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Symptoms of Sprengel Deformity
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Often, only one shoulder blade (i.e. one side of the body) is affected. However, in some cases both shoulder blades can be affected. Generally, these abnormalities tend to be painless. The degree of elevation and displacement in Sprengel deformity can vary greatly from one person to another and can range from very mild, in which the abnormality cannot be seen when wearing clothes, to severe cases in which the shoulder is noticeably elevated. Milder cases can go undiagnosed until adolescence. The reported range of displacement of the shoulder blade is 2-10 centimeters, or approximately a half an inch to 4 inches.The main signs and symptoms of Sprengel deformity are limited or restricted movement of the arm and shoulder blade on the affected side as well as the cervical spine. Some affected individuals have neck deformities as well, ranging from mild tilting (torticollis) to severe spine deformity. In severe cases, the neck may be abnormally short (brevicollis) and webbed. In approximately 75% of cases, Sprengel deformity is associated with additional abnormalities, most commonly Klippel-Feil syndrome, but also scoliosis, spina bifida, hemivertebrae, rib segmentation abnormalities, clavicular abnormalities, and underdevelopment (hypoplasia) of neck or shoulder muscles.
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Symptoms of Sprengel Deformity. Often, only one shoulder blade (i.e. one side of the body) is affected. However, in some cases both shoulder blades can be affected. Generally, these abnormalities tend to be painless. The degree of elevation and displacement in Sprengel deformity can vary greatly from one person to another and can range from very mild, in which the abnormality cannot be seen when wearing clothes, to severe cases in which the shoulder is noticeably elevated. Milder cases can go undiagnosed until adolescence. The reported range of displacement of the shoulder blade is 2-10 centimeters, or approximately a half an inch to 4 inches.The main signs and symptoms of Sprengel deformity are limited or restricted movement of the arm and shoulder blade on the affected side as well as the cervical spine. Some affected individuals have neck deformities as well, ranging from mild tilting (torticollis) to severe spine deformity. In severe cases, the neck may be abnormally short (brevicollis) and webbed. In approximately 75% of cases, Sprengel deformity is associated with additional abnormalities, most commonly Klippel-Feil syndrome, but also scoliosis, spina bifida, hemivertebrae, rib segmentation abnormalities, clavicular abnormalities, and underdevelopment (hypoplasia) of neck or shoulder muscles.
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Sprengel Deformity
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Causes of Sprengel Deformity
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The exact underlying cause is unknown. Most cases occur randomly, for no apparent reason (sporadically). Researchers believe that the disorder occurs early during fetal development. In a developing fetus, the shoulder blade initially forms near the vertebrae of the cervical spine. During the third month of pregnancy, the shoulder blade moves or ‘migrates’ down to its normal position. In individuals with Sprengel deformity this migration fails to occur. The developing shoulder blade remains too high and often fails to fully form. In some cases, an abnormal connection made up of fibrous bands of tissue develops between the displaced shoulder blade and the spine (omovertebral bar), which can severely limit movement of the shoulder. This structure may harden (ossify) and become known as the omovertebral bone. In extremely rare cases, Sprengel deformity has run in families suggesting that in these cases the disorder may occur as a genetic defect inherited in an autosomal dominant manner.
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Causes of Sprengel Deformity. The exact underlying cause is unknown. Most cases occur randomly, for no apparent reason (sporadically). Researchers believe that the disorder occurs early during fetal development. In a developing fetus, the shoulder blade initially forms near the vertebrae of the cervical spine. During the third month of pregnancy, the shoulder blade moves or ‘migrates’ down to its normal position. In individuals with Sprengel deformity this migration fails to occur. The developing shoulder blade remains too high and often fails to fully form. In some cases, an abnormal connection made up of fibrous bands of tissue develops between the displaced shoulder blade and the spine (omovertebral bar), which can severely limit movement of the shoulder. This structure may harden (ossify) and become known as the omovertebral bone. In extremely rare cases, Sprengel deformity has run in families suggesting that in these cases the disorder may occur as a genetic defect inherited in an autosomal dominant manner.
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Sprengel Deformity
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Affects of Sprengel Deformity
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Most reports in the medical literature state that Sprengel deformity affects females more often than males by a ratio of 3-1. However, other reports state that the disorder affects males and females in equal numbers.
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Affects of Sprengel Deformity. Most reports in the medical literature state that Sprengel deformity affects females more often than males by a ratio of 3-1. However, other reports state that the disorder affects males and females in equal numbers.
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Sprengel Deformity
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nord_1157_4
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Related disorders of Sprengel Deformity
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Symptoms of the following disorders can be similar to those of Sprengel deformity. Comparisons may be useful for a differential diagnosis:Scoliosis is a common condition in which the spine abnormally curves to the side instead of running straight up and down. Scoliosis can be mild, but can worsen as an affected child grows. In many cases, the exact cause of scoliosis is unknown (idiopathic). In other cases, the condition can develop as part of a large syndrome such as muscular dystrophy. Affected children may have uneven shoulders, one shoulder blade that appears to be more pronounced or prominent than the other, and uneven hips. Some children may experience backaches or lower back pain. Klippel-Feil syndrome (KFS) is a rare skeletal disorder primarily characterized by abnormal union or fusion of two or more bones of the spinal column (vertebrae) within the neck (cervical vertebrae). Some affected individuals may also have an abnormally short neck, restricted movement of the head and neck, and a low hairline at the back of the head (posterior hairline). The disorder is present at birth (congenital), but mild cases may go undiagnosed until later during life when symptoms worsen or first become apparent. In some individuals, KFS can be associated with a variety of additional symptoms and physical abnormalities. These may include Sprengel deformity, abnormal curvature of the spine (scoliosis), spina bifida occulta, absent rib(s) and other rib defects including cervical ribs, other skeletal abnormalities including skeletal malformations of the ear, nose, mouth and larynx including hearing impairment and cleft palate, malformations of the head and facial (craniofacial) area; anomalies of the urinary tract and/or kidney including absent or horse-shoe kidney; or structural abnormalities of the heart (congenital heart defects), mirror movements, webbing of the digits and digital hypoplasia. In addition, in some cases, neurological complications may result due to associated spinal cord injury. In many individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). In other cases, KFS may be inherited as an autosomal dominant or autosomal recessive trait. Researchers have determined that some cases of KFS are associated with mutations of the GDF6 gene on chromosome 8. (For more information, choose “Klippel Feil” as your search term in the Rare Disease Database.)
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Related disorders of Sprengel Deformity. Symptoms of the following disorders can be similar to those of Sprengel deformity. Comparisons may be useful for a differential diagnosis:Scoliosis is a common condition in which the spine abnormally curves to the side instead of running straight up and down. Scoliosis can be mild, but can worsen as an affected child grows. In many cases, the exact cause of scoliosis is unknown (idiopathic). In other cases, the condition can develop as part of a large syndrome such as muscular dystrophy. Affected children may have uneven shoulders, one shoulder blade that appears to be more pronounced or prominent than the other, and uneven hips. Some children may experience backaches or lower back pain. Klippel-Feil syndrome (KFS) is a rare skeletal disorder primarily characterized by abnormal union or fusion of two or more bones of the spinal column (vertebrae) within the neck (cervical vertebrae). Some affected individuals may also have an abnormally short neck, restricted movement of the head and neck, and a low hairline at the back of the head (posterior hairline). The disorder is present at birth (congenital), but mild cases may go undiagnosed until later during life when symptoms worsen or first become apparent. In some individuals, KFS can be associated with a variety of additional symptoms and physical abnormalities. These may include Sprengel deformity, abnormal curvature of the spine (scoliosis), spina bifida occulta, absent rib(s) and other rib defects including cervical ribs, other skeletal abnormalities including skeletal malformations of the ear, nose, mouth and larynx including hearing impairment and cleft palate, malformations of the head and facial (craniofacial) area; anomalies of the urinary tract and/or kidney including absent or horse-shoe kidney; or structural abnormalities of the heart (congenital heart defects), mirror movements, webbing of the digits and digital hypoplasia. In addition, in some cases, neurological complications may result due to associated spinal cord injury. In many individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). In other cases, KFS may be inherited as an autosomal dominant or autosomal recessive trait. Researchers have determined that some cases of KFS are associated with mutations of the GDF6 gene on chromosome 8. (For more information, choose “Klippel Feil” as your search term in the Rare Disease Database.)
