mental decay of the protagonist which becomes evident later in the story.
The upcoming DC Comics film Joker: Folie à Deux, a sequel to Joker (2019), shares its subtitle with the disorder.
Six Feet Under Season 4, Episode 3 (2004), George mentions Folie à deux to Ruth.
See also
References
Further reading
Books
Enoch, D., and H. Ball. 2001. "Folie à deux (et Folie à plusieurs)." In Uncommon psychiatric syndromes (4th ed.). London: Arnold. ISBN 0340763884
Halgin, R., and S. Whitbourne. 2002. Abnormal Psychology: Clinical Perspectives on Psychological Disorders. McGraw-Hill. ISBN 0072817216
Hatfield, Elaine; Caccioppo, John T & Rapson, Richard L. (1994). Emotional contagion (Studies in Emotional and Social Interaction). Cambridge, UK: Cambridge University Press. ISBN 0-521-44948-0.
Ketchum, James S. 2007. Chemical Warfare: Secrets Almost Forgotten A Personal Story of Medical Testing of Army Volunteers (2nd ed.). Chembook, Inc. ISBN 1424300800; ISBN 978-1424300808.
Metzner, Ralph, ed. (1999-06-02). Ayahuasca: Human Consciousness and the Spirits of Nature. New York, NY: Thunders Mouth Press. ISBN 1-56025-160-3.
Journal articles
Wehmeier PM, Barth N, Remschmidt H (2003). "Induced delusional disorder. a review of the concept and an unusual case of folie à famille". Psychopathology. 36 (1): 37–45. doi:10.1159/000069657. PMID 12679591. S2CID 144398794.
Abu-Salha, Mohammad (1998). "Folie á Deux: Two Case Reports". Jefferson Journal of Psychiatry. 14. doi:10.29046/JJP.014.1.002.
Ghasemzadeh, M. R.; Ghadiri Vasfi, M.; Nohesara, S.; Shabani, A. (2012). "Shared Psychotic Manic Syndrome in Monozygotic Twins: A Case Report". Iranian Journal of Psychiatry and Behavioral Sciences. 6 (1): 75–77. PMC 3939944. PMID 24644474.
Ohnuma, Tohru; Arai, Heii (2015). "Genetic or Psychogenic? A Case Study of "Folie à Quatre" Including Twins". Case Reports in Psychiatry. 2015: 1–3. doi:10.1155/2015/983212. PMC 4496465. PMID 26199782.
External links
Shared Delusional Disorder in a Cult |
Self-harm | Self-harm is intentional behavior that is considered harmful to oneself. This is most commonly regarded as direct injury of ones own skin tissues usually without a suicidal intention. Other terms such as cutting, self-injury and self-mutilation have been used for any self-harming behavior regardless of suicidal intent. It is not the same as masochism, as no sexual or nonsexual pleasure is obtained. The most common form of self-harm is using a sharp object to cut the skin. Other forms include scratching, hitting, or burning body parts. While earlier usage included interfering with wound healing, excessive skin-picking, hair-pulling, and the ingestion of toxins, current usage distinguishes these behaviors from self-harm. Likewise, tissue damage from drug abuse or eating disorders is not considered self-harm because it is ordinarily an unintended side-effect but context may be needed as intent for such acts varies.Although self-harm is by definition non-suicidal, it may still be life-threatening. People who do self-harm are more likely to die by suicide, and self-harm is found in 40–60% of suicides. Still, only a minority of self-harmers are suicidal.The desire to self-harm is a common symptom of some personality disorders. People with other mental disorders may also self-harm, including those with depression, anxiety disorders, substance abuse, mood disorders, eating disorders, post-traumatic stress disorder, schizophrenia, dissociative disorders and gender dysphoria. Studies also provide strong support for a self-punishment function, and modest evidence for anti-dissociation, interpersonal-influence, anti-suicide, sensation-seeking, and interpersonal boundaries functions. Self-harm can also occur in high-functioning individuals who have no underlying mental health diagnosis. The motivations for self-harm vary. Some use it as a coping mechanism to provide temporary relief of intense feelings such as anxiety, depression, stress, emotional numbness, or a sense of failure. Self-harm is often associated with a history of trauma, including emotional and sexual abuse. There are a number of different methods that can be used to treat self-harm and which concentrate on either treating the underlying causes or on treating the behavior itself. Other approaches involve avoidance techniques, which focus on keeping the individual occupied with other activities, or replacing the act of self-harm with safer methods that do not lead to permanent damage.Self-harm is most common between the ages of 12 and 24. Self-harm in childhood is relatively rare, but the rate has been increasing since the 1980s. Self-harm can also occur in the elderly population. The risk of serious injury and suicide is higher in older people who self-harm. Captive animals, such as birds and monkeys, are also known to participate in self-harming behavior.
Classification
Self-harm (SH), also referred to as self-injury (SI), self-inflicted violence (SIV), nonsuicidal self injury (NSSI) or self-injurious behavior (SIB), are different terms to ascribe behaviors where demonstrable injury is self-inflicted. The behavior involves deliberate tissue damage that is usually performed without suicidal intent. The most common form of self-harm involves cutting of the skin using a sharp object, e. g. a knife or razor blade. The term self-mutilation is also sometimes used, although this phrase evokes connotations that some find worrisome, inaccurate, or offensive. Self-inflicted wounds is a specific term associated with soldiers to describe non-lethal injuries inflicted in order to obtain early dismissal from combat. This differs from the common definition of self-harm, as damage is inflicted for a specific secondary purpose. A broader definition of self-harm might also include those who inflict harm on their bodies by means of disordered eating.The older literature has used several different terms. For this reason research in the past decades has inconsistently focused on self-harming behavior without and with suicidal intent (including suicide attempts) with varying definitions leading to inconsistent and unclear results.Nonsuicidal self-injury (NSSI) has been listed in section 2 of the DSM-5-TR under the category "other conditions that may be a focus of clinical attention". While NSSI is not a separate mental disorder, the DSM-5-TR adds a diagnostic code for the condition in-line with the ICD. The disorder is defined as intentional self-inflicted injury without the intent of dying by suicide. Criteria for NSSI include five or more days of self-inflicted harm over the course of one year without suicidal intent, and the individual must have been motivated by seeking relief from a negative state, resolving an interpersonal difficulty, or achieving a positive state.A common belief regarding self-harm is that it is an attention-seeking behavior; however, in many cases, this is inaccurate. Many self-harmers are very self-conscious of their wounds and scars and feel guilty about their behavior, leading them to go to great lengths to conceal their behavior from others. They may offer alternative explanations for their injuries, or conceal their scars with clothing. Self-harm in such individuals may not be associated with suicidal or para-suicidal behavior. People who self-harm are not usually seeking to end their own life; it has been suggested instead that they are using self-harm as a coping mechanism to relieve emotional pain or discomfort or as an attempt to communicate distress.Studies of individuals with developmental disabilities (such as intellectual disability) have shown self-harm being dependent on environmental factors such as obtaining attention or escape from demands. Some individuals may have dissociation harboring a desire to feel real or to fit into societys rules.
Signs and symptoms
Eighty percent of self-harm involves stabbing or cutting the skin with a sharp object, sometimes breaking through the skin entirely. However, the number of self-harm methods are only limited by an individuals inventiveness and their determination to harm themselves; this includes burning, self-poisoning, alcohol abuse, self-embedding of objects, hair pulling, bruising/hitting ones self, scratching to hurt ones self, knowingly abusing over-the-counter or prescription drugs, and forms of self-harm related to anorexia and bulimia. The locations of self-harm are often areas of the body that are easily hidden and concealed from the detection of others. As well as defining self-harm in terms of the act of damaging the body, it may be more accurate to define self-harm in terms of the intent, and the emotional distress that the person is attempting to deal with. Neither the DSM-IV-TR nor the ICD-10 provide diagnostic criteria for self-harm. It is often seen as only a symptom of an underlying disorder, though many people who self-harm would like this to be addressed.
Common signs that a person may be engaging in self-harm include the following: they ensure that there are always harmful objects close by, they are experiencing difficulties in their personal relationships, their behavior becomes unpredictable, they question their worth and identity, they make statements that display helplessness and hopelessness.
Cause
Mental disorder
Although some people who self-harm do not have any form of recognized mental disorder, many people experiencing various forms of mental illnesses do have a higher risk of self-harm. The key areas of disorder which exhibit an increased risk include autism spectrum disorders, borderline personality disorder, dissociative disorders, bipolar disorder, depression, phobias, and conduct disorders. As many as 70% of individuals with borderline personality disorder engage in self-harm. An estimated 30% of individuals with autism spectrum disorders engage in self-harm at some point, including eye-poking, skin-picking, hand-biting, and head-banging. Schizophrenia may also be a contributing factor for self-harm. Those diagnosed with schizophrenia have a high risk of suicide, which is particularly greater in younger patients as they may not have an insight into the serious effects that the disorder can have on their lives. There are parallels between self-harm and Münchausen syndrome, a psychiatric disorder in which individuals feign illness or trauma. There may be a common ground of inner distress culminating in self-directed harm in a Münchausen patient. However, a desire to deceive medical personnel in order to gain treatment and attention is more important in Münchausens than in self-harm.
Psychological factors
Self-harm is frequently described as an experience of depersonalization or a dissociative state. Abuse during childhood is accepted as a primary social factor increasing the incidence of self-harm, as is bereavement, and troubled parental or partner relationships. Factors such as war, poverty, unemployment, and substance abuse may also contribute. Other predictors of self-harm and suicidal behavior include feelings of entrapment, defeat, lack of belonging, and perceiving oneself as a burden along with having an impulsive personality and/or less effective social problem-solving skills. The onset of puberty, including the onset of sexual activity, often correlates with the onset of self-harm; this is because the pubertal period is associated with neurodevelopmental vulnerability and comes with an increased risk of emotional disorders and risk-taking behaviors. Transgender adolescents are significantly more likely to engage in self-harm than their cisgender peers. This can be attributed to distress caused by gender dysphoria as well as increased likelihoods of experiencing bullying, abuse, and mental illness.
Genetics
The most distinctive characteristic of the rare genetic condition, Lesch–Nyhan syndrome, is self-harm and may include biting and head-banging. Genetics may contribute to the risk of developing other psychological conditions, such as anxiety or depression, which could in turn lead to self-harming behavior. However, the link between genetics and self-harm in otherwise healthy patients is largely inconclusive.
Drugs and alcohol
Substance misuse, dependence and withdrawal are associated with self-harm. Benzodiazepine dependence as well as benzodiazepine withdrawal is associated with self-harming behavior in young people. Alcohol is a major risk factor for self-harm. A study which analysed self-harm presentations to emergency rooms in Northern Ireland found that alcohol was a major contributing factor and involved in 63.8% of self-harm presentations. A recent study in the relation between cannabis use and deliberate self-harm (DSH) in Norway and England found that, in general, cannabis use may not be a specific risk factor for DSH in young adolescents. Smoking has also been associated with self-harm in adolescents; one study found that suicide attempts were four times higher for adolescents that smoke than for those that do not. A more recent meta-analysis on literature concerning the association between cannabis use and self-injurious behaviors has defined the extent of this association, which is significant both at the cross-sectional (odds ratio = 1.569, 95% confidence interval [1.167-2.108]) and longitudinal (odds ratio = 2.569, 95% confidence interval [2.207-3.256]) levels, and highlighting the role of the chronic use of the substance, and the presence of depressive symptoms or of mental disorders as factors that might increase the risk of self-injury among cannabis users.
Pathophysiology
Self-harm is not typically suicidal behavior, although there is the possibility that a self-inflicted injury may result in life-threatening damage. Although the person may not recognise the connection, self-harm often becomes a response to profound and overwhelming emotional pain that cannot be resolved in a more functional way.The motivations for self-harm vary, as it may be used to fulfill a number of different functions. These functions include self-harm being used as a coping mechanism which provides temporary relief of intense feelings such as anxiety, depression, stress, emotional numbness and a sense of failure or self-loathing. There is also a positive statistical correlation between self-harm and emotional abuse. Self-harm may become a means of managing and controlling pain, in contrast to the pain experienced earlier in the persons life over which they had no control (e.g., through abuse).Other motives for self-harm do not fit into medicalized models of behavior and may seem incomprehensible to others, as demonstrated by this quotation:
"My motivations for self-harming were diverse, but included examining the interior of my arms for hydraulic lines. This may sound strange."Assessment of motives in a medical setting is usually based on precursors to the incident, circumstances, and information from the patient. However, limited studies show that professional assessments tend to suggest more manipulative or punitive motives than personal assessments.A UK Office for National Statistics study reported only two motives: "to draw attention" and "because of anger". For some people, harming themselves can be a means of drawing attention to the need for help and to ask for assistance in an indirect way. It may also be an attempt to affect others and to manipulate them in some way emotionally. However, those with chronic, repetitive self-harm often do not want attention and hide their scars carefully.Many people who self-harm state that it allows them to "go away" or dissociate, separating the mind from feelings that are causing anguish. This may be achieved by tricking the mind into believing that the present suffering being felt is caused by the self-harm instead of the issues they were facing previously: the physical pain therefore acts as a distraction from the original emotional pain. To complement this theory, one can consider the need to "stop" feeling emotional pain and mental agitation. "A person may be hyper-sensitive and overwhelmed; a great many thoughts may be revolving within their mind, and they may either become triggered or could make a decision to stop the overwhelming feelings."Alternatively, self-harm may be a means of feeling something, even if the sensation is unpleasant and painful. Those who self-harm sometimes describe feelings of emptiness or numbness (anhedonia), and physical pain may be a relief from these feelings. "A person may be detached from themselves, detached from life, numb and unfeeling. They may then recognise the need to function more, or have a desire to feel real again, and a decision is made to create sensation and wake up."Those who engage in self-harm face the contradictory reality of harming themselves while at the same time obtaining relief from this act. It may even be hard for some to actually initiate cutting, but they often do because they know the relief that will follow. For some self-harmers this relief is primarily psychological while for others this feeling of relief comes from the beta endorphins released in the brain. Endorphins are endogenous opioids that are released in response to physical injury, acting as natural painkillers and inducing pleasant feelings, and in response to self-harm would act to reduce tension and emotional distress. Many self-harmers report feeling very little to no pain while self-harming and, for some, deliberate self-harm may become a means of seeking pleasure.
As a coping mechanism, self-harm can become psychologically addictive because, to the self-harmer, it works; it enables them to deal with intense stress in the current moment. The patterns sometimes created by it, such as specific time intervals between acts of self-harm, can also create a behavioral pattern that can result in a wanting or craving to fulfill thoughts of self-harm.