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Sprengel Deformity
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nord_1157_5
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Diagnosis of Sprengel Deformity
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A diagnosis of Sprengel deformity is based upon the identification of characteristic symptoms, a thorough clinical evaluation, and a variety of specialized tests, particularly advanced imaging tests. An anteroposterior chest x-ray, or chest radiograph, can accurately be used to diagnose Sprengel deformity. Anteroposterior means ‘front to back’. During this x-ray exam, the individual’s back is against the film plate and the x-ray is in front. The exam can show the elevated and rotated shoulder blade. Advanced imaging techniques include computed tomography (CT) scans and magnetic resonance imaging (MRI), and are commonly used to confirm a diagnosis of Sprengel deformity. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. These tests can reveal the presence of an omovertebral bone. Advanced imaging techniques are also beneficial for planning and guiding surgery intervention. The presence of an omovertebral bone can sometimes be difficult to detect on imaging studies because off the possibility of superimposed bones.
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Diagnosis of Sprengel Deformity. A diagnosis of Sprengel deformity is based upon the identification of characteristic symptoms, a thorough clinical evaluation, and a variety of specialized tests, particularly advanced imaging tests. An anteroposterior chest x-ray, or chest radiograph, can accurately be used to diagnose Sprengel deformity. Anteroposterior means ‘front to back’. During this x-ray exam, the individual’s back is against the film plate and the x-ray is in front. The exam can show the elevated and rotated shoulder blade. Advanced imaging techniques include computed tomography (CT) scans and magnetic resonance imaging (MRI), and are commonly used to confirm a diagnosis of Sprengel deformity. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. These tests can reveal the presence of an omovertebral bone. Advanced imaging techniques are also beneficial for planning and guiding surgery intervention. The presence of an omovertebral bone can sometimes be difficult to detect on imaging studies because off the possibility of superimposed bones.
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Therapies of Sprengel Deformity
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The mainstay of treatment for Sprengel deformity is surgery. However, many affected individuals will not require surgical intervention because they have a mild form of the disorder with minimal restriction of movement. Children between 3-8 years of age are the best candidates for surgical intervention, which is based on significant cosmetic or functional (i.e. significant restriction of movement) concerns. In some cases, shoulder blade position and/or shoulder range of motion can still be abnormal even after surgery. The presence of additional abnormalities can affect the outcome of surgery. An omovertebral bone or its fibrous equivalent must be removed during surgery. There are several surgical procedures used to treat individuals with Sprengel deformity. The main two are the modified Green scapuloplasty and the Woodward procedure. Decisions concerning the specific surgical technique to use is best made with physicians and other members of the healthcare team in close consultation with the family based upon the specifics of the individual case, a thorough discussion of potential discussion of the potential benefits and risks, including long-term effects and other appropriate factors.
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Therapies of Sprengel Deformity. The mainstay of treatment for Sprengel deformity is surgery. However, many affected individuals will not require surgical intervention because they have a mild form of the disorder with minimal restriction of movement. Children between 3-8 years of age are the best candidates for surgical intervention, which is based on significant cosmetic or functional (i.e. significant restriction of movement) concerns. In some cases, shoulder blade position and/or shoulder range of motion can still be abnormal even after surgery. The presence of additional abnormalities can affect the outcome of surgery. An omovertebral bone or its fibrous equivalent must be removed during surgery. There are several surgical procedures used to treat individuals with Sprengel deformity. The main two are the modified Green scapuloplasty and the Woodward procedure. Decisions concerning the specific surgical technique to use is best made with physicians and other members of the healthcare team in close consultation with the family based upon the specifics of the individual case, a thorough discussion of potential discussion of the potential benefits and risks, including long-term effects and other appropriate factors.
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Sprengel Deformity
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nord_1158_0
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Overview of Staphylococcal Scalded Skin Syndrome
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Staphylococcal scalded skin syndrome (SSSS) is a disorder that develops because of a toxin produced by a staphylococcal infection. A toxin is a harmful substance that causes disease when it enters tissues of the body. In SSSS the toxin spreads to the skin through the blood stream and specifically binds to desmoglein 1, an adhesion molecule target protein very high in the epidermis (outer layer of the skin) producing total body reddening of the skin and blistering and sloughing of the skin resembling a hot water burn or scalding of the skin. The top layer of the skin may peel off and shed. Affected individuals may also experience nonspecific symptoms such as fever (usually low grade), chills and weakness. Unlike similar disorders that cause a scalded skin appearance, the mucous membranes are not affected. Infants and younger children are most susceptible, because they lack antibodies to the toxin and may be slow to clear the toxin-antibody complex in their immature kidneys, but the disorder can also occur in certain older children or adults such as people who have compromised immune systems or insufficient kidney (renal) function. Staphylococcal scalded skin syndrome is caused by toxins produced by certain strains (most commonly phage group 2 strains 55 and 71) of the bacterial germ Staphylococcus aureus.
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Overview of Staphylococcal Scalded Skin Syndrome. Staphylococcal scalded skin syndrome (SSSS) is a disorder that develops because of a toxin produced by a staphylococcal infection. A toxin is a harmful substance that causes disease when it enters tissues of the body. In SSSS the toxin spreads to the skin through the blood stream and specifically binds to desmoglein 1, an adhesion molecule target protein very high in the epidermis (outer layer of the skin) producing total body reddening of the skin and blistering and sloughing of the skin resembling a hot water burn or scalding of the skin. The top layer of the skin may peel off and shed. Affected individuals may also experience nonspecific symptoms such as fever (usually low grade), chills and weakness. Unlike similar disorders that cause a scalded skin appearance, the mucous membranes are not affected. Infants and younger children are most susceptible, because they lack antibodies to the toxin and may be slow to clear the toxin-antibody complex in their immature kidneys, but the disorder can also occur in certain older children or adults such as people who have compromised immune systems or insufficient kidney (renal) function. Staphylococcal scalded skin syndrome is caused by toxins produced by certain strains (most commonly phage group 2 strains 55 and 71) of the bacterial germ Staphylococcus aureus.
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Staphylococcal Scalded Skin Syndrome
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nord_1158_1
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Symptoms of Staphylococcal Scalded Skin Syndrome
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Initial symptoms can include fever (usually low grade), generalized redness and tenderness of the skin. The onset of symptoms is usually rapid. Some individuals may experience nonspecific symptoms that develop before the skin symptoms including a sore throat and inflammation of the eyelids known as conjunctivitis.Initially the affected skin may have a sandpaper-like feel before becoming red and wrinkled. Areas prone to movement are most commonly initially involved. In children, the area around the mouth, eyes and ears is often affected. In infants, the diaper area and the area around the bellybutton are most often affected. The rash spreads rapidly with a propensity to affect the area around the mouth (perioral area) and areas where the skin creases, especially on the legs, arms, groin and neck. The top layer of the epidermis, which is the top layer of the skin, may separate (detach) from the underlying layers resulting in loose blisters and shallow erosions (sores). Affected skin may slough off in sheets. Sloughing results in the exposure of moist, reddish tissue very close to the top of the epidermis and gives the skin a scalded or burned appearance. The application of gentle pressure to the skin will also cause sloughing which is known as a Nikolsky sign.Affected individuals may also experience additional symptoms including chills, weakness, aches and pain of the joints and muscles, fluid loss through the damaged skin and a general feeling of poor health (malaise). The loss of the top of the epidermis, which serves as a protective barrier, carries a risk of developing sepsis, a serious, potentially life-threatening infection of the blood and tissues of the body. However, in otherwise healthy children the risk of sepsis is rare. Pneumonia can also potentially occur.The severity of the disorder is highly variable. Staphylococcal scalded skin syndrome can cause mild disease or potentially it can progress to cause life-threatening complications. Such severe complications are rare in children, with the mortality rate below 5%. However, the mortality rate is higher in adults, due primarily to additional factors including the presence of other health issues (e.g., weakened immune system, poor kidney health).
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Symptoms of Staphylococcal Scalded Skin Syndrome. Initial symptoms can include fever (usually low grade), generalized redness and tenderness of the skin. The onset of symptoms is usually rapid. Some individuals may experience nonspecific symptoms that develop before the skin symptoms including a sore throat and inflammation of the eyelids known as conjunctivitis.Initially the affected skin may have a sandpaper-like feel before becoming red and wrinkled. Areas prone to movement are most commonly initially involved. In children, the area around the mouth, eyes and ears is often affected. In infants, the diaper area and the area around the bellybutton are most often affected. The rash spreads rapidly with a propensity to affect the area around the mouth (perioral area) and areas where the skin creases, especially on the legs, arms, groin and neck. The top layer of the epidermis, which is the top layer of the skin, may separate (detach) from the underlying layers resulting in loose blisters and shallow erosions (sores). Affected skin may slough off in sheets. Sloughing results in the exposure of moist, reddish tissue very close to the top of the epidermis and gives the skin a scalded or burned appearance. The application of gentle pressure to the skin will also cause sloughing which is known as a Nikolsky sign.Affected individuals may also experience additional symptoms including chills, weakness, aches and pain of the joints and muscles, fluid loss through the damaged skin and a general feeling of poor health (malaise). The loss of the top of the epidermis, which serves as a protective barrier, carries a risk of developing sepsis, a serious, potentially life-threatening infection of the blood and tissues of the body. However, in otherwise healthy children the risk of sepsis is rare. Pneumonia can also potentially occur.The severity of the disorder is highly variable. Staphylococcal scalded skin syndrome can cause mild disease or potentially it can progress to cause life-threatening complications. Such severe complications are rare in children, with the mortality rate below 5%. However, the mortality rate is higher in adults, due primarily to additional factors including the presence of other health issues (e.g., weakened immune system, poor kidney health).
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Causes of Staphylococcal Scalded Skin Syndrome
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Staphylococcal scalded skin syndrome is caused by a Staphylococcus or “Staph” infection. Staphylococcus is a type of bacterium of which there are more than 30 different varieties. Staphylococcus aureus is the most common form associated with disease. Staphylococcus aureus is commonly found on human skin and begins colonization immediately after birth. Usually, this bacterium resides on the skin and mucous membranes of humans but does no harm. However, it does predispose an individual to infection, especially when given the opportunity to break through the skin. Staphylococcus aureus is the underlying infection in individuals with staphylococcal scalded skin syndrome. However, in many healthy children no underlying bacterial infection can be detected clinically.Symptoms develops because a Staphylococcus aureus infection (or often only colonization when the Staph germ does not cause infection but makes toxin) releases toxins into the blood at the primary site of infection or colonization. The most common sites of colonization are at the mucocutaneous junction including the nasopharynx, medial canthi and the anogenital area, and the organisms can be cultured from these areas. These toxins spread to the skin and damage the upper part of the epidermis (outer part of the outer layer of the skin). Specifically, the toxins damage desmoglein 1, a molecule essential for epidermal cells to stick together (adhere) and form a protective barrier. Damaged desmoglein 1 prevents epidermal cells from sticking together causing the upper level of the epidermis to break apart and eventually pull away (detach) from the rest of the epidermis and the dermis (the layer of the skin beneath the epidermis which attaches to the underlying fat). Local release of the toxin into the skin results in bullous impetigo (see Disorders with Similar Symptoms below) at the site of primary infection or colonization. When these toxins enter the bloodstream and spread to affect the skin in other areas of the body, staphylococcal scalded skin syndrome develops.In newborns, the initial lesions are often in the diaper area or around the umbilical cord. In older children, the face is often the initial site of the rash.
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Causes of Staphylococcal Scalded Skin Syndrome. Staphylococcal scalded skin syndrome is caused by a Staphylococcus or “Staph” infection. Staphylococcus is a type of bacterium of which there are more than 30 different varieties. Staphylococcus aureus is the most common form associated with disease. Staphylococcus aureus is commonly found on human skin and begins colonization immediately after birth. Usually, this bacterium resides on the skin and mucous membranes of humans but does no harm. However, it does predispose an individual to infection, especially when given the opportunity to break through the skin. Staphylococcus aureus is the underlying infection in individuals with staphylococcal scalded skin syndrome. However, in many healthy children no underlying bacterial infection can be detected clinically.Symptoms develops because a Staphylococcus aureus infection (or often only colonization when the Staph germ does not cause infection but makes toxin) releases toxins into the blood at the primary site of infection or colonization. The most common sites of colonization are at the mucocutaneous junction including the nasopharynx, medial canthi and the anogenital area, and the organisms can be cultured from these areas. These toxins spread to the skin and damage the upper part of the epidermis (outer part of the outer layer of the skin). Specifically, the toxins damage desmoglein 1, a molecule essential for epidermal cells to stick together (adhere) and form a protective barrier. Damaged desmoglein 1 prevents epidermal cells from sticking together causing the upper level of the epidermis to break apart and eventually pull away (detach) from the rest of the epidermis and the dermis (the layer of the skin beneath the epidermis which attaches to the underlying fat). Local release of the toxin into the skin results in bullous impetigo (see Disorders with Similar Symptoms below) at the site of primary infection or colonization. When these toxins enter the bloodstream and spread to affect the skin in other areas of the body, staphylococcal scalded skin syndrome develops.In newborns, the initial lesions are often in the diaper area or around the umbilical cord. In older children, the face is often the initial site of the rash.
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Staphylococcal Scalded Skin Syndrome
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nord_1158_3
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Affects of Staphylococcal Scalded Skin Syndrome
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Staphylococcal scalded skin syndrome affects males and females in equal numbers. The incidence, which has doubled in the last decade (based on national hospitalization data), is estimated to be between .09 and .56 per 1,000,000 individuals in the general population. However, these estimates may reflect cases reported in the medical literature, and the disorder most likely is more common in the United States than estimated, particularly in infants and young children. Most cases are in children under the age of 6. Newborns (neonates) are at particular risk because they do not have fully developed immune systems, do not have neutralizing antibodies for the toxin, and their kidneys cannot fully clear toxins from the body yet. For similar reasons certain adults, specifically adults with a compromised immune system or poor kidney function, are at a greater risk than the general population of developing the disorder.
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Affects of Staphylococcal Scalded Skin Syndrome. Staphylococcal scalded skin syndrome affects males and females in equal numbers. The incidence, which has doubled in the last decade (based on national hospitalization data), is estimated to be between .09 and .56 per 1,000,000 individuals in the general population. However, these estimates may reflect cases reported in the medical literature, and the disorder most likely is more common in the United States than estimated, particularly in infants and young children. Most cases are in children under the age of 6. Newborns (neonates) are at particular risk because they do not have fully developed immune systems, do not have neutralizing antibodies for the toxin, and their kidneys cannot fully clear toxins from the body yet. For similar reasons certain adults, specifically adults with a compromised immune system or poor kidney function, are at a greater risk than the general population of developing the disorder.
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nord_1158_4
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Related disorders of Staphylococcal Scalded Skin Syndrome
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Symptoms of the following disorders can be similar to those of staphylococcal scalded skin syndrome and should be differentiated from SSSS. Comparisons may be useful for a differential diagnosis.Bullous impetigo is a skin disorder caused by the same toxins (produced by the same underlying infection) that causes staphylococcal scalded skin syndrome. In bullous impetigo pustules and blisters form at the initial site of infection and not in other areas of the body (localized disease). Because the blisters and pustules form so close to the surface of the epidermis, they rarely grow beyond 4-5 mm before rupturing and continue to expand at the border where oozing and yellow crusting occurs, and the infection can spread to nearby skin when patients scratch the rash. Most often, bullous impetigo develops on the face, hands, trunk or buttocks. The disorder most often occurs in young children or infants, but generalized redness and rash do not develop as in SSSS, because these children and adults have neutralizing antibody, from prior exposure to the organisms, which binds to the toxin which is quickly cleared by their mature kidneys.Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe allergic reactions usually caused by medications that trigger widespread blistering and sloughing of the skin and multiple mucous membranes. In SJS less than a third of the body surface is involved, and TEN affects larger areas. In SJS and TEN deep blisters and full thickness ulcerations develop at the bottom of the epidermis and the mucosa of the mouth, nose, eyes, urethra, vagina and anus which does not occur in SSSS. Although many drugs can cause SJS and TENS, sulfa drugs and certain antibiotics, anti-inflammatory and anti-seizure drugs (antiepileptics) are most commonly associated with these disorders. (For more information on these disorders, choose “Stevens Johnson syndrome” or “toxic epidermal necrolysis” as your search term in the Rare Disease Database.)Other infectious and non-infection related skin disorders can produce symptoms similar to those seen in staphylococcal scalded skin syndrome. Such disorders include epidermolysis bullosa, epidermolytic ichthyosis, peeling skin syndrome, scarlet fever, Kawasaki disease, thermal burns, erythema multiforme, eczema herpeticum, and various nutritional deficiencies. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) However, they are usually readily distinguished from SSSS.