Autonomic nervous system
Emotional pain activates the same regions of the brain as physical pain, so emotional stress can be a significantly intolerable state for some people. Some of this is environmental and some of this is due to physiological differences in responding. The autonomic nervous system is composed of two components: the sympathetic nervous system controls arousal and physical activation (e.g., the fight-or-flight response) and the parasympathetic nervous system controls physical processes that are automatic (e.g., saliva production). The sympathetic nervous system innervates (e.g., is physically connected to and regulates) many parts of the body involved in stress responses. Studies of adolescents have shown that adolescents who self-injure have greater physiological reactivity (e.g., skin conductance) to stress than adolescents who do not self-injure. This stress response persists over time, staying constant or even increasing in self-injuring adolescents, but gradually decreases in adolescents who do not self-injure.
Treatment
Several forms of psychosocial treatments can be used in self-harm including dialectical behavior therapy. Psychiatric and personality disorders are common in individuals who self-harm and as a result self-harm may be an indicator of depression and/or other psychological problems. Many people who self-harm have moderate or severe depression and therefore treatment with antidepressant medications may often be used. There is tentative evidence for the medication flupentixol; however, greater study is required before it can be recommended.
Therapy
Dialectical behavior therapy for adolescents (DBT-A) is a well-established treatment for self-injurious behavior in youth and probably useful for decreasing the risk of non suicidal self injury. Several other treatments including integrated CBT (I-CBT), attachment-based family therapy (ABFT), resourceful adolescent parent program (RAP-P), intensive interpersonal psychotherapy for adolescents (IPT-A-IN), mentalization-based treatment for adolescents (MBT-A), and integrated family therapy are probably efficacious. Cognitive behavioral therapy may also be used to assist those with Axis I diagnoses, such as depression, schizophrenia, and bipolar disorder. Dialectical behavior therapy (DBT) can be successful for those individuals exhibiting a personality disorder, and could potentially be used for those with other mental disorders who exhibit self-harming behavior. Diagnosis and treatment of the causes of self-harm is thought by many to be the best approach to treating self-harm. But in some cases, particularly in people with a personality disorder, this is not very effective, so more clinicians are starting to take a DBT approach in order to reduce the behavior itself. People who rely on habitual self-harm are sometimes hospitalized, based on their stability, their ability and especially their willingness to get help. In adolescents multisystem therapy shows promise. Pharmacotherapy has not been tested as a treatment for adolescents who self-harmed.A meta-analysis found that psychological therapy is effective in reducing self-harm. The proportion of the adolescents who self-harmed over the follow-up period was lower in the intervention groups (28%) than in controls (33%). Psychological therapies with the largest effect sizes were dialectical behavior therapy (DBT), cognitive-behavioral therapy (CBT), and mentalization-based therapy (MBT).In individuals with developmental disabilities, occurrence of self-harm is often demonstrated to be related to its effects on the environment, such as obtaining attention or desired materials or escaping demands. As developmentally disabled individuals often have communication or social deficits, self-harm may be their way of obtaining these things which they are otherwise unable to obtain in a socially appropriate way (such as by asking). One approach for treating self-harm thus is to teach an alternative, appropriate response which obtains the same result as the self-harm.
Avoidance techniques
Generating alternative behaviors that the person can engage in instead of self-harm is one successful behavioral method that is employed to avoid self-harm. Techniques, aimed at keeping busy, may include journaling, taking a walk, participating in sports or exercise or being around friends when the person has the urge to harm themselves. The removal of objects used for self-harm from easy reach is also helpful for resisting self-harming urges. The provision of a card that allows the person to make emergency contact with counselling services should the urge to self-harm arise may also help prevent the act of self-harm. Alternative and safer methods of self-harm that do not lead to permanent damage, for example the snapping of a rubber band on the wrist, may also help calm the urge to self-harm. Using biofeedback may help raise self-awareness of certain pre-occupations or particular mental state or mood that precede bouts of self-harming behavior, and help identify techniques to avoid those pre-occupations before they lead to self-harm. Any avoidance or coping strategy must be appropriate to the individuals motivation and reason for harming.
Epidemiology
It is difficult to gain an accurate picture of incidence and prevalence of self-harm. This is due in a part to a lack of sufficient numbers of dedicated research centres to provide a continuous monitoring system. However, even with sufficient resources, statistical estimates are crude since most incidences of self-harm are undisclosed to the medical profession as acts of self-harm are frequently carried out in secret, and wounds may be superficial and easily treated by the individual. Recorded figures can be based on three sources: psychiatric samples, hospital admissions and general population surveys.The World Health Organization estimates that, as of 2010, 880,000 deaths occur as a result of self-harm. About 10% of admissions to medical wards in the UK are as a result of self-harm, the majority of which are drug overdoses. However, studies based only on hospital admissions may hide the larger group of self-harmers who do not need or seek hospital treatment for their injuries, instead treating themselves. Many adolescents who present to general hospitals with deliberate self-harm report previous episodes for which they did not receive medical attention. In the United States up to 4% of adults self-harm with approximately 1% of the population engaging in chronic or severe self-harm.Current research suggests that the rates of self-harm are much higher among young people with the average age of onset between 14 and 24. The earliest reported incidents of self-harm are in children between 5 and 7 years old. In the UK in 2008 rates of self-harm in young people could be as high as 33%. In addition there appears to be an increased risk of self-harm in college students than among the general population. In a study of undergraduate students in the US, 9.8% of the students surveyed indicated that they had purposefully cut or burned themselves on at least one occasion in the past. When the definition of self-harm was expanded to include head-banging, scratching oneself, and hitting oneself along with cutting and burning, 32% of the sample said they had done this. In Ireland, a study found that instances of hospital-treated self-harm were much higher in city and urban districts, than in rural settings. The CASE (Child & Adolescent Self-harm in Europe) study suggests that the life-time risk of self-injury is ~1:7 for women and ~1:25 for men.
Gender differences
In general, the latest aggregated research has found no difference in the prevalence of self-harm between men and women. This is in contrast to past research which indicated that up to four times as many females as males have direct experience of self-harm. However, caution is needed in seeing self-harm as a greater problem for females, since males may engage in different forms of self-harm (e.g., hitting themselves) which could be easier to hide or explained as the result of different circumstances. Hence, there remain widely opposing views as to whether the gender paradox is a real phenomenon, or merely the artifact of bias in data collection.The WHO/EURO Multicentre Study of Suicide, established in 1989, demonstrated that, for each age group, the female rate of self-harm exceeded that of the males, with the highest rate among females in the 13–24 age group and the highest rate among males in the 12–34 age group. However, this discrepancy has been known to vary significantly depending upon population and methodological criteria, consistent with wide-ranging uncertainties in gathering and interpreting data regarding rates of self-harm in general. Such problems have sometimes been the focus of criticism in the context of broader psychosocial interpretation. For example, feminist author Barbara Brickman has speculated that reported gender differences in rates of self-harm are due to deliberate socially biased methodological and sampling errors, directly blaming medical discourse for pathologising the female.This gender discrepancy is often distorted in specific populations where rates of self-harm are inordinately high, which may have implications on the significance and interpretation of psychosocial factors other than gender. A study in 2003 found an extremely high prevalence of self-harm among 428 homeless and runaway youths (aged 16–19) with 72% of males and 66% of females reporting a history of self-harm. However, in 2008, a study of young people and self-harm saw the gender gap widen in the opposite direction, with 32% of young females, and 22% of young males admitting to self-harm. Studies also indicate that males who self-harm may also be at a greater risk of completing suicide.There does not appear to be a difference in motivation for self-harm in adolescent males and females. Triggering factors such as low self-esteem and having friends and family members who self-harm are also common between both males and females. One limited study found that, among those young individuals who do self-harm, both genders are just as equally likely to use the method of skin-cutting. However, females who self-cut are more likely than males to explain their self-harm episode by saying that they had wanted to punish themselves. In New Zealand, more females are hospitalized for intentional self-harm than males. Females more commonly choose methods such as self-poisoning that generally are not fatal, but still serious enough to require hospitalization.
Elderly
In a study of a district general hospital in the UK, 5.4% of all the hospitals self-harm cases were aged over 65. The male to female ratio was 2:3 although the self-harm rates for males and females over 65 in the local population were identical. Over 90% had depressive conditions, and 63% had significant physical illness. Under 10% of the patients gave a history of earlier self-harm, while both the repetition and suicide rates were very low, which could be explained by the absence of factors known to be associated with repetition, such as personality disorder and alcohol abuse. However, NICE Guidance on Self-harm in the UK suggests that older people who self-harm are at a greater risk of completing suicide, with 1 in 5 older people who self-harm going on to end their life. A study completed in Ireland showed that older Irish adults have high rates of deliberate self-harm, but comparatively low rates of suicide.
Developing world
Only recently have attempts to improve health in the developing world concentrated on not only physical illness but also mental health. Deliberate self-harm is common in the developing world. Research into self-harm in the developing world is however still very limited although an important case study is that of Sri Lanka, which is a country exhibiting a high incidence of suicide and self-poisoning with agricultural pesticides or natural poisons. Many people admitted for deliberate self-poisoning during a study by Eddleston et al. were young and few expressed a desire to die, but death was relatively common in the young in these cases. The improvement of medical management of acute poisoning in the developing world is poor and improvements are required in order to reduce mortality.
Some of the causes of deliberate self-poisoning in Sri Lankan adolescents included bereavement and harsh discipline by parents. The coping mechanisms are being spread in local communities as people are surrounded by others who have previously deliberately harmed themselves or attempted suicide. One way of reducing self-harm would be to limit access to poisons; however many cases involve pesticides or yellow oleander seeds, and the reduction of access to these agents would be difficult. Great potential for the reduction of self-harm lies in education and prevention, but limited resources in the developing world make these methods challenging.
Prison inmates
Deliberate self-harm is especially prevalent in prison populations. A proposed explanation for this is that prisons are often violent places, and prisoners who wish to avoid physical confrontations may resort to self-harm as a ruse, either to convince other prisoners that they are dangerously insane and resilient to pain or to obtain protection from the prison authorities. Self-harm also occurs frequently in inmates who are placed in solitary confinement.
History
Self-harm was, and in some cases continues to be, a ritual practice in many cultures and religions.
The Maya priesthood performed auto-sacrifice by cutting and piercing their bodies in order to draw blood. A reference to the priests of Baal "cutting themselves with blades until blood flowed" can be found in the Hebrew Bible. However, in Judaism, such self-harm is forbidden under Mosaic law. It occurred in ancient Canaanite mourning rituals, as described in the Ras Shamra tablets.
Self-harm is practized in Hinduism by the ascetics known as sadhus. In Catholicism it is known as mortification of the flesh. Some branches of Islam mark the Day of Ashura, the commemoration of the martyrdom of Imam Hussein, with a ritual of self-flagellation, using chains and swords.Dueling scars such as those acquired through academic fencing at certain traditional German universities are an early example of scarification in European society. Sometimes, students who did not fence would scar themselves with razors in imitation.Constance |
Self-harm | Lytton, a prominent suffragette, used a stint in Holloway Prison during March 1909 to mutilate her body. Her plan was to carve Votes for Women from her breast to her cheek, so that it would always be visible. But after completing the V on her breast and ribs she requested sterile dressings to avoid blood poisoning, and her plan was aborted by the authorities. She wrote of this in her memoir Prisons and Prisoners.
Kikuyu girls cut each others vulvas in the 1950s as a symbol of defiance, in the context of the campaign against female genital mutilation in colonial Kenya. The movement came to be known as Ngaitana ("I will circumcise myself"), because to avoid naming their friends the girls said they had cut themselves. Historian Lynn Thomas described the episode as significant in the history of FGM because it made clear that its victims were also its perpetrators.
Classification
The term "self-mutilation" occurred in a study by L. E. Emerson in 1913 where he considered self-cutting a symbolic substitution for masturbation. The term reappeared in an article in 1935 and a book in 1938 when Karl Menninger refined his conceptual definitions of self-mutilation. His study on self-destructiveness differentiated between suicidal behaviors and self-mutilation. For Menninger, self-mutilation was a non-fatal expression of an attenuated death wish and thus coined the term partial suicide. He began a classification system of six types:
neurotic – nail-biters, pickers, extreme hair removal and unnecessary cosmetic surgery.
religious – self-flagellants and others.
puberty rites – hymen removal, circumcision or clitoral alteration.
psychotic – eye or ear removal, genital self-mutilation and extreme amputation
organic brain diseases – which allow repetitive head-banging, hand-biting, finger-fracturing or eye removal.
conventional – nail-clipping, trimming of hair and shaving beards.Pao (1969) differentiated between delicate (low lethality) and coarse (high lethality) self-mutilators who cut. The "delicate" cutters were young, multiple episodic of superficial cuts and generally had borderline personality disorder diagnosis. The "coarse" cutters were older and generally psychotic. Ross and McKay (1979) categorized self-mutilators into 9 groups: cutting, biting, abrading, severing, inserting, burning, ingesting or inhaling, hitting, and constricting.After the 1970s the focus of self-harm shifted from Freudian psycho-sexual drives of the patients.Walsh and Rosen (1988) created four categories numbered by Roman numerals I–IV, defining Self-mutilation as rows II, III and IV.
Favazza and Rosenthal (1993) reviewed hundreds of studies and divided self-mutilation into two categories: culturally sanctioned self-mutilation and deviant self-mutilation. Favazza also created two subcategories of sanctioned self-mutilations; rituals and practices. The rituals are mutilations repeated generationally and "reflect the traditions, symbolism, and beliefs of a society" (p. 226). Practices are historically transient and cosmetic such as piercing of earlobes, nose, eyebrows as well as male circumcision (for non-Jews) while Deviant self-mutilation is equivalent to self-harm.
Awareness and opposition
There are many movements among the general self-harm community to make self-harm itself and treatment better known to mental health professionals, as well as the general public. For example, March 1 is designated as Self-injury Awareness Day (SIAD) around the world. On this day, some people choose to be more open about their own self-harm, and awareness organizations make special efforts to raise awareness about self-harm.
Other animals
Self-harm in non-human mammals is a well-established but not widely known phenomenon. Its study under zoo or laboratory conditions could lead to a better understanding of self-harm in human patients.Zoo or laboratory rearing and isolation are important factors leading to increased susceptibility to self-harm in higher mammals, e.g., macaque monkeys. Non-primate mammals are also known to mutilate themselves under laboratory conditions after administration of drugs. For example, pemoline, clonidine, amphetamine, and very high (toxic) doses of caffeine or theophylline are known to precipitate self-harm in lab animals.In dogs, canine obsessive-compulsive disorder can lead to self-inflicted injuries, for example canine lick granuloma. Captive birds are sometimes known to engage in feather-plucking, causing damage to feathers that can range from feather shredding to the removal of most or all feathers within the birds reach, or even the mutilation of skin or muscle tissue.Breeders of show mice have noticed similar behaviors.
One known as "barbering" involves a mouse obsessively grooming the whiskers and facial fur off of themselves and cage-mates.