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Related disorders of Staphylococcal Scalded Skin Syndrome. Symptoms of the following disorders can be similar to those of staphylococcal scalded skin syndrome and should be differentiated from SSSS. Comparisons may be useful for a differential diagnosis.Bullous impetigo is a skin disorder caused by the same toxins (produced by the same underlying infection) that causes staphylococcal scalded skin syndrome. In bullous impetigo pustules and blisters form at the initial site of infection and not in other areas of the body (localized disease). Because the blisters and pustules form so close to the surface of the epidermis, they rarely grow beyond 4-5 mm before rupturing and continue to expand at the border where oozing and yellow crusting occurs, and the infection can spread to nearby skin when patients scratch the rash. Most often, bullous impetigo develops on the face, hands, trunk or buttocks. The disorder most often occurs in young children or infants, but generalized redness and rash do not develop as in SSSS, because these children and adults have neutralizing antibody, from prior exposure to the organisms, which binds to the toxin which is quickly cleared by their mature kidneys.Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe allergic reactions usually caused by medications that trigger widespread blistering and sloughing of the skin and multiple mucous membranes. In SJS less than a third of the body surface is involved, and TEN affects larger areas. In SJS and TEN deep blisters and full thickness ulcerations develop at the bottom of the epidermis and the mucosa of the mouth, nose, eyes, urethra, vagina and anus which does not occur in SSSS. Although many drugs can cause SJS and TENS, sulfa drugs and certain antibiotics, anti-inflammatory and anti-seizure drugs (antiepileptics) are most commonly associated with these disorders. (For more information on these disorders, choose “Stevens Johnson syndrome” or “toxic epidermal necrolysis” as your search term in the Rare Disease Database.)Other infectious and non-infection related skin disorders can produce symptoms similar to those seen in staphylococcal scalded skin syndrome. Such disorders include epidermolysis bullosa, epidermolytic ichthyosis, peeling skin syndrome, scarlet fever, Kawasaki disease, thermal burns, erythema multiforme, eczema herpeticum, and various nutritional deficiencies. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) However, they are usually readily distinguished from SSSS.
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Staphylococcal Scalded Skin Syndrome
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Diagnosis of Staphylococcal Scalded Skin Syndrome
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A diagnosis of staphylococcal scalded skin syndrome is based upon identification of characteristic symptoms, a thorough clinical evaluation and a detailed patient history. Although not usually necessary, in some cases, a skin biopsy, in which a tiny piece of affected skin is removed and studied under a microscope, may be performed. A biopsy can reveal non-inflammatory superficial splitting of the epidermis, which is indicative of the disorder and can differentiate it from similar disorders.Cultures can be taken from areas that harbor the bacterial germ including the conjunctiva (corners of the eyes), nasal passages, umbilicus and the upper area of the throat that connects with the nasal passages (nasopharynx area). Rarely, underling serious infections such as pneumonia, meningitis, arthritis and deep skin infection can trigger SSSS, and cultures may need to be taken from these sites. Cultures from blisters (bullae) and skin erosions are usually sterile because they are triggered by toxin and not direct bacterial infection.A complete blood count (CBC) can reveal elevated levels of white blood cells or an elevated erythrocyte sedimentation rate, which measures how long it takes red blood cells (erythrocytes) to settle in a test tube over a given period. However, neither the white blood cell count nor the erythrocyte sedimentation rate is elevated in all individuals.
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Diagnosis of Staphylococcal Scalded Skin Syndrome. A diagnosis of staphylococcal scalded skin syndrome is based upon identification of characteristic symptoms, a thorough clinical evaluation and a detailed patient history. Although not usually necessary, in some cases, a skin biopsy, in which a tiny piece of affected skin is removed and studied under a microscope, may be performed. A biopsy can reveal non-inflammatory superficial splitting of the epidermis, which is indicative of the disorder and can differentiate it from similar disorders.Cultures can be taken from areas that harbor the bacterial germ including the conjunctiva (corners of the eyes), nasal passages, umbilicus and the upper area of the throat that connects with the nasal passages (nasopharynx area). Rarely, underling serious infections such as pneumonia, meningitis, arthritis and deep skin infection can trigger SSSS, and cultures may need to be taken from these sites. Cultures from blisters (bullae) and skin erosions are usually sterile because they are triggered by toxin and not direct bacterial infection.A complete blood count (CBC) can reveal elevated levels of white blood cells or an elevated erythrocyte sedimentation rate, which measures how long it takes red blood cells (erythrocytes) to settle in a test tube over a given period. However, neither the white blood cell count nor the erythrocyte sedimentation rate is elevated in all individuals.
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Staphylococcal Scalded Skin Syndrome
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Therapies of Staphylococcal Scalded Skin Syndrome
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Treatment
Treatment is directed toward the specific symptoms that are apparent in each individual and may require the coordinated efforts of a team of specialists. Hospitalization may be required. However, older infants and children who are still eating and drinking well can often be treated as outpatients with local skin care and oral antibiotics. Rarely, severe cases may require treatment in a burn center, but aggressive debridement of blisters and erosions should be avoided, since in healthy individuals the superficial sloughing of the skin heals quickly and trauma to the skin may prolong healing.Most individuals respond to oral or intravenous antibiotic therapy, specifically penicillase-resistance antibiotics with activity against Staphylococcal infections. Initial antibiotics therapy may include nafcillin, oxacillin or cephalosporin, and oral antibiotics should be considered in healthy patients who are still taking fluids well. In areas with a high prevalence of methicillin-resistant Staphylococcal aureus (MRSA) infection, vancomycin may be considered. Vancomycin can also be used for individuals who do not respond to initial therapy. Interestingly, most cases (over 95%) are caused by methicillin sensitive Staphylococcus aureus bacteria, and resistance to clindamycin has been increasing and may be over 20% in many areas. Topical agents such as mupirocin can be used as adjunct therapy at the site of colonization in an attempt to eradicate colonization.Exposed, damaged areas should be treated with gentle ointments, such as petroleum jelly, that soothe and moisturize the skin (emollients). Emollients should be applied as often as possible to the lips to facilitate oral intake. Topical wound care should be conservative in general, and dressings should be changed as infrequently as possible and, in many areas, only emollients may be required. In otherwise healthy children healing usually begins in 24-48 hours and is often complete in a few more days. Seven to 10 days later many patients will develop innocent dry peeling.Fluid replacement with electrolytes may be necessary in patients who are unable to eat or drink.Pain management may be required for a few days with specific medications such as paracetamol and acetaminophen. Nonsteroidal anti-inflammatories (NSAIDs) should not be given for pain because they may reduce kidney function and complicate the disorder. Steroids should not be given because they can worsen immune system function.
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Therapies of Staphylococcal Scalded Skin Syndrome. Treatment
Treatment is directed toward the specific symptoms that are apparent in each individual and may require the coordinated efforts of a team of specialists. Hospitalization may be required. However, older infants and children who are still eating and drinking well can often be treated as outpatients with local skin care and oral antibiotics. Rarely, severe cases may require treatment in a burn center, but aggressive debridement of blisters and erosions should be avoided, since in healthy individuals the superficial sloughing of the skin heals quickly and trauma to the skin may prolong healing.Most individuals respond to oral or intravenous antibiotic therapy, specifically penicillase-resistance antibiotics with activity against Staphylococcal infections. Initial antibiotics therapy may include nafcillin, oxacillin or cephalosporin, and oral antibiotics should be considered in healthy patients who are still taking fluids well. In areas with a high prevalence of methicillin-resistant Staphylococcal aureus (MRSA) infection, vancomycin may be considered. Vancomycin can also be used for individuals who do not respond to initial therapy. Interestingly, most cases (over 95%) are caused by methicillin sensitive Staphylococcus aureus bacteria, and resistance to clindamycin has been increasing and may be over 20% in many areas. Topical agents such as mupirocin can be used as adjunct therapy at the site of colonization in an attempt to eradicate colonization.Exposed, damaged areas should be treated with gentle ointments, such as petroleum jelly, that soothe and moisturize the skin (emollients). Emollients should be applied as often as possible to the lips to facilitate oral intake. Topical wound care should be conservative in general, and dressings should be changed as infrequently as possible and, in many areas, only emollients may be required. In otherwise healthy children healing usually begins in 24-48 hours and is often complete in a few more days. Seven to 10 days later many patients will develop innocent dry peeling.Fluid replacement with electrolytes may be necessary in patients who are unable to eat or drink.Pain management may be required for a few days with specific medications such as paracetamol and acetaminophen. Nonsteroidal anti-inflammatories (NSAIDs) should not be given for pain because they may reduce kidney function and complicate the disorder. Steroids should not be given because they can worsen immune system function.
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Overview of Status Epilepticus
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Status epilepticus (SE) is considered a neurological emergency. Left untreated (or undertreated), prolonged seizures can cause permanent neurological injury or death. Rapid treatment must be initiated. If initial agents fail, it may be necessary to induce an iatrogenic coma. In any case, the person in status epilepticus must be closely watched, and often requires continuous EEG in order to confirm that the seizures have stopped not only clinically but electrically as well.
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Overview of Status Epilepticus. Status epilepticus (SE) is considered a neurological emergency. Left untreated (or undertreated), prolonged seizures can cause permanent neurological injury or death. Rapid treatment must be initiated. If initial agents fail, it may be necessary to induce an iatrogenic coma. In any case, the person in status epilepticus must be closely watched, and often requires continuous EEG in order to confirm that the seizures have stopped not only clinically but electrically as well.
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Symptoms of Status Epilepticus
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Epilepsy is a group of disorders characterized by electrical discharges in the brain. There are no established factors that bring on an epileptic seizure that are common to all patients. However, visual phenomena such as flickering lights or sunbursts, are frequently cited by people with epilepsy as preceding an attack. In certain patients the likelihood of having a seizure increases with stress, fatigue, insufficient food intake and/or the failure to take prescribed medications.The Status Epilepticus are classified as follows:Generalized Convulsive Status Epilepticus (GCSE): Overt (70 percent of GCSE): This consists of continuous tonic and/or clonic activity with impairment or loss of awareness.Subtle (30 percent of GCSE): This is less obvious than the overt type, consisting of facial twitching, nystagmoid eye movements, or subtle jerking of the extremities.Non-Convulsive Status Epilepticus (NCSE): Complex Partial Status Epilepticus: This type occurs in patients with a history of partial seizures, but can also arise as a result of acute injury (like a new stroke). This type may cause focal motor manifestations (like nystagmus), but can also cause more subtle findings such as confusion, personality changes or psychosis. Absence (Typical) Status Epilepticus: This occurs in patients with idiopathic generalized epilepsy. As with complex partial status, the clinical symptoms can be subtle, consisting of confusion or personality changes.
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Symptoms of Status Epilepticus. Epilepsy is a group of disorders characterized by electrical discharges in the brain. There are no established factors that bring on an epileptic seizure that are common to all patients. However, visual phenomena such as flickering lights or sunbursts, are frequently cited by people with epilepsy as preceding an attack. In certain patients the likelihood of having a seizure increases with stress, fatigue, insufficient food intake and/or the failure to take prescribed medications.The Status Epilepticus are classified as follows:Generalized Convulsive Status Epilepticus (GCSE): Overt (70 percent of GCSE): This consists of continuous tonic and/or clonic activity with impairment or loss of awareness.Subtle (30 percent of GCSE): This is less obvious than the overt type, consisting of facial twitching, nystagmoid eye movements, or subtle jerking of the extremities.Non-Convulsive Status Epilepticus (NCSE): Complex Partial Status Epilepticus: This type occurs in patients with a history of partial seizures, but can also arise as a result of acute injury (like a new stroke). This type may cause focal motor manifestations (like nystagmus), but can also cause more subtle findings such as confusion, personality changes or psychosis. Absence (Typical) Status Epilepticus: This occurs in patients with idiopathic generalized epilepsy. As with complex partial status, the clinical symptoms can be subtle, consisting of confusion or personality changes.
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Causes of Status Epilepticus
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The exact cause of epilepsy is unknown. Hereditary factors have been suggested as a possible cause in essential epilepsy. Some types of epilepsy occur as a symptom of other disorders, while others are thought to be caused by head injuries. In some families there may be a genetic predisposition to epilepsy, but scientists do not understand the hereditary factors that may make a person vulnerable to getting seizures.The most common causes of recurring seizures in infants include: genetic inborn errors of metabolism; other metabolic disorders; developmental brain defects; injuries occurring a few months before birth or a few weeks after birth (perinatal); and/or a severe lack of oxygen (hypoxia). In children the typical causes of new-onset epileptic seizures can include: inflammation of the membranes that surround the brain and the spinal cord (meningitis); inflammation of the brain (encephalitis); brain abscesses and/or tumors; exposure to poisons or toxins; diseases that affect the blood vessel system (vascular diseases); degenerative diseases of the brain; and/or head trauma.Epileptic seizures that occur in infants or children as a result of an abnormally high fever (febrile seizures) generally do not recur. In adults the beginning of epileptic seizures can sometimes be associated with a brain tumor, trauma to the head, stroke, cerebrovascular disease and/or degenerative brain disease. However, in many cases the cause cannot be identified.
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Causes of Status Epilepticus. The exact cause of epilepsy is unknown. Hereditary factors have been suggested as a possible cause in essential epilepsy. Some types of epilepsy occur as a symptom of other disorders, while others are thought to be caused by head injuries. In some families there may be a genetic predisposition to epilepsy, but scientists do not understand the hereditary factors that may make a person vulnerable to getting seizures.The most common causes of recurring seizures in infants include: genetic inborn errors of metabolism; other metabolic disorders; developmental brain defects; injuries occurring a few months before birth or a few weeks after birth (perinatal); and/or a severe lack of oxygen (hypoxia). In children the typical causes of new-onset epileptic seizures can include: inflammation of the membranes that surround the brain and the spinal cord (meningitis); inflammation of the brain (encephalitis); brain abscesses and/or tumors; exposure to poisons or toxins; diseases that affect the blood vessel system (vascular diseases); degenerative diseases of the brain; and/or head trauma.Epileptic seizures that occur in infants or children as a result of an abnormally high fever (febrile seizures) generally do not recur. In adults the beginning of epileptic seizures can sometimes be associated with a brain tumor, trauma to the head, stroke, cerebrovascular disease and/or degenerative brain disease. However, in many cases the cause cannot be identified.
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Affects of Status Epilepticus
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It is estimated that 150,000 people develop epilepsy each year in the United States. Per the MMWR report from the CDC, the overall prevalence for Epilepsy is 4.6/1000 in the general population while it is 4.1/1000 for population less than 15 years in age. The incidence of Epilepsy is more predominant in the extremes of age i.e. more frequent among children and older adults. Approximately 15 percent of people who have epilepsy have Status Epilepticus. Combined together approximately two to three million Americans have epilepsy but the majority of affected individuals are seizure free due to effective medications.