See also
Self-destructive behavior
Self-hatred
Self-Injurious Behavior Inhibiting System
References
External links
Information about self-harm from the Royal College of Psychiatrists |
Separation anxiety disorder | Separation anxiety disorder (SAD) is an anxiety disorder in which an individual experiences excessive anxiety regarding separation from home and/or from people to whom the individual has a strong emotional attachment (e.g., a parent, caregiver, significant other, or siblings). Separation anxiety is a natural part of the developmental process. It is most common in infants and little children, typically between the ages of six to seven months to three years, although it may pathologically manifest itself in older children, adolescents and adults. Unlike SAD (indicated by excessive anxiety), normal separation anxiety indicates healthy advancements in a childs cognitive maturation and should not be considered a developing behavioral problem.According to the American Psychiatric Association (APA), separation anxiety disorder is an excessive display of fear and distress when faced with situations of separation from the home and/or from a specific attachment figure. The anxiety that is expressed is categorized as being atypical of the expected developmental level and age. The severity of the symptoms ranges from anticipatory uneasiness to full-blown anxiety about separation.SAD may cause significant negative effects within areas of social and emotional functioning, family life, and physical health of the disordered individual. The duration of this problem must persist for at least four weeks and must present itself before a child is eighteen years of age to be diagnosed as SAD in children, but can now be diagnosed in adults with a duration typically lasting six months in adults as specified by the DSM-5.
Background
The origins of separation anxiety disorder stem from attachment theory which has roots in the attachment theories both of Sigmund Freud and John Bowlby. Freuds attachment theory, which has similarities to learning theory, proposes that infants have instinctual impulses, and when these impulses go unnoticed, it traumatizes the infant. The infant then learns that when their mother is absent, this will be followed by a distressing lack of gratification, thus making the mothers absence a conditioned stimulus that triggers anxiety in the infant who then expects their needs to be ignored. The result of this association is that the child becomes fearful of all situations that include distance from their caregiver.
John Bowlbys attachment theory also contributed to the thinking process surrounding separation anxiety disorder. His theory is a framework in which to contextualize the relationships that humans form with one another. Bowlby suggests that infants are instinctively motivated to seek proximity with a familiar caregiver, especially when they are alarmed, and they expect that in these moments they will be met with emotional support and protection. He poses that all infants become attached to their caregivers, however, there are individual differences in the way that these attachments develop. There are 4 main attachment styles according to Bowlby; secure attachment, anxious-avoidant attachment, disorganized attachment, and anxious-ambivalent attachment. Anxious-ambivalent attachment is most relevant here because its description, when an infant feels extreme distress and anxiety when their caregiver is absent and does not feel reassured when they return, is very similar to SAD.
Signs and symptoms
Academic setting
As with other anxiety disorders, children with SAD tend to face more obstacles at school than those without anxiety disorders. Adjustment and relating school functioning have been found to be much more difficult for anxious children. In some severe forms of SAD, children may act disruptively in class or may refuse to attend school altogether. It is estimated that nearly 75% of children with SAD exhibit some form of school refusal behavior.There are several possible manifestations of this disorder when the child is introduced into an academic setting. A child with SAD may protest profusely upon arrival at school. They might have a hard time saying goodbye to their parents and exhibit behaviors like tightly clinging to the parent in a way that makes it nearly impossible for the parent to detach from them. They might scream and cry but in a way that makes it seem as though they were in pain. The child might scream and cry for an extended period of time after his or her parents are gone (for several minutes to upwards of an hour) and refuse to interact with other children or teachers, rejecting their attention. They might feel an overwhelming need to know where their parents are and that they are okay.
This is a serious problem because, as children fall further behind in coursework, it becomes increasingly difficult for them to return to school.Short-term problems resulting from academic refusal include poor academic performance or decline in performance, alienation from peers, and conflict within the family.Although school refusal behavior is common among children with SAD, it is important to note that school refusal behavior is sometimes linked to generalized anxiety disorder or possibly a mood disorder. That being said, a majority of children with separation anxiety disorder have school refusal as a symptom. Up to 80% of children who refuse school qualify for a diagnosis of separation anxiety disorder.
Home setting
Symptoms for SAD might persist even in a familiar and/or comfortable setting for the child, like the home. The child might be afraid to be in a room alone even if they know that their parent is in the next room over. They might fear being alone in the room, or going to sleep in a dark room. Problems might present themselves during bedtime, as the child might refuse to go to sleep unless their parent is near and visible. During the day, the child might "shadow" the parent and cling to their side.
Workplace
Just how SAD affects a childs attendance and participation in school, their avoidance behaviors stay with them as they grow and enter adulthood. Recently, "the effects of mental illness on workplace productivity have become a prominent concern on both the national and international fronts". In general, mental illness is a common health problem among working adults, 20% to 30% of adults will suffer from at least one psychiatric disorder. Mental illness is linked to decreased productivity, and with individuals diagnosed with SAD their levels at which they function decreases dramatically resulting in partial work-days, increase in number of total absences, and "holding back" when it comes to carrying out and completing tasks.
Cause
Factors that contribute to the disorder include a combination and interaction of biological, cognitive, environmental, child temperament, and behavioral factors.
Children are more likely to develop SAD if one or both of their parents was diagnosed with a psychological disorder. Recent research by Daniel Schechter and colleagues have pointed to difficulties of mothers who have themselves had early adverse experiences such as maltreatment and disturbed attachments with their own caregivers, who then go on to develop responses to their infants and toddlers normative social bids in the service of social referencing, emotion regulation, and joint attention, which responses are linked to these mothers own psychopathology (i.e. maternal post-traumatic stress disorder (PTSD) and depression.) These atypical maternal responses which have been shown to be associated with separation anxiety have been related to disturbances in maternal stress physiologic response to mother-toddler separation as well as lower maternal neural activity in the brain region of the medial prefrontal cortex when mothers with and without PTSD were shown video excerpts of their own and unfamiliar toddlers during mother-child separation versus free-play.Many psychological professionals have suggested that early or traumatic separation from a central caregiver in a childs life can increase the likelihood of them being diagnosed with SAD, school phobia, and depressive-spectrum disorders. Some children can be more vulnerable to SAD due to their temperament, for example, their level of anxiety when placed in new situations.
Environmental
Most often, the onset of separation anxiety disorder is caused by a stressful life-event, especially a loss of a loved one or pet, but can also include parental divorce, change of school or neighbourhood, natural disasters, or circumstances which forced the individual to be separated from their attachment figure(s). In older individuals, stressful life experiences may include going away to college, moving out for the first time, or becoming a parent. According to the DSM-5 young adults with separation anxiety disorder have different examples of stress, including leaving their parents home, entering a romantic relationship, and becoming a parent. In some cases parental overprotectiveness may be associated with separation anxiety disorder.
Genetic and physiological
There may be a genetic predisposition in children with separation anxiety disorder. "Separation anxiety disorder in children may be heritable." "Heritability was estimated at 73% in a community sample of 6-year-old twins, with higher rates in girls."A childs temperament can also impact the development of SAD. Timid and shy behaviors may be referred to as "behaviorally inhibited temperaments" in which the child may experience anxiety when they are not familiar with a particular location or person.
Mechanism
Preliminary evidence shows that heightened activity of the amygdala may be associated with symptoms of separation anxiety disorder. Defects in the ventrolateral and dorsomedial areas of the prefrontal cortex are also correlated to anxiety disorders in children.
Diagnosis
Separation anxiety occurs in many infants and young children as they are becoming acclimated with their surroundings. This anxiety is viewed as a normal developmental phase between the months of early infancy until age two. Separation anxiety is normal in young children, until they age 3–4 years, when children are left in a daycare or preschool, away from their parent or primary caregiver. Other sources note that a definite diagnosis of SAD should not be presented until after the age of three.Some studies have shown that hormonal influences during pregnancy can result in lower cortisol levels later in life, which can later lead to psychological disorders, such as SAD. It is also important to note significant life changes experienced by the child either previous to or present at the onset of the disorder. For example, children who emigrated from another country at an early age may have a stronger tendency for developing this disorder, as they have already felt displaced from a location they were starting to become accustomed to. It is not uncommon for them to incessantly cling to their caregiver at first upon arrival to the new location, especially if the child is unfamiliar with the language of their new country. These symptoms may diminish or go away as the child becomes more accustomed to the new surroundings. Other sources note that a definite diagnosis of SAD should not be presented until after the age of three. Separation anxiety may be diagnosed as a disorder if the childs anxiety related to separation from the home or attachment figure is deemed excessive; if the level of anxiety surpasses that of the acceptable caliber for the childs developmental level and age; and if the anxiety negatively impacts the childs everyday life.Many psychological disorders begin to emerge during childhood. Nearly two-thirds of adults with psychological disorder show signs of their disorder earlier in life. However, not all psychological disorders are present before adulthood. In many cases, there are no signs during childhood.Behavioral inhibition (BI) plays a large role in many anxiety disorders, SAD included. Compared to children without it, children with BI demonstrate more signs of fear when experiencing a new stimulus, particularly those that are social in nature. Children with BI are at a higher risk for developing a mental disorder, particularly anxiety disorders, than children without BI.Separation anxiety is normal in young children, until they age 3–4 years, when children are left in a daycare or preschool, away from their parent or primary caregiver.To be diagnosed with SAD, one must display at least three of the following criteria:
Recurrent excessive distress when anticipating or experiencing separation from home or from major attachment figures
Persistent and excessive worry about losing major attachment figures or about possible harm to them, such as illness, injury, disasters, or death
Persistent and excessive worry about experiencing an untoward event (e.g., getting lost, being kidnapped, having an accident, becoming ill) that causes separation from a major attachment figure
Persistent reluctance or refusal to go out, away from home, to school, to work, or elsewhere because of fear of separation
Persistent and excessive fear of or reluctance about being alone or without major attachment figures at home or in other settings
Persistent reluctance or refusal to sleep away from home or to go to sleep without being near a major attachment figure
Repeated nightmares involving the theme of separation
Repeated complaints of physical symptoms (e.g., headaches, stomachaches, nausea, vomiting) when separation from major attachment figures occurs or is anticipated
Classification
Separation anxiety is common for infants between the ages of eight and fourteen months and occurs as infants begin to understand their own selfhood—or understand that they are separate persons from their primary caregiver. Infants oftentimes look for their caregivers to give them a sense of comfort and familiarity, which causes separation to become challenging. Subsequently, the concept of object permanence emerges—which is when children learn that something still exists when it cannot be seen or heard, thus increasing their awareness of being separated from their caregiver. Consequently, during the developmental period where an infants sense self, incorporating object permanence as well, the child also begins to understand that they can in fact be separated from their primary caregiver. They see this separation as something final though, and dont yet understand that their caregiver will return causing fear and distress for the infant. It is when an individual (infant, child, or otherwise) consistently reacts to separation with excessive anxiety and distress and experiences a great deal of interference from their anxiety that a diagnosis of separation anxiety disorder (SAD) can be warranted.One of the difficulties in the identification of separation anxiety disorder in children is that it is highly comorbid with other behavioral disorders, especially generalized anxiety disorder. Behaviors such as refusal or hesitancy in attending school or homesickness for example, can easily reflect similar symptoms and behavioral patterns that are commonly associated with SAD, but could be an overlap of symptoms. The prevalence of co-occurring disorders in adults with separation anxiety disorder is common and includes a much broader spectrum of diagnostic possibilities. Common co-morbidities can include specific phobias, PTSD, panic disorder, obsessive-compulsive disorder, and personality disorders. It is very common for psychological disorders to overlap and even lead to the manifestation of another, especially when it comes to anxiety disorders. Because of the variation and overlap in symptoms a proper, thorough evaluation of the individual is critical to distinguish the differences and significance. An important signifier to establish a difference between SAD and other anxiety or psychological disorders is to investigate where the individuals fear of separation is stemming from; this can be accomplished by asking "what they fear will occur during a separation from their significant other".What stands out about SAD, as mentioned above, are the avoidance behaviors which present within an individual. Individuals "typically exhibit excessive distress manifested by crying, repeated complaints of physical symptoms (e.g., stomach aches, headaches, etc.), avoidance (e.g., refusing to go to school, to sleep alone, to be left alone in the home, to engage in social events, to go to work, etc.), and engagement in safety behaviors (e.g., frequent calls to or from significant others, or primary caregivers)".
Assessment methods
Assessment methods include diagnostic interviews, self-report measures from both the parent and child, observation of parent-child interaction, and specialized assessment for preschool-aged children. Various facets of a childs development including social life, feeding and sleep schedules, medical issues, traumatic events experienced, family history of mental or anxiety health issues are explored. The compilation of aspects of a childs life aids in capturing a multi-dimensional view of the childs life.Additionally, while much research has been done in efforts to further understand separation anxiety in regards to the relationship between infants and their caregivers, it was behavioral psychologist, Mary Ainsworth, who devised a behavioral evaluation method, The Strange Situation (1969), which, at the time, was considered to be the most valuable and famous body of research in the study of separation anxiety. The Strange Situation process assisted in evaluating and measuring the individual attachment styles of infants between the ages of 9 and 18 months. In this observational study an environment is created that fluctuates between familiar and unfamiliar situations that would be experienced in everyday life. The variations in stressfulness and the childs responses are observed and, based on the interaction behavior that is directed towards the caregiver, the infant is categorized into one of four different types of attachment styles: 1. Secure, 2. Anxious-avoidant, insecure, 3. Anxious-ambivalent/resistant, insecure and 4. Disorganized/disoriented.Clinicians may utilize interviews as an assessment tool to gauge the symptomatic occurrences to aid in diagnosing SAD. Interviews may be conducted with the child and also with the attachment figure. Interviewing both child and parent separately allows for the clinician to compile different points of view and information.Commonly used interviews include:
Anxiety Disorders Interview Schedule for the DSM-IV, Child Parent Versions (ADIS-IV-C/P)
Diagnostic Interview Schedule for Children, Version IV (DISC-IV)
Schedule for Affective Disorders and Schizophrenia for School-aged Children-Present and lifetime version IV (K-SADS-IV)
Self-report measures
This form of assessment should not be the sole basis of a SAD diagnosis. It is also important to verify that the child who is reporting on their experiences has the cognitive and communication skills appropriate to accurately comprehend and respond to these measurements.
An example of a self-report tool that has been tested is: The Separation Anxiety Assessment Scale for Children (SAAS-C). The scale contains 34 items and is divided into six dimensions. The dimensions in order are: Abandonment, Fear of Being Alone, Fear of Physical Illness, Worry about Calamitous Events, Frequency of Calamitous Events, and Safety Signal Index. The first five dimensions have a total of five items while the last one contains nine items. The scale goes beyond assessing symptoms; it focuses on individual cases and treatment planning.