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Affects of Status Epilepticus. It is estimated that 150,000 people develop epilepsy each year in the United States. Per the MMWR report from the CDC, the overall prevalence for Epilepsy is 4.6/1000 in the general population while it is 4.1/1000 for population less than 15 years in age. The incidence of Epilepsy is more predominant in the extremes of age i.e. more frequent among children and older adults. Approximately 15 percent of people who have epilepsy have Status Epilepticus. Combined together approximately two to three million Americans have epilepsy but the majority of affected individuals are seizure free due to effective medications.
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Related disorders of Status Epilepticus
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Symptoms of the following disorders can be similar to those of Status Epilepticus. Comparisons may be useful for a differential diagnosis:Wilson's Disease is a rare inherited disorder that affects the liver, eyes and neuromuscular system. Symptoms develop due to the excessive accumulation of copper in body tissues, particularly the liver, brain and eyes. Early diagnosis and treatment of Wilson's Disease may prevent serious long-term disabilities. Neuromuscular symptoms of Wilson's Disease generally appear between the ages of 12 and 32 years. These symptoms may include drooling, joint pain (dysarthria), impaired speech (dysphasia), lack of muscle coordination, tremors, involuntary jerky muscle movements, muscle rigidity and double vision. Other late symptoms of Wilson's Disease may include a decrease in cognitive abilities, behavioral changes, kidney stones, depression and other psychiatric disturbances. (For more information on this disorder, choose “Wilson's” as your search term in the Rare Disease Database.)Kok Disease (Hyperexplexia) is a very rare inherited disorder of the neurological system. People with Kok Disease have an excessive startle reaction to sudden and/or unexpected noise, movement or touch. When the individual with Kok Disease is startled, the head may arch back and there may be jerking muscle movements (myoclonic jerks). When startled the individual may also fall to the ground in a rigid position. Some people with Kok Disease also experience seizures. (For more information on this disorder, choose “Kok Disease” or “Hyperexplexia” as your search term in the Rare Disease Database.)Myoclonus is a neurological movement disorder in which a skeletal muscle undergoes sudden, involuntary contractions resulting in jerky movements. There are 3 types of Myoclonus: Intention, rhythmical, and arrhythmic. Intention myoclonus is characterized by episodes of involuntary muscle contractions that are triggered by voluntary movements, such as a purposeful action. In arrhythmic myoclonus, muscle jerks are arrhythmic and sudden. The muscle jerking may be confined to a single muscle or involve the all of the skeletal muscles on one or both sides of the body. The stimulus for the onset of an episode may be sensory (visual, auditory, and/or tactile), or it may be fatigue, stress or anxiety. An extreme startle response may also be present. Rhythmical (segmental) myoclonus is characterized by very rapid and frequent muscle jerks. In contrast to Arrhythmic Myoclonus, this type of Myoclonus is not relieved by sleep and is not triggered by sudden stimuli or voluntary movements. Myoclonic muscle jerks may sometimes be confused with the muscle jerks and rigidity that occur in some forms of Epilepsy. (For more information on this disorder, choose “Myoclonus” as your search term in the Rare Disease Database.)Narcolepsy is a rare neurological sleep disorder characterized by extreme unnatural drowsiness during the day, sudden loss of voluntary muscle tone (cataplexy), hallucinations, sleep paralysis, and/or disrupted sleep during the night. Symptoms usually begin between the ages of 10 and 20 years. The development and severity of symptoms vary greatly among patients. Exaggerated daytime drowsiness is usually the first symptom. The person with Narcolepsy may describe a feeling of sleepiness, tiredness, lack of energy, a “sleep attack”, and/or the inability to resist sleep. People with Narcolepsy who have cataplexy can fall asleep so suddenly that they appear to drop to the floor unconscious. In sleep paralysis, the person with Narcolepsy want to move but cannot do so. (For more information on this disorder, choose “Narcolepsy” as your search term on the Rare Disease Database.)
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Related disorders of Status Epilepticus. Symptoms of the following disorders can be similar to those of Status Epilepticus. Comparisons may be useful for a differential diagnosis:Wilson's Disease is a rare inherited disorder that affects the liver, eyes and neuromuscular system. Symptoms develop due to the excessive accumulation of copper in body tissues, particularly the liver, brain and eyes. Early diagnosis and treatment of Wilson's Disease may prevent serious long-term disabilities. Neuromuscular symptoms of Wilson's Disease generally appear between the ages of 12 and 32 years. These symptoms may include drooling, joint pain (dysarthria), impaired speech (dysphasia), lack of muscle coordination, tremors, involuntary jerky muscle movements, muscle rigidity and double vision. Other late symptoms of Wilson's Disease may include a decrease in cognitive abilities, behavioral changes, kidney stones, depression and other psychiatric disturbances. (For more information on this disorder, choose “Wilson's” as your search term in the Rare Disease Database.)Kok Disease (Hyperexplexia) is a very rare inherited disorder of the neurological system. People with Kok Disease have an excessive startle reaction to sudden and/or unexpected noise, movement or touch. When the individual with Kok Disease is startled, the head may arch back and there may be jerking muscle movements (myoclonic jerks). When startled the individual may also fall to the ground in a rigid position. Some people with Kok Disease also experience seizures. (For more information on this disorder, choose “Kok Disease” or “Hyperexplexia” as your search term in the Rare Disease Database.)Myoclonus is a neurological movement disorder in which a skeletal muscle undergoes sudden, involuntary contractions resulting in jerky movements. There are 3 types of Myoclonus: Intention, rhythmical, and arrhythmic. Intention myoclonus is characterized by episodes of involuntary muscle contractions that are triggered by voluntary movements, such as a purposeful action. In arrhythmic myoclonus, muscle jerks are arrhythmic and sudden. The muscle jerking may be confined to a single muscle or involve the all of the skeletal muscles on one or both sides of the body. The stimulus for the onset of an episode may be sensory (visual, auditory, and/or tactile), or it may be fatigue, stress or anxiety. An extreme startle response may also be present. Rhythmical (segmental) myoclonus is characterized by very rapid and frequent muscle jerks. In contrast to Arrhythmic Myoclonus, this type of Myoclonus is not relieved by sleep and is not triggered by sudden stimuli or voluntary movements. Myoclonic muscle jerks may sometimes be confused with the muscle jerks and rigidity that occur in some forms of Epilepsy. (For more information on this disorder, choose “Myoclonus” as your search term in the Rare Disease Database.)Narcolepsy is a rare neurological sleep disorder characterized by extreme unnatural drowsiness during the day, sudden loss of voluntary muscle tone (cataplexy), hallucinations, sleep paralysis, and/or disrupted sleep during the night. Symptoms usually begin between the ages of 10 and 20 years. The development and severity of symptoms vary greatly among patients. Exaggerated daytime drowsiness is usually the first symptom. The person with Narcolepsy may describe a feeling of sleepiness, tiredness, lack of energy, a “sleep attack”, and/or the inability to resist sleep. People with Narcolepsy who have cataplexy can fall asleep so suddenly that they appear to drop to the floor unconscious. In sleep paralysis, the person with Narcolepsy want to move but cannot do so. (For more information on this disorder, choose “Narcolepsy” as your search term on the Rare Disease Database.)
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Diagnosis of Status Epilepticus
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Diagnosis of Status Epilepticus.