Observation
As noted by Altman, McGoey & Sommer, it is important to observe the child, "in multiple contexts, on numerous occasions, and in their everyday environments (home, daycare, preschool)". It is beneficial to view parent and child interactions and behaviors that may contribute to SAD.Dyadic Parent-Child Interaction Coding System and recently the Dyadic Parent-Child Interaction Coding System II (DPICS II) are methods used when observing parents and children interactions.Separation Anxiety Daily Diaries (SADD) have also been used to "assess anxious behaviors along with their antecedents and consequences and may be particularly suited to SAD given its specific focus on parent–child separation" (Silverman & Ollendick, 2005). The diaries are carefully evaluated for validity.
Preschool-aged children
At the preschool-aged stage, early identification and intervention is crucial. The communication abilities of young children are taken into consideration when creating age-appropriate assessments.A commonly used assessment tool for preschool-aged children (ages 2–5) is the Preschool Age Psychiatric Assessment (PAPA). Additional questionnaires and rating scales that are used to assess the younger population include the Achenbach Scales, the Fear Survey Schedule for Infants and Preschoolers, and The Infant–Preschool Scale for Inhibited Behaviors.Preschool children are also interviewed. Two interviews that are sometimes conducted are Attachment Doll-Play and Emotional Knowledge. In both of the assessments the interviewer depicts a scenario where separation and reunion occur; the child is then told to point at one of the four facial expressions presented. These facial expressions show emotions such as anger or sadness. The results are then analyzed.Behavioral observations are also utilized when assessing the younger population. Observations enable the clinician to view some of the behaviors and emotions in specific contexts.
Treatment
Non-medication based
Non-medication based treatments are the first choice when treating individuals diagnosed with separation anxiety disorder. Counseling tends to be the best replacement for drug treatments. There are two different non-medication approaches to treat separation anxiety. The first is a psychoeducational intervention, often used in conjunction with other therapeutic treatments. This specifically involves educating the individual and their family so that they are knowledgeable about the disorder, as well as parent counseling and guiding teachers on how to help the child. The second is a psychotherapeutic intervention when prior attempts are not effective. Psychotherapeutic interventions are more structured and include behavioral, cognitive-behavioral, contingency, psychodynamic psychotherapy, and family therapy.
Exposure and behavioral therapy
Behavioral therapies are types of non-medication based treatment which are mainly exposure-based techniques. These include techniques such as systematic desensitization, emotive imagery, participant modelling and contingency management. Behavioral therapies carefully expose individuals by small increments to slowly reduce their anxiety over time and mainly focuses on their behavior. Exposure based therapy works under the principle of habituation that is derived from learning theory. The core concept of exposure therapy is that anxiety about situations, people, and things does not go away when people avoid the things that they fear, but rather, the uncomfortable feelings are simply kept at bay. In order to effectively diminish the negative feelings associated with the situation of fear, one must address them directly. In order to administer this treatment, the therapist and the anxious child might sit together and identify progressively intense situations. As each situation is dealt with masterfully, the child advances to the next phase of intensity. This pattern continues until the child is able to handle being away from their parent in a developmentally typical way that causes them and their caregiver(s) minimal amounts of stress. While there is some controversy about using exposure therapy with children, it is generally agreed upon that exposure therapy in the context of SAD is acceptable as it may be the most effective form of therapy in treating this disorder and there is minimal risk associated with the intervention in this context.
Contingency management
Contingency management is a form of treatment found to be effective for younger children with SAD. Contingency management revolves around a reward system with verbal or tangible reinforcement requiring parental involvement. A contingency contract is written up between the parent and the child, which entails a written agreement about specific goals that the child will try to achieve and the specific reward the parent will provide once the task is accomplished. When the child undergoing contingency management shows signs of independence or achieves their treatment goals, they are praised or given their reward. This facilitates a new positive experience with what used to be filled with fear and anxiety. Children in preschool who show symptoms of SAD do not have the communicative ability to express their emotions or the self-control ability to cope with their separation anxiety on their own, so parental involvement is crucial in younger cases of SAD.
Cognitive behavioral therapy
Cognitive behavioral therapy (CBT) focuses on helping children with SAD reduce feelings of anxiety through practices of exposure to anxiety-inducing situations and active metacognition to reduce anxious thoughts.CBT has three phases: education, application and relapse prevention. In the education phase, the individual is informed on the different effects anxiety can have physically and more importantly mentally. By understanding and being able to recognize their reactions, it will help to manage and eventually reduce their overall response.According to Kendall and colleagues, there are four components which must be taught to a child undergoing CBT:
Recognizing anxious feelings and behaviors
Discussing situations that provoke anxious behaviors
Developing a coping plan with appropriate reactions to situations
Evaluating effectiveness of the coping planIn the application phase, individuals can take what they know and apply it in real time situations for helpful exposure. The most important aspect of this phase is for the individuals to ultimately manage themselves throughout the process. In the relapse prevention phase, the individual is informed that continued exposure and application of what worked for them is the key to continual progress.A study investigated the content of thoughts in anxious children who suffered from separation anxiety as well as from social phobia or generalized anxiety. The results suggested that cognitive therapy for children suffering from separation anxiety (along with social phobia and generalized anxiety) should be aimed at identifying negative cognition of ones own behavior in the threat of anxiety-evoking situations and to modify these thoughts to promote self-esteem and ability to properly cope with the given situation.Cognitive procedures are a form of treatment found to be ideal for older children with SAD. The theory behind this technique is that the childs dysfunctional thoughts, attitudes, and beliefs are what leads to anxiety and causes anxious behavior. Children who are being treated with cognitive procedures are taught to ask themselves if there is "evidence" to support their anxious thoughts and behaviors. They are taught "coping thoughts" to replace previously distorted thoughts during anxiety-inducing situations such as doing a reality check to assess the realistic danger of a situation and then to praise themselves for handling the situation bravely. Examples of such disordered thoughts include polarized thinking, overgeneralization, filtering (focusing on negative), jumping to conclusions, catastrophizing, emotional reasoning, labeling, "shoulds", and placing blame on self and others. Sometimes therapists will involve parents and teach them behavioral tactics such as contingency management.
Medication
The use of medication is applied in extreme cases of SAD when other treatment options have been utilized and failed. However, it has been difficult to prove the benefits of drug treatment in patients with SAD because there have been many mixed results. Despite all the studies and testings, there has yet to be a specific medication for SAD. Medication prescribed for adults from the Food and Drug Administration (FDA) are often used and have been reported to show positive results for children and adolescents with SAD.There are mixed results regarding the benefits of using tricyclic antidepressants (TCAs), which includes imipramine and clomipramine. One study suggested that imipramine is helpful for children with "school phobia," who also had an underlying diagnosis of SAD. However, other studies have also shown that imipramine and clomipramine had the same effect of children who were treated with the medication and placebo. The most promising medication is the use of selective serotonin reuptake inhibitors (SSRI) in adults and children. Several studies have shown that patients treated with fluvoxamine were significantly better than those treated with placebo. They showed decreasing anxiety symptoms with short-term and long-term use of the medication.
Prognosis
Discomfort from separations in children from ages 8 to 14 months is normal. Children oftentimes get nervous or afraid of unfamiliar people and places but if the behavior still occurs after the age of six and if it lasts longer than four weeks, the child might have separation anxiety disorder.
About 4% of children have the disorder. Separation anxiety disorder is very treatable especially when caught early on with medication and behavioral therapies. Helping children with separation anxiety to identify the circumstances that elicit their anxiety (upcoming separation events) is important. A childs ability to tolerate separations should gradually increase over time when he or she is gradually exposed to the feared events. Encouraging a child with separation anxiety disorder to feel competent and empowered, as well as to discuss feelings associated with anxiety-provoking events promotes recovery.
Children with separation anxiety disorder often respond negatively to perceived anxiety in their caretakers, in that parents and caregivers who also have anxiety disorders may unwittingly confirm a childs unrealistic fears that something terrible may happen if they are separated from each other. Thus, it is critical that parents and caretakers become aware of their own feelings and communicate a sense of safety and confidence about separation.
Longitudinal effects
Several studies aim to understand the long-term mental health consequences of SAD. SAD contributed to vulnerability and acted as a strong risk factor for developing other mental disorders in people aged 19–30. Specifically disorders including panic disorder and depressive disorders were more likely to occur. Other sources also support the increased likelihood of displaying either of the two psychopathologies with previous history of childhood SAD.Studies show that children who have separation anxiety at younger ages have more complex fear acquisition. This means that there is likely an interplay between associative and non-associative processes concerning fear and anxiety later in life.
Epidemiology
Anxiety disorders are the most common type of psychopathology to occur in todays youth, affecting from 5–25% of children worldwide. Of these anxiety disorders, SAD accounts for a large proportion of diagnoses. SAD may account for up to 50% of the anxiety disorders as recorded in referrals for mental health treatment. SAD is noted as one of the earliest-occurring of all anxiety disorders. Adult separation anxiety disorder affects roughly 7% of adults. It has also been reported that the clinically anxious pediatric population are considerably larger. For example, according to Hammerness et al. (2008) SAD accounted for 49% of admissions.Research suggests that 4.1% of children will experience a clinical level of separation anxiety. Of that 4.1% it is calculated that nearly a third of all cases will persist into adulthood if left untreated. Research continues to explore the implications that early dispositions of SAD in childhood may serve as risk factors for the development of mental disorders throughout adolescence and adulthood. It is presumed that a much higher percentage of children suffer from a small amount of separation anxiety, and are not actually diagnosed. Multiple studies have found higher rates of SAD in girls than in boys, and that paternal absence may increase the chances of SAD in girls.
See also
Homesickness
Stranger anxiety
References
External links
The Strange Situation: Window on a Childs Past and Future
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Separation anxiety disorder | Are you gonna leave me? Separation anxiety is associated with increased amygdala responsiveness and volume |
Nevus lipomatosus superficialis | Nevus lipomatosus (cutaneous) superficialis (NLS or NLCS, also known as "Nevus lipomatosis of Hoffman and Zurhelle") is characterized by soft, yellowish papules or cerebriform plaques, usually of the buttock or thigh, less often of the ear or scalp, with a wrinkled rather than warty surface.: 625 It is usually congenital
in origin or appears within the first three decades.A pedunculated lipofibroma is a solitary variant of nevus lipomatosus superficialis. It usually appears in adult life, and usually on the axilla, knee, ear, arm, scalp and the lower trunk.
In both multiple and solitary variants, the histopathology shows variable amounts of mature lipocytes within the dermis. Occasionally, there is an excessive fibrocollagenous tissue proliferation. The main differential diagnoses are acrochordon, seborrheic keratosis, intradermal melanocytic nevi, neurofibromas, verrucae and fibroepithelioma of Pinkus.
See also
Skin lesion
List of cutaneous conditions
== References == |
Spina bifida | Spina bifida (Latin for split spine; SB) is a birth defect in which there is incomplete closing of the spine and the membranes around the spinal cord during early development in pregnancy. There are three main types: spina bifida occulta, meningocele and myelomeningocele. Meningocele and myelomeningocele may be grouped as spina bifida cystica. The most common location is the lower back, but in rare cases it may be in the middle back or neck.Occulta has no or only mild signs, which may include a hairy patch, dimple, dark spot or swelling on the back at the site of the gap in the spine. Meningocele typically causes mild problems, with a sac of fluid present at the gap in the spine. Myelomeningocele, also known as open spina bifida, is the most severe form. Problems associated with this form include poor ability to walk, impaired bladder or bowel control, accumulation of fluid in the brain (hydrocephalus), a tethered spinal cord and latex allergy. Learning problems are relatively uncommon.Spina bifida is believed to be due to a combination of genetic and environmental factors. After having one child with the condition, or if one of the parents has the condition, there is a 4% chance that the next child will also be affected. Not having enough folate (vitamin B9) in the diet before and during pregnancy also plays a significant role. Other risk factors include certain antiseizure medications, obesity and poorly controlled diabetes. Diagnosis may occur either before or after a child is born. Before birth, if a blood test or amniocentesis finds a high level of alpha-fetoprotein (AFP), there is a higher risk of spina bifida. Ultrasound examination may also detect the problem. Medical imaging can confirm the diagnosis after birth. Spina bifida is a type of neural tube defect related to but distinct from other types such as anencephaly and encephalocele.Most cases of spina bifida can be prevented if the mother gets enough folate before and during pregnancy. Adding folic acid to flour has been found to be effective for most women. Open spina bifida can be surgically closed before or after birth. A shunt may be needed in those with hydrocephalus, and a tethered spinal cord may be surgically repaired. Devices to help with movement such as crutches or wheelchairs may be useful. Urinary catheterization may also be needed.Rates of other types of spina bifida vary significantly by country, from 0.1 to 5 per 1,000 births. On average, in developed countries, including the United States, it occurs in about 0.4 per 1,000 births. In India, it affects about 1.9 per 1,000 births. Europeans are at higher risk compared to Africans.
Types
Spina bifida occulta
Occulta is Latin for hidden. This is the mildest form of spina bifida.
In occulta, the outer part of some of the vertebrae is not completely closed. The splits in the vertebrae are so small that the spinal cord does not protrude. The skin at the site of the lesion may be normal, or it may have some hair growing from it; there may be a dimple in the skin, or a birthmark. Unlike most other types of neural tube defects, spina bifida occulta is not associated with increased AFP, a common screening tool used to detect neural tube defects in utero. This is because, unlike in most of the other neural tube defects, the dural lining is maintained.Many people with this type of spina bifida do not even know they have it, as the condition is asymptomatic in most cases.
A systematic review of radiographic research studies found no relationship between spina bifida occulta and back pain. More recent studies not included in the review support the negative findings.However other studies suggest spina bifida occulta is not always harmless. One study found that among patients with back pain severity is worse if spina bifida occulta is present.Incomplete posterior fusion is not a true spina bifida and is very rarely of neurological significance.
Meningocele
A posterior meningocele () or meningeal cyst () is the least common form of spina bifida. In this form, a single developmental defect allows the meninges to herniate between the vertebrae. As the nervous system remains undamaged, individuals with meningocele are unlikely to have long-term health problems, although cases of tethered cord have been reported. Causes of meningocele include teratoma and other tumors of the sacrococcyx and of the presacral space, and Currarino syndrome.A meningocele may also form through dehiscences in the base of the skull. These may be classified by their localisation as occipital, frontoethmoidal or nasal. Endonasal meningoceles lie at the roof of the nasal cavity and may be mistaken for a nasal polyp. They are treated surgically. Encephalomeningoceles are classified in the same way and also contain brain tissue.
Myelomeningocele
Myelomeningocele (MMC), also known as meningomyelocele, is the type of spina bifida that often results in the most severe complications and affects the meninges and nerves. In individuals with myelomeningocele, the unfused portion of the spinal column allows the spinal cord to protrude through an opening. Myelomeningocele occurs in the third week of embryonic development, during neural tube pore closure. MMC is a failure of this to occur completely. The meningeal membranes that cover the spinal cord also protrude through the opening, forming a sac enclosing the spinal elements, such as meninges, cerebrospinal fluid, and parts of the spinal cord and nerve roots. Myelomeningocele is also associated with Arnold–Chiari malformation, necessitating a VP shunt placement.Toxins and conditions associated with MMC formation include: calcium-channel blockers, carbamazepine, cytochalasins, hyperthermia, and valproic acid.
Myelocele
Spina bifida with myelocele is the most severe form of myelomeningocele. In this type, the involved area is represented by a flattened, plate-like mass of nervous tissue with no overlying membrane. The exposure of these nerves and tissues make the baby more prone to life-threatening infections such as meningitis.The protruding portion of the spinal cord and the nerves that originate at that level of the cord are damaged or not properly developed. As a result, there is usually some degree of paralysis and loss of sensation below the level of the spinal cord defect. Thus, the more cranial the level of the defect, the more severe the associated nerve dysfunction and resultant paralysis may be. Symptoms may include ambulatory problems, loss of sensation, deformities of the hips, knees or feet, and loss of muscle tone.
Signs and symptoms
Physical problems
Physical signs of spina bifida may include:
Leg weakness and paralysis
Orthopedic abnormalities (i.e., club foot, hip dislocation, scoliosis)
Bladder and bowel control problems, including incontinence, urinary tract infections, and poor kidney function
Pressure sores and skin irritations
Abnormal eye movement68% of children with spina bifida have an allergy to latex, ranging from mild to life-threatening. The common use of latex in medical facilities makes this a particularly serious concern. The most common approach to avoid developing an allergy is to avoid contact with latex-containing products such as examination gloves and condoms and catheters that do not specify they are latex-free, and many other products, such as some commonly used by dentists.The spinal cord lesion or the scarring due to surgery may result in a tethered spinal cord. In some individuals, this causes significant traction and stress on the spinal cord and can lead to a worsening of associated paralysis, scoliosis, back pain, and worsening bowel and/or bladder function.
Neurological problems
Many individuals with spina bifida have an associated abnormality of the cerebellum, called the Arnold Chiari II malformation. In affected individuals, the back portion of the brain is displaced from the back of the skull down into the upper neck. In about 90% of the people with myelomeningocele, hydrocephalus also occurs because the displaced cerebellum interferes with the normal flow of cerebrospinal fluid, causing an excess of the fluid to accumulate. In fact, the cerebellum also tends to be smaller in individuals with spina bifida, especially for those with higher lesion levels.The corpus callosum is abnormally developed in 70–90% of individuals with spina bifida myelomeningocele; this affects the communication processes between the left and right brain hemispheres. Further, white matter tracts connecting posterior brain regions with anterior regions appear less organized. White matter tracts between frontal regions have also been found to be impaired.Cortex abnormalities may also be present. For example, frontal regions of the brain tend to be thicker than expected, while posterior and parietal regions are thinner. Thinner sections of the brain are also associated with increased cortical folding. Neurons within the cortex may also be displaced.
Executive function
Several studies have demonstrated difficulties with executive functions in youth with spina bifida, with greater deficits observed in youth with shunted hydrocephalus. Unlike typically developing children, youths with spina bifida do not tend to improve in their executive functioning as they grow older. Specific areas of difficulty in some individuals include planning, organizing, initiating, and working memory. Problem-solving, abstraction, and visual planning may also be impaired. Further, children with spina bifida may have poor cognitive flexibility. Although executive functions are often attributed to the frontal lobes of the brain, individuals with spina bifida have intact frontal lobes; therefore, other areas of the brain may be implicated.Individuals with spina bifida, especially those with shunted hydrocephalus, often have attention problems. Children with spina bifida and shunted hydrocephalus have higher rates of ADHD than children without those conditions (31% vs. 17%). Deficits have been observed for selective attention and focused attention, although poor motor speed may contribute to poor scores on tests of attention. Attention deficits may be evident at a very early age, as infants with spina bifida lag behind their peers in orienting to faces.
Academic skills
Individuals with spina bifida may struggle academically, especially in the subjects of mathematics and reading. In one study, 60% of children with spina bifida were diagnosed with a learning disability. In addition to brain abnormalities directly related to various academic skills, achievement is likely affected by impaired attentional control and executive functioning. Children with spina bifida may perform well in elementary school, but begin to struggle as academic demands increase.Children with spina bifida are more likely than their peers without spina bifida to be dyscalculic. Individuals with spina bifida have demonstrated stable difficulties with arithmetic accuracy and speed, mathematical problem-solving, and general use and understanding of numbers in everyday life. Mathematics difficulties may be directly related to the thinning of the parietal lobes (regions implicated in mathematical functioning) and indirectly associated with deformities of the cerebellum and midbrain that affect other functions involved in mathematical skills. Further, higher numbers of shunt revisions are associated with poorer mathematics abilities. Working memory and inhibitory control deficiencies have been implicated for math difficulties, although visual-spatial difficulties are not likely involved. Early intervention to address mathematics difficulties and associated executive functions is crucial.Individuals with spina bifida tend to have better reading skills than mathematics skills. Children and adults with spina bifida have stronger abilities in reading accuracy than in reading comprehension. Comprehension may be especially impaired for text that requires an abstract synthesis of information rather than a more literal understanding. Individuals with spina bifida may have difficulty with writing due to deficits in fine motor control and working memory.
Cause
Spina bifida is believed to be caused by a combination of genetic and environmental factors. After having one child with the condition, or if a parent has the condition, there is a 4% chance the next child will also be affected. A folic acid deficiency during pregnancy also plays a significant role. Other risk factors include certain antiseizure medications, obesity, and poorly managed diabetes. Alcohol misuse can trigger macrocytosis which discards folate. After stopping the drinking of alcohol, a time period of months is needed to rejuvenate bone marrow and recover from the macrocytosis.Those who are white or Hispanic have a higher risk. Girls are more prone to being born with spina bifida.
Pathophysiology
Spina bifida occurs when local regions of the neural tube fail to fuse or there is failure in formation of the vertebral neural arches. Neural arch formation occurs in the first month of embryonic development (often before the mother knows she is pregnant). Some forms are known to occur with primary conditions that cause raised central nervous system pressure, raising the possibility of a dual pathogenesis.In normal circumstances, the closure of the neural tube occurs around the 23rd (rostral closure) and 27th (caudal closure) day after fertilization. However, if something interferes and the tube fails to close properly, a neural tube defect will occur. Medications such as some anticonvulsants, diabetes, obesity, and having a relative with spina bifida can all affect the probability of neural tube malformation.Extensive evidence from mouse strains with spina bifida indicates that there is sometimes a genetic basis for the condition. Human spina bifida, like other human diseases, such as cancer, hypertension and atherosclerosis (coronary artery disease), likely results from the interaction of multiple genes and environmental factors.Research has shown the lack of folic acid (folate) is a contributing factor in the pathogenesis of neural tube defects, including spina bifida. Supplementation of the mothers diet with folate can reduce the incidence of neural tube defects by about 70%, and can also decrease the severity of these defects when they occur. It is unknown how or why folic acid has this effect.Spina bifida does not follow direct patterns of heredity as do muscular dystrophy or haemophilia. Studies show a woman having had one child with a neural tube defect such as spina bifida has about a 3% risk of having another affected child. This risk can be reduced with folic acid supplementation before pregnancy. For the general population, low-dose folic acid supplements are advised (0.4 mg/day).
Prevention
There is neither a single cause of spina bifida nor any known way to prevent it entirely. However, dietary supplementation with folic acid has been shown to be helpful in reducing the incidence of spina bifida. Sources of folic acid include whole grains, fortified breakfast cereals, dried beans, leaf vegetables and fruits. However it is difficult for women to get the recommended 400 micrograms of folic acid a day from unfortified foods. Globally, fortified wheat flour is credited with preventing 50 thousand neural tube birth defects like spina bifida a year, but 230,000 could be prevented every year through this strategy.Folate fortification of enriched grain products has been mandatory in the United States since 1998. This prevents an estimated 600 to 700 incidents of spina bifida a year in the U.S. and saves $400 - $600 million in healthcare expenses. The U.S. Food and Drug Administration, Public Health Agency of Canada and the UK Department of Health and Social Care (DHSC) recommended amount of folic acid for women of childbearing age and women planning to become pregnant is at least 0.4 mg/day of folic acid from at least three months before conception, and continued for the first 12 weeks of pregnancy.
Women who have already had a baby with spina bifida or other type of neural tube defect, or are taking anticonvulsant medication, should take a higher dose of 4–5 mg/day.Certain mutations in the gene VANGL1 have been linked with spina bifida in some families with a history of the condition.
Screening
Open spina bifida can usually be detected during pregnancy by fetal ultrasound. Increased levels of maternal serum alpha-fetoprotein (MSAFP) should be followed up by two tests – an ultrasound of the fetal spine and amniocentesis of the mothers amniotic fluid (to test for alpha-fetoprotein and acetylcholinesterase). AFP tests are now mandated by some state laws (including California) and failure to provide them can have legal ramifications. In one case, a man born with spina bifida was awarded a $2-million settlement after court found his mothers OBGYN negligent for not performing these tests. Spina bifida may be associated with other malformations as in dysmorphic syndromes, often resulting in spontaneous miscarriage. In the majority of cases, though, spina bifida is an isolated malformation.Genetic counseling and further genetic testing, such as amniocentesis, may be offered during the pregnancy, as some neural tube defects are associated with genetic disorders such as trisomy 18. Ultrasound screening for spina bifida is partly responsible for the decline in new cases, because many pregnancies are terminated out of fear that a newborn might have a poor future quality of life. With modern medical care, the quality of life of patients has greatly improved.
Treatment
There is no known cure for the nerve damage caused by spina bifida. Standard treatment is surgery after delivery. This surgery aims to prevent further damage of the nervous tissue and to prevent infection; pediatric neurosurgeons operate to close the opening on the back. The spinal cord and its nerve roots are put back inside the spine and covered with meninges. In addition, a shunt may be surgically installed to provide a continuous drain for the excess cerebrospinal fluid produced in the brain, as happens with hydrocephalus. Shunts most commonly drain into the abdomen or chest wall.
Pregnancy
Standard treatment is after delivery. There is tentative evidence about treatment for severe disease before delivery while the baby is inside the womb. As of 2014, however, the evidence remains insufficient to determine benefits and harms.Treatment of spina bifida during pregnancy is not without risk. To the mother, this includes scarring of the uterus. To the baby, there is the risk of preterm birth.Broadly, there are two forms of prenatal treatment. The first is open fetal surgery, where the uterus is opened and the spina bifida repair performed. The second is via fetoscopy. These techniques may be an option to standard therapy.
Childhood
Most individuals with myelomeningocele will need periodic evaluations by a variety of specialists:
Physiatrists coordinate the rehabilitation efforts of different therapists and prescribe specific therapies, adaptive equipment, or medications to encourage as high of a functional performance within the community as possible.
Orthopedists monitor growth and development of bones, muscles, and joints.
Neurosurgeons perform surgeries at birth and manage complications associated with tethered cord and hydrocephalus.
Neurologists treat and evaluate nervous system issues, such as seizure disorders.
Urologists to address kidney, bladder, and bowel dysfunction – many will need to manage their urinary systems with a program of catheterization. Bowel management programs aimed at improving elimination are also designed.
Ophthalmologists evaluate and treat complications of the eyes.
Orthotists design and customize various types of assistive technology, including braces, crutches, walkers, and wheelchairs to aid in mobility. As a general rule, the higher the level of the spina bifida defect, the more severe the paralysis, but paralysis does not always occur. Thus, those with low levels may need only short leg braces, whereas those with higher levels do best with a wheelchair, and some may be able to walk unaided.
Physical therapists, occupational therapists, psychologists, and speech/language pathologists aid in rehabilitative therapies and increase independent living skills.
Transition to adulthood
Although many childrens hospitals feature integrated multidisciplinary teams to coordinate healthcare of youth with spina bifida, the transition to adult healthcare can be difficult because the above healthcare professionals operate independently of each other, requiring separate appointments, and communicate among each other much less frequently. Healthcare professionals working with adults may also be less knowledgeable about spina bifida because it is considered a childhood chronic health condition. Due to the potential difficulties of the transition, adolescents with spina bifida and their families are encouraged to begin to prepare for the transition around ages 14–16, although this may vary depending on the adolescents cognitive and physical abilities and available family support. The transition itself should be gradual and flexible. The adolescents multidisciplinary treatment team may aid in the process by preparing comprehensive, up-to-date documents detailing the adolescents medical care, including information about medications, surgery, therapies, and recommendations. A transition plan and aid in identifying adult healthcare professionals are also helpful to include in the transition process.Further complicating the transition process is the tendency for youths with spina bifida to be delayed in the development of autonomy, with boys particularly at risk for slower development of independence. An increased dependence on others (in particular family members) may interfere with the adolescents self-management of health-related tasks, such as catheterization, bowel management, and taking medications. As part of the transition process, it is beneficial to begin discussions at an early age about educational and vocational goals, independent living, and community involvement.Certain locations feature multidisciplinary clinics in order to offer coordinated care between specialists, such as Cincinnati Childrens Center for Spina Bifida.
Epidemiology
Rates of other types of spina bifida vary significantly by country from 0.1 to 5 per 1000 births. On average in developed countries it occurs in about 0.4 per 1000 births. In the United States it affected about 0.7 per 1000 births, and in India about 1.9 per 1000 births. Part of this difference is believed to be due to race, with Caucasians at higher risk, and part due to environmental factors. It is most common in the Celtic people (12.5 per 10,000 live births), and it is rare in Asians and people of African descent.In the United States, rates are higher on the East Coast than on the West Coast, and higher in white people (one case per 1000 live births) than in black people (0.1–0.4 case per 1000 live births). Immigrants from Ireland have a higher incidence of spina bifida than do natives. Highest rates of the defect in the USA can be found in Hispanic youth.The highest incidence rates worldwide were found in Ireland and Wales, where three to four cases of myelomeningocele per 1000 population have been reported during the 1970s, along with more than six cases of anencephaly (both live births and stillbirths) per 1000 population. The reported overall incidence of myelomeningocele in the British Isles was 2.0–3.5 cases per 1000 births. Since then, the rate has fallen dramatically with 0.15 per 1000 live births reported in 1998, though this decline is partially accounted for because some fetuses are aborted when tests show signs of spina bifida (see Pregnancy screening above).
Research
1980 – Fetal surgical techniques using animal models were first developed at the University of California, San Francisco by Michael R. Harrison, N. Scott Adzick and research colleagues.