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Therapies of Status Epilepticus
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SE is treated with anticonvulsant drugs that attempt to prevent and control seizures. The drugs that are currently used include phenytoin, valproic acid, carbamazepine, phenobarbital, clonazepam, ethosuximide (Zarontin), primidone, acteazolamide, paraldehyde, trimethadione, corticotropin and corticosteroids. Brain surgery for epilepsy that is caused by a brain tumor or drug-resistant temporal lobe epilepsy may be tried after medications have failed to stop seizures. Surgery is generally not performed until other treatment methods have failed. The success rate for such surgeries is approximately 55 to 70 percent.It is very important to protect the epilepsy patient from self-injury during a seizure. Protective measures should include clearing the area of any object that is hard or sharp, loosening tight clothing and placing a flat, soft object under the head. The patient should be turned on the side and if possible something soft and flat (such as a pad or wallet) may be placed between the teeth. Restraint is not advised. The administration of artificial respiration should be attempted only if breathing does not start after the seizure has stopped. When the seizure is over, the patient should be allowed to sleep or be helped home if he or she seems confused. If the patient wants to sleep, the head and shoulders should be raised.It is possible that some people with epilepsy who have had no seizures during an extended period of time (several years) may reduce or discontinue anticonvulsant medications under close supervision by a doctor.The Food and Drug Administration (FDA) has approved the anti-convulsant drug Felbamate for use in hard-to-treat epilepsy such as Lennox-Gastaut. One of the main advantages of this drug is that it is not a sedative, so it will not make the user feel sleepy or sluggish. Felbamate is manufactured by Wallace Laboratories of Cranbury Run, NJ, and will be marketed under the brand name Felbatol. Due to occurrences of rare but serious side effects from this drug, physicians should contact the manufacturer or FDA before prescribing.The Food and Drug Administration has approved the drug Lamotrigine (Lamictal) for the treatment of hard-to-control partial seizures. The drug is manufactured by Burroughs-Wellcome Company.The drug fosphenytoin sodium (cerebyx) has been approved by the FDA for the treatment of epilepsy. Fosphenytoin sodium is manufactured by Warner-Lambert.The drug tipiramate (Topamax) has been approved by the FDA for the treatment of epilepsy in addition to other medications. Topiramate is manufactured by Ortho-McNeil. In addition, Neurontin (gabapentin) has also been approved for use in the treatment of epilepsy.The drug Diastat (diazepam suppository rectal gel) has been approved by the FDA for the treatment of epilepsy. Diastat is manufactured by Athena Neuosciences Inc.The drug carbamazepine extended release capsules (Carbatrol) has been approved by the FDA for the treatment of epilepsy. Carbatrol is manufactured by Shire Pharmaceuticals.
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Therapies of Status Epilepticus. SE is treated with anticonvulsant drugs that attempt to prevent and control seizures. The drugs that are currently used include phenytoin, valproic acid, carbamazepine, phenobarbital, clonazepam, ethosuximide (Zarontin), primidone, acteazolamide, paraldehyde, trimethadione, corticotropin and corticosteroids. Brain surgery for epilepsy that is caused by a brain tumor or drug-resistant temporal lobe epilepsy may be tried after medications have failed to stop seizures. Surgery is generally not performed until other treatment methods have failed. The success rate for such surgeries is approximately 55 to 70 percent.It is very important to protect the epilepsy patient from self-injury during a seizure. Protective measures should include clearing the area of any object that is hard or sharp, loosening tight clothing and placing a flat, soft object under the head. The patient should be turned on the side and if possible something soft and flat (such as a pad or wallet) may be placed between the teeth. Restraint is not advised. The administration of artificial respiration should be attempted only if breathing does not start after the seizure has stopped. When the seizure is over, the patient should be allowed to sleep or be helped home if he or she seems confused. If the patient wants to sleep, the head and shoulders should be raised.It is possible that some people with epilepsy who have had no seizures during an extended period of time (several years) may reduce or discontinue anticonvulsant medications under close supervision by a doctor.The Food and Drug Administration (FDA) has approved the anti-convulsant drug Felbamate for use in hard-to-treat epilepsy such as Lennox-Gastaut. One of the main advantages of this drug is that it is not a sedative, so it will not make the user feel sleepy or sluggish. Felbamate is manufactured by Wallace Laboratories of Cranbury Run, NJ, and will be marketed under the brand name Felbatol. Due to occurrences of rare but serious side effects from this drug, physicians should contact the manufacturer or FDA before prescribing.The Food and Drug Administration has approved the drug Lamotrigine (Lamictal) for the treatment of hard-to-control partial seizures. The drug is manufactured by Burroughs-Wellcome Company.The drug fosphenytoin sodium (cerebyx) has been approved by the FDA for the treatment of epilepsy. Fosphenytoin sodium is manufactured by Warner-Lambert.The drug tipiramate (Topamax) has been approved by the FDA for the treatment of epilepsy in addition to other medications. Topiramate is manufactured by Ortho-McNeil. In addition, Neurontin (gabapentin) has also been approved for use in the treatment of epilepsy.The drug Diastat (diazepam suppository rectal gel) has been approved by the FDA for the treatment of epilepsy. Diastat is manufactured by Athena Neuosciences Inc.The drug carbamazepine extended release capsules (Carbatrol) has been approved by the FDA for the treatment of epilepsy. Carbatrol is manufactured by Shire Pharmaceuticals.
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Overview of STEC Hemolytic Uremic Syndrome
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The hemolytic uremic syndrome is defined by the sudden occurrence of acute hemolytic anemia with fragmented red blood cells, low levels of platelets in the blood (thrombocytopenia), and acute kidney injury. Hemolytic uremic syndrome is a general term that covers five main subtypes STEC (typical), atypical hemolytic uremic syndrome [complement dysregulation], Sp HUS (Streptococcal pneumonia associated HUS) and metabolic causes of HUS. This report covers STEC (typical) hemolytic uremic syndrome, which is most often associated with E. coli infection and bloody diarrhea. NORD has a separate report on the rarer atypical hemolytic uremic syndrome, which is not caused by infection with E. coli and is often the result of a genetic mutation.Typical hemolytic uremic syndrome (HUS) is an uncommon disease that occurs in 5 to 15 percent of individuals, especially children, who are infected by the Escherichia coli (E. coli) bacterium, usually O157:H7 but also 0104:H4. This organism releases toxins into the gut that are absorbed into the bloodstream and may be transported by white blood cells (leukocytes) to the kidneys. This results in acute renal injury. There may also be damage to the brain with seizures and even coma, the pancreas with pancreatitis and occasionally diabetes mellitus, and other organs.STEC HUS mainly affects young children between one and 10 years. More recently large numbers of adults were affected by STEC HUS in Europe [serotype 0104:H4]. The onset of HUS is preceded by an illness characterized by vomiting, abdominal pain, fever, and, usually, bloody diarrhea.
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Overview of STEC Hemolytic Uremic Syndrome. The hemolytic uremic syndrome is defined by the sudden occurrence of acute hemolytic anemia with fragmented red blood cells, low levels of platelets in the blood (thrombocytopenia), and acute kidney injury. Hemolytic uremic syndrome is a general term that covers five main subtypes STEC (typical), atypical hemolytic uremic syndrome [complement dysregulation], Sp HUS (Streptococcal pneumonia associated HUS) and metabolic causes of HUS. This report covers STEC (typical) hemolytic uremic syndrome, which is most often associated with E. coli infection and bloody diarrhea. NORD has a separate report on the rarer atypical hemolytic uremic syndrome, which is not caused by infection with E. coli and is often the result of a genetic mutation.Typical hemolytic uremic syndrome (HUS) is an uncommon disease that occurs in 5 to 15 percent of individuals, especially children, who are infected by the Escherichia coli (E. coli) bacterium, usually O157:H7 but also 0104:H4. This organism releases toxins into the gut that are absorbed into the bloodstream and may be transported by white blood cells (leukocytes) to the kidneys. This results in acute renal injury. There may also be damage to the brain with seizures and even coma, the pancreas with pancreatitis and occasionally diabetes mellitus, and other organs.STEC HUS mainly affects young children between one and 10 years. More recently large numbers of adults were affected by STEC HUS in Europe [serotype 0104:H4]. The onset of HUS is preceded by an illness characterized by vomiting, abdominal pain, fever, and, usually, bloody diarrhea.