1994 – A surgical model that simulates the human disease is the fetal lamb model of myelomeningocele (MMC) introduced by Meuli and Adzick in 1994. The MMC-like defect was surgically created at 75 days of gestation (term 145 to 150 days) by a lumbo-sacral laminectomy. Approximately 3 weeks after creation of the defect a reversed latissimus dorsi flap was used to cover the exposed neural placode and the animals were delivered by cesarean section just prior term. Human MMC-like lesions with similar neurological deficit were found in the control newborn lambs. In contrast, animals that underwent closure had near-normal neurological function and well-preserved cytoarchitecture of the covered spinal cord on histopathological examination. Despite mild paraparesis, they were able to stand, walk, perform demanding motor test and demonstrated no signs of incontinence. Furthermore, sensory function of the hind limbs was present clinically and confirmed electrophysiologically. Further studies showed that this model, when combined with a lumbar spinal cord myelotomy leads to the hindbrain herniation characteristic of the Chiari II malformation and that in utero surgery restores normal hindbrain anatomy by stopping the leak of cerebrospinal fluid through the myelomeningocele lesion.Surgeons at Vanderbilt University, led by Joseph Bruner, attempted to close spina bifida in 4 human fetuses using a skin graft from the mother using a laparoscope. Four cases were performed before stopping the procedure - two of the four fetuses died.
1998 – N. Scott Adzick and team at The Childrens Hospital of Philadelphia performed open fetal surgery for spina bifida in an early gestation fetus (22-week gestation fetus) with a successful outcome. Open fetal surgery for myelomeningocele involves surgically opening the pregnant mothers abdomen and uterus to operate on the fetus. The exposed fetal spinal cord is covered in layers with surrounding fetal tissue at mid-gestation (19–25 weeks) to protect it from further damage caused by prolonged exposure to amniotic fluid. Between 1998 and 2003, Dr. Adzick, and his colleagues in the Center for Fetal Diagnosis and Treatment at The Childrens Hospital Of Philadelphia, performed prenatal spina bifida repair in 58 mothers and observed significant benefit in the babies.Fetal surgery after 25 weeks has not shown benefit in subsequent studies.
MOMS trial
Management of myelomeningocele study (MOMS) was a phase III clinical trial designed to compare two approaches to the treatment of spina bifida: surgery before birth and surgery after birth.The trial concluded that the outcomes after prenatal spina bifida treatment are improved to the degree that the benefits of the surgery outweigh the maternal risks. This conclusion requires a value judgment on the relative value of fetal and maternal outcomes on which opinion is still divided.To be specific, the study found that prenatal repair resulted in:
Reversal of the hindbrain herniation component of the Chiari II malformation
Reduced need for ventricular shunting (a procedure in which a thin tube is introduced into the brains ventricles to drain fluid and relieve hydrocephalus)
Reduced incidence or severity of potentially devastating neurologic effects caused by the spines exposure to amniotic fluid, such as impaired motor function
At one year of age, 40 percent of the children in the prenatal surgery group had received a shunt, compared to 83 percent of the children in the postnatal group. During pregnancy, all the fetuses in the trial had hindbrain herniation. However, at age 12 months, one-third (36 percent) of the infants in the prenatal surgery group no longer had any evidence of hindbrain herniation, compared to only 4 percent in the postnatal surgery group. Further surveillance is ongoing.
Fetoscopic surgery
In contrast to the open fetal operative approach performed in the MOMS trial, a minimally invasive fetoscopic approach (akin to keyhole surgery) has been developed. This approach has been evaluated by independent authors of a controlled study which showed some benefit in survivors, but others are more skeptical.The observations in mothers and their fetuses that were operated over the past two and a half years by the matured minimally invasive approach showed the following results: Compared to the open fetal surgery technique, fetoscopic repair of myelomeningocele results in far less surgical trauma to the mother, as large incisions of her abdomen and uterus are not required. In contrast, the initial punctures have a diameter of 1.2 mm only. As a result, thinning of the uterine wall or dehiscence which have been among the most worrisome and criticized complications after the open operative approach do not occur following minimally invasive fetoscopic closure of spina bifida aperta. The risks of maternal chorioamnionitis or fetal death as a result of the fetoscopic procedure run below 5%. Women are discharged home from hospital |
Spina bifida | one week after the procedure. There is no need for chronic administration of tocolytic agents since postoperative uterine contractions are barely ever observed. The current cost of the entire fetoscopic procedure, including hospital stay, drugs, perioperative clinical, ECG, ultrasound and MRI-examinations, is approximately €16,000.In 2012, these results of the fetoscopic approach were presented at various national and international meetings, among them at the 1st European Symposium “Fetal Surgery for Spina bifida“ in April 2012 in Giessen, at the 15th Congress of the German Society for Prenatal Medicine and Obstetrics in May 2012 in Bonn, at the World Congress of the Fetal Medicine Foundation in June 2012 and at the World Congress of the International Society of Obstetrics and Gynecology (ISUOG) in Copenhagen in September 2012, and published in abstract form.Since then more data has emerged. In 2014, two papers were published on fifty one patients. These papers suggested that the risk to the mother is small. The main risk appears to be preterm labour, on average at about 33 weeks.
Placenta
The placenta is a critical determinant of fetal growth, yet placental development has not been well studied in pregnancies with fetal neural tube defects. Folate bioavailability is associated not only with isolated fetal neural tube defects, but is also required for optimal placental development. Pregnancies with folate-responsive neural tube defects may thus be at increased risk for poor placental development. A study comprehensively assessing the prevalence of placental pathology in a large cohort of fetuses with isolated neural tube defects found that these fetuses had higher risk of placental pathology and altered offspring growth outcomes at birth compared to controls, suggesting increased risk of placental maldevelopment that may contribute to poor fetal growth in pregnancies with neural tube defects.
See also
Meningohydroencephalocoele
Rachischisis
Congenital dermal sinus
References
External links
Spina bifida at Curlie
CDC: Spina bifida |
Waldmann disease | Waldmann disease is a rare disease characterized by enlargement of the lymph vessels supplying the lamina propria of the small intestine. Although its prevalence is unknown, it being classified as a "rare disease" means that less than 200,000 of the population of the United States are affected by this condition and its subtypes.
Signs and symptoms
Signs and symptoms of the disease include diarrhea, nausea, swelling of the legs, protein-losing enteropathy, immunodeficiency and loss of lymphatic fluid into the intestines. It is usually diagnosed before the patient is 3 years old, but it is sometimes diagnosed in adults.
Pathophysiology
The illness is usually caused by lymphatic vessels that were misshaped at birth, causing obstruction and subsequent enlargement. The condition can also be a result of other illnesses such as constrictive pericarditis and pancreatitis.
Diagnosis
The disease is diagnosed by doing a biopsy of the affected area. Severity of the disease is then determined by measuring alpha1-antitrypsin proteins in a stool sample.
Management
Once the main cause of the disease is treated, a diet of low-fat and high-protein aliments, supplemental calcium and certain vitamins has been shown to reduce symptom effects. This diet, however, is not a cure. If the diet is stopped, the symptoms will eventually reappear.
History
The disease was first reported in 1961 by T.A. Waldmann. He described 18 cases of patients having a low level 131I-albumin. Biopsies of the small intestine were examined under the microscope and found various levels of dilatation of the lymph vessels.
References
== External links == |
Hypermobility spectrum disorder | Hypermobility spectrum disorder (HSD), related to earlier diagnoses such as hypermobility syndrome (HMS), and joint hypermobility syndrome (JHS) is a heritable connective tissue disorder that affects joints and ligaments. Different forms and sub-types have been distinguished, but it does not include asymptomatic joint hypermobility, sometimes known as double-jointedness.
Symptoms can include the inability to walk properly or for long distances, and pain in affected areas. Some people with HSD have hypersensitive nerves and a weaker immune system. It can also cause severe fatigue and some cases cause depressive episodes. It is somewhat similar to other genetic connective tissue disorders such as Ehlers–Danlos syndromes.
There is a strong association between HSD and neurodevelopmental disorders such as ADHD (Attention deficit hyperactivity disorder) and ASD (autism spectrum disorder).
Classification
Hypermobility spectrum disorders are diagnosed when individuals have symptomatic joint hypermobility but do not meet the criteria for other connective tissue disorders, such as Ehlers-Danlos syndrome.The term "hypermobility spectrum disorder" was coined in 2017 after criteria for hypermobile Ehlers-Danlos syndrome were made more restrictive. In part, this classification change was designed to address the overlap between joint hypermobility syndrome and what was then known as Ehlers-Danlos syndrome, hypermobility type (EDS-HT), which some researchers believed were the same condition. While hypermobility spectrum disorders are most analogous to JHS, the 2017 diagnostic criteria for hypermobile Ehlers-Danlos syndrome excludes many people who fit the old criteria, who would instead be diagnosed with hypermobility spectrum disorders.Hypermobility syndrome and hypermobility spectrum disorders do not include people with asymptomatic hypermobility or people with double-jointedness but no other symptoms. Hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders may be equally severe.
Signs and symptoms
Some common symptoms of hypermobility spectrum disorder include:
Joint pain (pain can arise in every joint)
Exhaustion (typically when affected area is the legs);
Swelling around the joint when joint is being exerted;
Depression;
Weaker immune system;
Muscle pain
Varying pain levels around the affected areas.
Muscle spasms.Other symptoms can appear and not everyone affected experiences the same symptoms.
Diagnosis
Being diagnosed with hypermobility syndrome can be a difficult task. There is a lack of wide understanding of the condition and it can be considered a zebra condition. As hypermobility syndrome can be easily mistaken for being double-jointed or categorised as nothing more than perhaps an achy body from lack of exercise, medical professionals may diagnose those affected incorrectly and not adequately investigate the symptoms. Due to these circumstances many affected individuals can live not knowing they have it. As a result, those affected without a proper diagnosis can easily injure themselves and not take proper care to ensure they go about working safely.
The Beighton Score can be used to determine generalised joint hypermobility (GJH) related to hypermobility syndrome. The newer term "generalised hypermobility spectrum disorder" includes people with generalised joint hypermobility, often determined using the Beighton Score, and other symptoms. Those who do not meet the Beighton Score criteria may be diagnosed with historical joint hypermobility spectrum disorder, peripheral hypermobility spectrum disorder, or localised hypermobility spectrum disorder.In comparison to the diagnostic criteria of hypermobile Ehlers-Danlos syndrome, the criteria for hypermobile spectrum disorder are less strict. However, these criteria are differentiated from criteria of other EDS types and therefore its less-strict criteria are only comparable to the criteria of hEDS. As those with HSD experience a considerable amount of discomfort, it is important to focus on the treatment, not the labels. The severity of each condition can be equivalent. In particular, musculoskeletal involvement is a requirement for diagnosis with any form of hypermobility spectrum disorder but not for hypermobile Ehlers-Danlos syndrome. Like hypermobile Ehlers-Danlos syndrome, hypermobility spectrum disorders are associated with orthostatic tachycardia, gastrointestinal disorders, and pelvic and bladder dysfunction.
Treatment
Treating hypermobility syndrome can be difficult. The condition has no direct cure, but its symptoms can be treated. Physiotherapy, particularly exercise, is the main treatment for the condition, although there is only limited evidence for its effectiveness.Treatments for pain include:
Bandaging the affected area;
Placing an ice pack on the affected area;
Taking over the counter pain killers such as paracetamol or ibuprofen.
Prevalence
Prevalence of the condition is unknown, but can be high in those attending musculoskeletal services.
== References == |
Ventricular aneurysm | Ventricular aneurysms are one of the many complications that may occur after a heart attack. The word aneurysm refers to a bulge or pocketing of the wall or lining of a vessel commonly occurring in the blood vessels at the base of the septum, or within the aorta. In the heart, they usually arise from a patch of weakened tissue in a ventricular wall, which swells into a bubble filled with blood. This, in turn, may block the passageways leading out of the heart, leading to severely constricted blood flow to the body. Ventricular aneurysms can be fatal. They are usually non-rupturing because they are lined by scar tissue.
A left ventricular aneurysm can be associated with ST elevation.
Signs and symptoms
Ventricular aneurysms usually grow at a very slow pace, but can still pose problems. Usually, this type of aneurysm grows in the left ventricle. This bubble has the potential to block blood flow to the rest of the body, and thus limit the patients stamina. In other cases, a similarly developed pseudoaneurysm ("false aneurysm") may burst, sometimes resulting in the death of the patient. Also, blood clots may form on the inside of ventricular aneurysms, and form embolisms. If such a clot escapes from the aneurysm, it will be moved in the circulation throughout the body. If it gets stuck inside a blood vessel, it may cause ischemia in a limb, a painful condition that can lead to reduced movement and tissue death in the limb. Alternatively, if a clot blocks a vessel going to the brain, it can cause a stroke. In certain cases, ventricular aneurysms cause ventricular failure or arrythmia. At this stage, treatment is necessary.
Causes
Ventricular aneurysms are usually complications resulting from a heart attack. When the heart muscle (cardiac muscle) partially dies during a heart attack, a layer of muscle may survive, and, being severely weakened, start to become an aneurysm. Blood may flow into the surrounding dead muscle and inflate the weakened flap of muscle into a bubble. It may also be congenital.
Diagnosis
When a person visits the hospital or doctor with other symptoms, especially with a history of heart problems, they will normally be required to undergo an electrocardiogram, which monitors electrical activity within the heart and shows abnormalities when a cardiac aneurysm is present. It can also appear as a bulge on a chest x-ray, and a more accurate diagnosis will then be made using an echocardiogram, which uses ultrasound to photograph the heart and how it functions while it beats.
Differential diagnosis
It should also not be confused with a pseudoaneurysm, coronary artery aneurysm or a myocardial rupture (which involves a hole in the wall, not just a bulge.)
Cardiac Diverticulum
Cardiac diverticulum or ventricular diverticulum is defined as a congenital malformation of the fibrous or muscular part of the heart which is only visible during chest x-rays or during an echocardiogram reading. This should not be confused with ventricular diverticulum, as the latter is a sub type derived from the latter in congenital cases. it is usually asymptomatic and is only detected using imaging. Fibrous diverticulum is characterised by a calcification if present at the tip ( apex) or a thrombi that may detaches to form an emboli. Muscular diverticulum is characterised by appendix forming at the ether of the ventricles. it is a rare anomaly and can be diagnosed prenatal. Diagnosis is usually done by a chest X-ray and silhouette is viewed around the heart. Echocardiogram reading present a similar picture to ventricular aneurysms on the ST segment. Management is dependent on the situation presented and the severity of the case. Usually, surgical resection is advised but in prenatal cases, due to combination with other cardiac abnormalities, especially in latter trimesters, but pericardiocentesis is useful technique to reduce pleural effusion or/ and secondary disorders.
Treatment
Some people live with this type of aneurysm for many years without any specific treatment. Treatment is limited to surgery (ventricular reduction) for this defect of the heart. However, surgery is not required in most cases but, limiting the patients physical activity levels to lower the risk of making the aneurysm bigger is advised. Also, ACE Inhibitors seem to prevent Left Ventricular remodeling and aneurysm formation.Blood thinning agents may be given to help reduce the likelihood of blood thickening and clots forming, along with the use of drugs to correct the irregular rhythm of the heart (seen on the electrocardiogram)
See also
Coronary artery aneurysm
References
Further reading
Graber, J.D.; Oakley, C.M.; Pickering, B.N.; Goodwin, J.F.; Raphael, M.J.; Steiner, R.E. (1972). "Ventricular aneurysm. An appraisal of diagnosis and surgical treatment". British Heart Journal. PubMed. 34 (8): 831–838. doi:10.1136/hrt.34.8.831. PMC 486989. PMID 5070115.
Alenghat, FJ; Couper, GC; Givertz, MM (2013). "Giant left ventricular aneurysm as a late complication of inferior myocardial infarction". European Heart Journal. 24 (5): 344. doi:10.1093/eurheartj/ehs357. PMID 23095983.
== External links == |
Dissecting cellulitis of the scalp | Dissecting cellulitis of the scalp, also known as dissecting folliculitis, perifolliculitis capitis abscedens et suffodiens of Hoffman, perifolliculitis abscedens et suffodiens, or folliculitis abscedens et suffodiens, is an inflammatory condition of the scalp that can lead to scarring alopecia, which begins with deep inflammatory nodules, primarily over occiput, that progresses to coalescing regions of boggy scalp. Boggy tissue has a high fluid level that results in a spongy feeling. Isotretinoin proves to be the medicine of choice for the treatment of the disease.: 649 : 761
See also
List of cutaneous conditions
References
== External links == |
Ligamentous laxity | Ligamentous laxity, or ligament laxity, means loose ligaments. Ligamentous laxity is a cause of chronic body pain characterized by loose ligaments. When this condition affects joints in the entire body, it is called generalized joint hypermobility, which occurs in about ten percent of the population, and may be genetic. Loose ligaments can appear in a variety of ways and levels of severity. It also does not always affect the entire body. One could have loose ligaments of the feet, but not of the arms.
Someone with ligamentous laxity, by definition, has loose ligaments. Unlike other, more pervasive diseases, the diagnosis does not require the presence of loose tendons, muscles or blood vessels, hyperlax skin or other connective tissue problems. In heritable connective tissue disorders associated with joint hypermobility (such as Marfan syndrome and Ehlers–Danlos syndrome types I–III, VII, and XI), the joint laxity usually is apparent before adulthood. However, age of onset and extent of joint laxity are variable in Marfan syndrome, and joint laxity may be confined to the hands alone, as in Ehlers–Danlos syndrome type I. In addition, ligamentous laxity may appear in conjunction with physical co-ordination conditions such as dyspraxia.
Presentation
While ligamentous laxity may be genetic and affect an individual from a very early age, it can also be the result of an injury. Injuries, especially those involving the joints, invariably damage ligaments either by stretching them abnormally or even tearing them.
Loose or lax ligaments in turn are not capable of supporting joints as effectively as healthy ones, making the affected individual prone to further injury as well as compensation for the weakness using other parts of the body. Affected individuals may improve over time and lose some of their juvenile hyperlaxity as they age. Individuals over age 40 often have recurrent joint problems and almost always have chronic pain. Back patients with ligamentous laxity in the area of the spine may also experience osteoarthritis and disc degeneration.
In the case of extreme laxity, or hypermobility, affected individuals often have a decreased ability to sense joint position, which can contribute to joint damage. The resulting poor limb positions can lead to the acceleration of degenerative joint conditions. Many hypermobility patients have osteoarthritis, disorders involving nerve compression, chondromalacia patellae, excessive anterior mandibular movement, mitral valve prolapse, uterine prolapse and varicose veins.
Symptoms
Arthralgia, or symptoms such as frequent sprained ankles, shoulder dislocations, knee effusions and back problems are common among individuals with ligamentous laxity. Affected individuals are also prone to bone dislocation, and those with a sedentary job often report back pain. In addition, people may experience referred pain, that is, pain in an area of the body away from the injured or otherwise affected site.
Individuals with extremely lax, or hypermobile joints, can be identified by their ability to bend their elbows, knees or hips past a position of neutrality. They may also be able to easily touch their hands flat to the floor while bending forward from the waist. The ability to touch the thumb to the forearm is also common.
Referred pain is created by ligamentous laxity around a joint, but is felt at some distance from the injury. (Pain will not only occur at the site of the injury and loose ligaments, but may also be referred to other parts of the body.) These painful points that refer pain elsewhere are called trigger points, and will be dealt with later. Abnormal joint movement also creates many "protective actions" by adjacent tissues. Muscles will contract in spasm in an attempt to pull the joint back to the correct location or stabilize it to protect it from further damage.
When this occurs in the back, orthopedic surgeons will often try to reduce vertebral instability by fusing the vertebrae with bone and/or metal fixation.
Feet
Those who have loose ligaments in the legs and feet may appear to have flat feet. While their feet have an arch when not supporting weight, when stood upon, the arch will flatten. This is because the loose ligaments cannot support the arch in the way that they should. This can make walking and standing painful and tiring.
Pain will usually occur in the feet and lower legs, but can also spread to the back due to abnormal standing and walking habits. Wearing shoes that have good arch support can help minimize the discomfort. The underlying problem, however, is not solved by wearing shoes with arch supports, or worsened by wearing shoes without arch support. There is currently no cure for the condition.In addition, people with ligamentous laxity often have clumsy or deliberate gaits, owing to the body having to overcompensate for the greater amount of energy required to offset the weakened ligaments. The feet may be spread apart at a wide angle, and the knees may flex backwards slightly after each stride.
Those who have this disease may experience sprained ankles more frequently than other people.
Cause
In most people, ligaments (which are the tissues that connect bones to each other) are naturally tight in such a way that the joints are restricted to normal ranges of motion. This creates normal joint stability. If muscular control does not compensate for ligamentous laxity, joint instability may result. The trait is almost certainly hereditary, and is usually something the affected person would just be aware of, rather than a serious medical condition. However, if there is widespread laxity of other connective tissue, then this may be a sign of Ehlers–Danlos syndrome.
Ligamentous laxity may also result from injury, such as from a vehicle accident. It can result from whiplash and be overlooked for years by doctors who are not looking for it, despite the chronic pain that accompanies the resultant spinal instability. Ligamentous laxity will show up on an upright magnetic resonance imaging (MRI), the only kind of MRI that will show soft tissue damage. It can be seen in standing stress radiographs in flexion, extension, and neutral views as well, and also digital motion X-ray, or DMX.
An advantage to having lax ligaments and joints is the ability to withstand pain from hyperextension; however, this is also a disadvantage as a lack of perceived pain can prevent a person from removing the ligament from insult, leading to ligament damage. People with hypermobile joints (or "double-jointed" people), almost by definition, have lax ligaments.
References
== External links == |
Thoracic insufficiency syndrome | Thoracic insufficiency syndrome is the inability of the thorax to support normal respiration. It is frequently associated with chest and/or spinal abnormalities. Treatment options are limited, but include supportive pulmonary care and surgical options (thoracoplasty and/or implantation of vertical expandable prosthetic titanium rib (VEPTR) devices).
== References == |
Noma (disease) | Noma (also known as necrotizing ulcerative stomatitis, gangrenous stomatitis, or cancrum oris) is a rapidly progressive and often fatal infection of the mouth and face. This disease predominantly affects children between the ages of two and six years old in the least developed countries around the world.
Signs and symptoms
The mucous membranes of the mouth develop ulcers, followed by rapid, painful tissue degeneration and necrosis of the tissues of the bones in the face.
Causes
The underlying causes for this disease are primarily poor sanitation and malnutrition. Although the causative organisms are common in many environments, this disease nearly exclusively affects extremely impoverished and malnourished children in tropical regions.Noma is often reported as a sequela to acute necrotizing ulcerative gingivitis. Fusobacterium necrophorum and Prevotella intermedia are important bacterial pathogens in this disease process, interacting with one or more other bacterial organisms (such as Treponema denticola, Treponema vincentii, Porphyromonas gingivalis, Tannerella forsythia, Staphylococcus aureus, and certain species of nonhemolytic Streptococcus). Treatment of these organisms can help arrest the infection, but does not restore already-missing or disfigured tissue.Predisposing factors include:
malnutrition
vitamin deficiency (particularly deficiencies of Vitamin A and Vitamin B)
contaminated drinking water
immunodeficiency
poor hygiene, particularly oral
recent illness (especially acute necrotizing ulcerative gingivitis, measles, malaria, and severe diarrhea)
living in proximity to livestock
Treatment
The progression of the disease can be halted with the use of antibiotics and improved nutrition; however, its physical effects are permanent and may require oral and maxillofacial surgery or reconstructive plastic surgery to repair. Reconstruction is usually very challenging and should be delayed until full recovery (usually about one year following initial intervention).
Prognosis
Noma is associated with a very high morbidity, and a mortality rate of approximately 90 percent.
Epidemiology
The disease affects mainly children in the poorest countries of Africa, Asia and South America. Most people who acquire this disease are between the ages of two and six years old. The World Health Organization estimates that 500,000 people are affected, and that 140,000 new cases are reported each year.
History
Known in antiquity to such physicians as Hippocrates and Galen, noma was once reported around the world, including Europe and the United States. With improvements in hygiene and nutrition, noma has disappeared from industrialized countries since the 20th century, except during World War II when it was endemic to Auschwitz and Belsen concentration camps. The disease and treatments were studied by Berthold Epstein, a Czech physician and forced-labor prisoner who had recommended the study under Josef Mengeles direction.
Society and culture
Children and other noma survivors in Africa are helped by a few international charitable organizations, such as Facing Africa, a UK registered charity that helps affected Ethiopian, and Swiss charity Winds of Hope. There is one dedicated noma hospital in Nigeria, the Noma Children Hospital Sokoto, staffed by resident and visiting medical teams supported by Médecins Sans Frontières. In other countries, such as Ethiopia, international charities work in collaboration with the local health care system to provide complex reconstructive surgery which can give back facial functions such as eating, speaking and smiling. Teams of volunteer medics coming from abroad are often needed to support the local capacity to address the most severe cases, which can be extremely challenging even for senior maxillofacial surgeons. On 10 June 2010 the work of such volunteer surgeons was featured in a UK BBC Two documentary presented by Ben Fogle, Make Me a New Face: Hope for Africas Hidden Children.
See also
Necrotizing fasciitis
Noma neonatorum
References
Further reading
== External links == |
Lymphangitis carcinomatosa | Lymphangitis carcinomatosa is inflammation of the lymph vessels (lymphangitis) caused by a malignancy. Breast, lung, stomach, pancreas, and prostate cancers are the most common tumors that result in lymphangitis. Lymphangitis carcinomatosa was first described by pathologist Gabriel Andral in 1829 in a patient with uterine cancer. Lymphangitis carcinomatosa may show the presence of Kerley B lines on chest X-ray.
Lymphangitis carcinomatosa most often affects people 40–49 years of age.Lymphangitis carcinomatosa may be caused by the following malignancies as suggested by the mnemonic: "Certain Cancers Spread By Plugging The Lymphatics" (cervical cancer, colon cancer, stomach cancer, breast cancer/bronchiogenic carcinoma, pancreatic cancer, thyroid cancer, laryngeal cancer)
Pathology
In most cases, lymphangitis carcinomatosis is caused by the dissemination of a tumor with its cells along the lymphatics. However, in about 20 percent of cases, the inflammation of the lymphatic tubules (lymphangitis) is caused by a tumor that blocks the drainage of the lymph duct. In the lung, this is often caused by a centrally located mass, near the hilum of the lung that blocks lymphatic drainage.
Prognosis
Previously, the finding of lymphangitis carcinomatosis meant about a six-month life expectancy. However, improved treatment has improved survival in patients with lymphangitis carcinomatosis, with patients often surviving three or more years with treatment.
History
Lymphangitis carcinomatosa was first described by pathologist Gabriel Andral in 1829 in a patient with uterine cancer.
See also
Lymphangitis
References
== External links == |
Pleural thickening | Pleural thickening is an increase in the bulkiness of one or both of the pulmonary pleurae.
Causes
Pleural plaques
Pleural plaques are patchy collections of hyalinized collagen in the parietal pleura. They have a holly leaf appearance on X-ray. They are indicators of asbestos exposure, and the most common asbestos-induced lesion. They usually appear after 20 years or more of exposure and never degenerate into mesothelioma. They appear as fibrous plaques on the parietal pleura, usually on both sides, and at the posterior and inferior part of the chest wall as well as the diaphragm.
See also
Pleural disease
== References == |
Acheiropodia | Acheiropodia (ACHP) is an autosomal-recessive disorder that results in hemimelia, a lack of formation of the distal extremities.
This is a congenital defect that consists of bilateral amputations of the distal upper and lower extremities, as well as aplasia of the hands and feet. It was first discovered and is prevalent almost exclusively in Brazil.
Genetics
ACHP has been associated with a mutation in the LMBR1 gene. The disorder is inherited in an autosomal-recessive manner. This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
Diagnosis
References
External links
Overview at Orphanet
PDF of Am. J. of Human Genetics article |
Parasystole | Parasystole is a kind of arrhythmia caused by the presence and function of a secondary pacemaker in the heart, which works in parallel with the SA node. Parasystolic pacemakers are protected from depolarization by the SA node by some kind of entrance block. This block can be complete or incomplete.
Parasystolic pacemakers can exist in both the atrium or the ventricle. Atrial parasystolia are characterized by narrow QRS complexes
Two forms of ventricular parasystole have been described in the literature, fixed parasystole and modulated parasystole. Fixed ventricular parasystole occurs when an ectopic pacemaker is protected by entrance block, and thus its activity is completely independent from the sinus pacemaker activity. Hence, the ectopic pacemaker is expected to fire at a fixed rate.
Therefore, on ECG, the coupling intervals of the manifest ectopic beats will wander through the basic cycle of the sinus rhythm. Accordingly, the traditional electrocardiographic criteria used to recognize the fixed form of parasystole are:
the presence of variable coupling intervals of the manifest ectopic beats;
inter-ectopic intervals that are simple multiples of a common denominator;
fusion beats.According to the modulated parasystole hypothesis, rigid constancy of a pacemaker might be expected if the entrance block were complete, but if there is an escape route available for the emergence of ectopic activity, then clearly there must be an effective ionic communication, not complete insulation, between the two tissues. If there is an electrical
communication between the two, then the depolarization of the surrounding ventricle may influence the ectopic pacemaker. That influence will be electrotonic; depolarization of the surrounding field will induce a partial depolarization
of the pacemaker cells. Therefore, appropriate diagnosis of modulated parasystole relies upon the construction of a “phase response curve” as theoretical evidence of modulation of the ectopic pacemaker cycle length by the electrotonic activity generated by the sinus discharges across the area of protection. In this case, the timing of the arrival of the electronic stimulus will serve to delay or advance the subsequent pacemaker activation. In this case, the coupling intervals between the manifest ectopic and sinus discharges will be either fixed or variable, depending on the cycle length relations between the two pacemakers.
See also
Extrasystole
References
External links
ventricular parasystole
atrial parasystole |
Phocomelia | Phocomelia is a condition that involves malformations of human arms and legs. Although many factors can cause phocomelia, the prominent roots come from the use of the drug thalidomide and from genetic inheritance.
Occurrence in an individual results in various abnormalities to the face, limbs, ears, nose, vessels and many other underdevelopments. Although operations may improve some abnormalities, many are not surgically treatable due to the lack of nerves and other related structures.
The term is from Ancient Greek φώκη phōkē, "seal (animal)" + -o- interfix + μέλος melos, "limb" + English suffix -ia). Phocomelia is an extremely rare congenital disorder involving malformation of the limbs (dysmelia). Étienne Geoffroy Saint-Hilaire coined the term in 1836.
Signs and symptoms
The symptoms of phocomelia syndrome are undeveloped limbs and absent pelvic bones; however, various abnormalities can occur to the limbs and bones. Usually the upper limbs are not fully formed and sections of the "hands and arms may be missing." Short arm bones, fused fingers, and missing thumbs will often occur. Sometimes hands or fingers will be present but limp due to having no bones or being loosely attached. Legs and feet are also affected similarly to the arms and hands. Individuals with phocomelia will often lack thigh bones, and the hands or feet may be abnormally small or appear as stumps due to their close "attachment to the body."According to National Organization for Rare Disorders (NORD), individuals carrying phocomelia syndrome will generally show symptoms of growth retardation previous to and after birth. The syndrome can also cause severe mental deficiencies in infants. Infants born with phocomelia will normally have a petite head with "sparse hair" that may appear "silvery-blonde." Hemangioma, the abnormal buildup of blood vessels, will possibly develop around the facial area at birth and the eyes may be set widely apart, a condition known as orbital hypertelorism. The pigment of the eyes will be a bluish white. Phocomelia can also cause: an undeveloped nose with slender nostrils, disfigured ears, irregularly petite jaws (a condition known as micrognathia), and a cleft lip with cleft palate. According to NORD, severe symptoms of phocomelia include:
A fissure of the skull and a projecting brain known as (encephalocele)
An accumulation of spinal fluid under the skull also known as hydrocephalus; causing vomiting and migraines
An abnormally shaped uterus (bicornuate)
Inability to clot blood efficiently due to a low amount of platelets running through the blood
Malformations in the kidney and heart
Shortened neck
Abnormalities in the urethra
Thalidomide syndrome symptoms
When an individual is born with phocomelia due to drugs or pharmaceuticals, it is known as thalidomide syndrome. The symptoms of thalidomide syndrome are defined by absent or shortened limbs; causing flipper hands and feet. According to Anthony J Perri III, and Sylvia Hsu they can additionally receive:
Palsy disorder of the face
Ear and eye abnormalities; resulting in limited/complete loss of hearing or sight
Gastrointestinal and genitourinary tract disorders
Ingrown genitalia
Undeveloped/missing lungs
Distorted digestive tract, heart, kidney
disorders to the limbsThe infants that were exposed to thalidomide during development phases had a 40% chance of survival. The McMredie-McBride hypothesis explains that the limbs of the infants become malformed as a result of the thalidomide harming the neural tissue—simply because the neural tissue has such a large impact on formation and development of the limbs.
Causes
Thalidomide
Thalidomide was released onto the market in 1958 in West Germany under the name Contergan. Primarily prescribed as a sedative or hypnotic, thalidomide also claimed to cure "anxiety, insomnia, gastritis, and tension". Afterwards it was used against nausea and to alleviate morning sickness in pregnant women. Thalidomide became an over-the-counter drug in Germany around 1960, i.e. it could be bought without a prescription. Shortly after the drug was sold, in Germany between 5,000 and 7,000 infants were born with phocomelia. Only 40% of these children survived.Research also proves that although phocomelia did exist through the 1940s and 1950s cases of severe phocomelia multiplied in the 1960s when thalidomide was released in Germany; the direct cause was traced to thalidomide. The statistic was given that "50 percent of the mothers with deformed children had taken thalidomide during the first trimester of pregnancy." Throughout Europe, Australia and the United States 10,000 cases were reported of infants with phocomelia; only 50% of the 10,000 survived. Thalidomide became effectively linked to death or severe disabilities among babies. Those subjected to thalidomide while in the womb experienced limb deficiencies in that the long limbs either were not developed or presented themselves as stumps. Other effects included deformed eyes, hearts, alimentary and urinary tracts, blindness and deafness.
Genetic inheritance
According to National Organization for Rare Disorders (NORD): when phocomelia is transmitted [in its familial genetic form] it is seen as an autosomal recessive trait and the mutation is linked to chromosome 8.A study of Roberts Syndrome, a genetic disorder showing similar symptoms to phocomelia, has shed light on the possible causes. An individual afflicted with Roberts Syndrome will have chromosome copies that do not connect at the centromeres, making them unable to line up accordingly. As a result, the newly made cells contain an excess or reduced number of chromosomes. In both Roberts Syndrome and phocomelia the cells cease to develop, or die, preventing proper development of the limbs, eyes, brain, palate, or other structures.
Treatment
Prosthesis is a synthetic alternative for missing limbs, teeth, and various other body parts. Advances in prosthetic limbs have increased greatly during the twentieth century. The use of new materials such as modern plastics, complex procedures and better pigments have created lighter in weight and more realistic looking artificial limbs. With the advancement of myoelectric prosthetic limbs, patients are able to move their limbs without the use of cords or other devices. The myoelectric limbs can detect electric signals from the nervous system and muscles. They were first used on adults, but now they are being fitted to children.Patients that receive a loss of limbs due to phocomelia are typically treated with prosthetics. Infants at the age of six months are recommended to have a prosthetic mitten fitted; enabling them to get used to the prosthesis. A hook will be added when the child reaches the age of two years. Eventually the patient may receive a myoelectric prosthetic limb. Patients are treated in this way due to the lack of understanding at a young age and the absence of necessary tissues and bones to hold the prosthetic limb.
Notable cases
Mat Fraser was born with phocomelia due to his mother taking thalidomide while she was pregnant. He is known as the drummer of rock bands including Fear of Sex, The Reasonable Strollers, Joyride, The Grateful Dub, and Living in Texas. He is also an actor and performing artist.
Alison Lapper was born with phocomelia. She is arm deficient and has shortened bones and legs. Lapper graduated from Brighton University in 1994, established herself as a visual artist, and in 2000 gave birth to a son, Parys. Lapper produces cards and calendars for The Mouth and Foot Painters Association. She does not wear prosthetic limbs.
Ronan Tynan was born with phocomelia. He became a track and field athlete, competing in the 1984 and 1988 Summer Paralympics. Tynan went on to a career as a physician, and later, a singer.
Ame Barnbrook was born without arms and only the lower half of her left leg, and three toes. She has a rarer form of phocomelia, meaning all of her limbs are affected. She graduated from the University of Wollongong with a Bachelor of Creative Arts. Barnbrook plays the trumpet with her foot and is a competitive sailor. She sails a SKUD18 at world championship level. She did not qualify for the 2012 Paralympic Games in London, but she trained for the 2016 Paralympic Games in Rio de Janeiro.
Thomas Quasthoff, an opera singer.
Nick Vujicic, evangelist, motivational speaker, author, and director of Life Without Limbs.
Eli Bowen, who made his living performing in sideshows.
Hee Ah Lee, a pianist who has two fingers on each hand.
Rahma Haruna was born in Nigeria with severe phocomelia. She had no limbs, except for a partially formed right hand that was attached to her axilla. Rahmas story came out when a local journalist saw her on the street with her brother, after which the story was shared widely on social media. She died at the age of 19, on 25 December 2016.
Enos Stutsman, Pioneer settler of North Dakota. Namesake of Stutsman County.
Beknur Zhanibek is a Kazakh singer, born with phocomelia. He represented Kazakhstan in the Junior Eurovision Song Contest 2021.
References
== External links == |
Nephrocalcinosis | Nephrocalcinosis, once known as Albrights calcinosis after Fuller Albright, is a term originally used to describe deposition of calcium salts in the renal parenchyma due to hyperparathyroidism. The term nephrocalcinosis is used to describe the deposition of both calcium oxalate and calcium phosphate. It may cause acute kidney injury. It is now more commonly used to describe diffuse, fine, renal parenchymal calcification in radiology. It is caused by multiple different conditions and is determined progressive kidney dysfunction. These outlines eventually come together to form a dense mass. During its early stages, nephrocalcinosis is visible on x-ray, and appears as a fine granular mottling over the renal outlines. It is most commonly seen as an incidental finding with medullary sponge kidney on an abdominal x-ray.
It may be severe enough to cause (as well as be caused by) renal tubular acidosis or even end stage kidney disease, due to disruption of the kidney tissue by the deposited calcium.
Signs and symptoms
Though this condition is usually asymptomatic, if symptoms are present they are usually related to the causative process, (e.g. hypercalcemia). Some of the symptoms that can happen are blood in the urine, fever and chills, nausea and vomiting, severe pain in the belly area, flanks of the back, groin, or testicles.
These include renal colic, polyuria and polydipsia:
Renal colic is usually caused by pre-existing nephrolithiasis, as may occur in patients with chronic hypercalciuria. Less commonly, it can result from calcified bodies moving into the calyceal system.
Nocturia, polyuria, and polydipsia from reduced urinary concentrating capacity (i.e. nephrogenic diabetes insipidus) as can be seen in hypercalcemia, medullary nephrocalcinosis of any cause, or in children with Bartter syndrome in whom essential tubular salt reabsorption is compromised.There are several causes of nephrocalcinosis that are typically acute and present only with kidney failure. These include tumor lysis syndrome, acute phosphate nephropathy, and occasional cases of enteric hyperoxaluria.
Cause
Nephrocalcinosis is connected with conditions that cause hypercalcemia, hyperphosphatemia, and the increased excretion of calcium, phosphate, and/or oxalate in the urine. A high urine pH can lead to Nephrocalcinosis but only if it is accompanied by hypercalciuria and hypocitraturia, since having a normal urinary citrate usually inhibits the crystallization of calcium. In conjunction with Nephrocalcinosis, hypercalcemia and hypercalciuria the following can occur:
Primary hyperparathyroidism: Nephrocalcinosis is one of the most common symptoms of primary hyperparathyroidism.
Sarcoidosis: Nephrocalcinosis is one of the most common symptoms.
Vitamin D: This can cause nephrocalcinosis because of Vitamin D therapy because it increases the absorption of ingested calcium and bone resorption, resulting in hypercalcemia and hypercalciuria.
Medullary nephrocalcinosis
Medullary sponge kidney
Distal renal tubular acidosis
Hyperoxaluria
Renal papillary necrosisAnd other causes of hypercalcemia (and thus hypercalciuria)
Immobilization (leading to hypercalcemia and hypercalciuria)
Milk-alkali syndrome
Hypervitaminosis D
Multiple myeloma
Hypercalciuria without hypercalcemia
These conditions can cause nephrocalcinosis in association with hypercalciuria without hypercalcemia:
Distal renal tubular acidosis
Medullary sponge kidney
Neonatal nephrocalcinosis and loop diuretics
Inherited tubulopathies
Chronic hypokalemia
Beta thalassemia
Mechanism
Nephrocalcinosis is caused by an increase in the urinary excretion of calcium, phosphate, and/or oxalate. Nephrocalcinosis is closely associated with nephrolithiasis, and patients frequently present with both conditions, however there have been cases where one occurs without the other. Calcium oxalate and calcium phosphate crystals form when the concentration of the reactants exceeds the limit. The deposits are collected in the inner medullary interstitium in the basement membranes of the thin limbs of the loop of Henle. The calcium phosphate plaques can enlarge into the surrounding interstitial tissue, or even rupture into the tubule lumen and can promote calcium oxalate stone formation.
Diagnosis
Nephrocalcinosis is diagnosed for the most part by imaging techniques. The imagings used are ultrasound (US), abdominal plain film and CT imaging. Of the 3 techniques CT and US are the more preferred. Nephrocalcinosis is considered present if at least two radiologists make the diagnosis on US and/or CT. In some cases a renal biopsy is done instead if imaging is not enough to confirm nephrocalcinosis. Once the diagnosis is confirmed additional testing is needed to find the underlying cause because the underlying condition may require treatment for reasons independent of nephrocalcinosis. These additional tests will measure serum, electrolytes, calcium, and phosphate, and the urine pH. If no underlying cause can be found then urine collection should be done for 24 hours and measurements of the excretion of calcium, phosphate, oxalate, citrate, and creatinine are looked at.
Stages of nephrocalcinosis
Chemical or Molecular nephrocalcinosis: Defined as a measurable increase in intracellular calcium concentrations, however, it is not visible through X-ray or microscopically.
Microscopic nephrocalcinosis: Occurs when depositis are visible by light microscope by obtaining a tissue sample from a biopsy. However, this cannot be seen in an X-ray.
Macroscopic nephrocalcinosis: Occurs when calcification can be seen through X-ray imaging.
Treatment
Increasing fluid intake to yield a urine output of greater than 2 liters a day can be advantageous for all patients with nephrocalcinosis. Patients with hypercalciuria can reduce calcium excretion by restricting animal protein, limiting sodium intake to less than 100 meq a day and being lax of potassium intake. If changing ones diet alone does not result in a suitable reduction of hypercalciuria, a thiazide diuretic can be administered in patients who do not have hypercalcemia. Citrate can increase the solubility of calcium in urine and limit the development of nephrocalcinosis. Citrate is not given to patients who have urine pH equal to or greater than 7.
Prognosis
The prognosis of nephrocalcinosis is determined by the underlying cause. Most cases of nephrocalcinosis do not progress to end stage renal disease, however if not treated it can lead to renal dysfunction this includes primary hyperoxaluria, hypomagnesemic hypercalciuric nephrocalcinosis and Dents disease. Once nephrocalcinosis is found, it is unlikely to be reversed, however, partial reversal has been reported in patients who have had successful treatment of hypercalciuria and hyperoxaluria following corrective intestinal surgery.
Recent research
In recent findings they have found that there is a genetic predisposition to nephrocalciosis, however the specific genetic and epigenetic factors are not clear. There seems to be multiple genetic factors that regulate the excretion of the different urinary risk factors. There has been some correlation seen that shows gene polymorphisms related to stone formation for calcium-sensing receptor and vitamin D receptors. Repeated calcium stones associated with medullary sponge kidney may be related to an autosomal dominant mutation of a still unknown gene, however the genes is GDNF seems to be a gene involved in renal morphogenesis. In conjunction with the gene research is another theory of how the disease manifests. This is called the free particle theory. This theory says that the increasing concentration of lithogenic solutes along the segments of the nephron leads to the formation, growth, and collection of crystals that might get trapped in the tubular lumen and begin the process of stone formation. Some of the backing behind this theory is the speed of growth of the crystals, the diameter of the segments of the nephron, and the transit time in the nephron. All of these combined show more and more support for this theory.
References
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