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STEC Hemolytic Uremic Syndrome
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Symptoms of STEC Hemolytic Uremic Syndrome
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The symptoms and severity of STEC HUS vary greatly from one person to another. The disorder can be mild or it can progress to cause life-threatening complications. Most children with STEC HUS recover without permanent damage; however, about a small percent recover with complications. Chronic complications include chronic kidney disease, proteinuria, hypertension, diabetes mellitus, gall stones, neurological deficits.The symptoms of STEC HUS are usually preceded by infection of the digestive tract (gastroenteritis) characterized by abdominal cramps and pain, fever and diarrhea. Diarrhea eventually becomes bloody within a few days. Nausea and vomiting also occur in many cases. Approximately 3 to 10 days after the development of gastroenteritis, additional symptoms appear including sudden onset of paleness (pallor), irritability, weakness, diminished excretion of urine (oliguria) or no urine [anuria], and lack of energy (lethargy). In some cases, seizures also occur during this initial phase.Some infants may also develop small, unexplained bruises, small red or purple, pinhead-sized spots on the skin or mucous membranes (petechiae), and, rarely, bleeding from the nose or mouth.Almost all affected persons have kidney injury and more than half of the children with STEC HUS develop impaired kidney (renal) function that may progress to renal failure and require dialysis. STEC HUS is the most common cause of acute renal failure in young children that is not related to complications of treatment of procedures. Renal failure is characterized by an inability of the kidneys to process waste products from the blood and excrete them in the urine, regulate the balance of salt and water in the body, excrete potassium, acids [metabolic acidosis] and phosphorus, and perform other vital functions such as control of blood pressure and production of erythropoietin and calcitriol. Acute renal failure may result in diminished amounts of urine [oliguria, anuria]; blood in the urine (hematuria); excess concentrations of protein in the urine (proteinuria), high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (edema); In some cases, acute renal failure may lead to life-threatening complications such as severe acidosis, high potassium and very low sodium levels.Most individuals with STEC HUS completely recover from the renal failure. However, approximately 10 percent of affected individuals may develop chronic renal failure. This is extremely uncommon after recovery from an episode of STEC HUS. Those who have severe permanent kidney damage with proteinuria, elevated blood pressures and an increase in serum creatinine concentrations may have progressive loss of kidney function approximately five to 10 years after the acute episode. A small percentage of patients will require chronic dialysis and kidney transplantation.Some individuals with STEC HUS develop symptoms associated with the central nervous system including (as mentioned above) the sudden onset of lethargy and irritability and seizures. Additional CNS symptoms include an impaired ability to control voluntary movements (ataxia), weakness on one side of the body (hemiparesis), confusion, and coma.The pancreas may become involved in STEC HUS. The pancreas is an important organ located behind the stomach that secretes enzymes that aid in digestion. The pancreas also secretes insulin, which helps break down sugar. Pancreatic involvement is usually mild, but fluid accumulation in the pancreas (pseudocysts) and destruction of pancreatic tissue (necrosis) can occur. In about 3 percent of patients, insulin-dependent diabetes can develop. A small number of patients may develop gall bladder stones.
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Symptoms of STEC Hemolytic Uremic Syndrome. The symptoms and severity of STEC HUS vary greatly from one person to another. The disorder can be mild or it can progress to cause life-threatening complications. Most children with STEC HUS recover without permanent damage; however, about a small percent recover with complications. Chronic complications include chronic kidney disease, proteinuria, hypertension, diabetes mellitus, gall stones, neurological deficits.The symptoms of STEC HUS are usually preceded by infection of the digestive tract (gastroenteritis) characterized by abdominal cramps and pain, fever and diarrhea. Diarrhea eventually becomes bloody within a few days. Nausea and vomiting also occur in many cases. Approximately 3 to 10 days after the development of gastroenteritis, additional symptoms appear including sudden onset of paleness (pallor), irritability, weakness, diminished excretion of urine (oliguria) or no urine [anuria], and lack of energy (lethargy). In some cases, seizures also occur during this initial phase.Some infants may also develop small, unexplained bruises, small red or purple, pinhead-sized spots on the skin or mucous membranes (petechiae), and, rarely, bleeding from the nose or mouth.Almost all affected persons have kidney injury and more than half of the children with STEC HUS develop impaired kidney (renal) function that may progress to renal failure and require dialysis. STEC HUS is the most common cause of acute renal failure in young children that is not related to complications of treatment of procedures. Renal failure is characterized by an inability of the kidneys to process waste products from the blood and excrete them in the urine, regulate the balance of salt and water in the body, excrete potassium, acids [metabolic acidosis] and phosphorus, and perform other vital functions such as control of blood pressure and production of erythropoietin and calcitriol. Acute renal failure may result in diminished amounts of urine [oliguria, anuria]; blood in the urine (hematuria); excess concentrations of protein in the urine (proteinuria), high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (edema); In some cases, acute renal failure may lead to life-threatening complications such as severe acidosis, high potassium and very low sodium levels.Most individuals with STEC HUS completely recover from the renal failure. However, approximately 10 percent of affected individuals may develop chronic renal failure. This is extremely uncommon after recovery from an episode of STEC HUS. Those who have severe permanent kidney damage with proteinuria, elevated blood pressures and an increase in serum creatinine concentrations may have progressive loss of kidney function approximately five to 10 years after the acute episode. A small percentage of patients will require chronic dialysis and kidney transplantation.Some individuals with STEC HUS develop symptoms associated with the central nervous system including (as mentioned above) the sudden onset of lethargy and irritability and seizures. Additional CNS symptoms include an impaired ability to control voluntary movements (ataxia), weakness on one side of the body (hemiparesis), confusion, and coma.The pancreas may become involved in STEC HUS. The pancreas is an important organ located behind the stomach that secretes enzymes that aid in digestion. The pancreas also secretes insulin, which helps break down sugar. Pancreatic involvement is usually mild, but fluid accumulation in the pancreas (pseudocysts) and destruction of pancreatic tissue (necrosis) can occur. In about 3 percent of patients, insulin-dependent diabetes can develop. A small number of patients may develop gall bladder stones.
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Causes of STEC Hemolytic Uremic Syndrome
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In most people, STEC HUS occurs in association with infection by a particular strain of (E. coli) known as O157:H7. In a recent European outbreak, the strain was O104:H4 and there were 4320 people with bloody diarrhea, 850 people with HUS and 82 deaths. The bacterium may reside in the intestinal tract of domestic animals, mainly cattle, and may be transmitted to humans through the consumption of unpasteurized milk or infected, undercooked meat or poultry. Cases have been reported in which STEC HUS occurred after the consumption of unpasteurized or otherwise untreated apple juice or cider. Epidemics have followed ingestion of contaminated lettuce, spinach or bean sprouts. It is important to note that transmission may be the result of person-to-person contact within a family or at a kindergarten or an infected wading pool.Although most people with STEC HUS have an associated E. coli infection, other related Shiga-toxin-producing bacteria, such as Shigella dysenteriae type I, have caused STEC HUS.The O157:H7 strain of E. coli produces a poison known as Shiga toxin or verotoxin that is absorbed through the intestines. Verotoxin damages specific cells (endothelial cells) that line the inner walls of the blood vessels, particularly those of the glomeruli [filtering bodies] in the kidneys. Damage to these blood vessels (microangiopathy) leads to complications such as anemia, thrombocytopenia, acute renal failure, and the other symptoms and findings associated with STEC HUS. For example, microangiopathic hemolytic anemia occurs when red blood cells are destroyed or damaged as they pass through the small damaged blood vessels. Circulating platelets are consumed in the small clots in these microscopic blood vessels resulting in thrombocytopenia and the abnormal accumulation of platelets within narrowed blood vessels, causing the formation of small blood clots (microthrombi). As a result, blood flow to organs such as the kidneys, brain, and pancreas variably decreases leading to multiple organ dysfunction or failure.
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Causes of STEC Hemolytic Uremic Syndrome. In most people, STEC HUS occurs in association with infection by a particular strain of (E. coli) known as O157:H7. In a recent European outbreak, the strain was O104:H4 and there were 4320 people with bloody diarrhea, 850 people with HUS and 82 deaths. The bacterium may reside in the intestinal tract of domestic animals, mainly cattle, and may be transmitted to humans through the consumption of unpasteurized milk or infected, undercooked meat or poultry. Cases have been reported in which STEC HUS occurred after the consumption of unpasteurized or otherwise untreated apple juice or cider. Epidemics have followed ingestion of contaminated lettuce, spinach or bean sprouts. It is important to note that transmission may be the result of person-to-person contact within a family or at a kindergarten or an infected wading pool.Although most people with STEC HUS have an associated E. coli infection, other related Shiga-toxin-producing bacteria, such as Shigella dysenteriae type I, have caused STEC HUS.The O157:H7 strain of E. coli produces a poison known as Shiga toxin or verotoxin that is absorbed through the intestines. Verotoxin damages specific cells (endothelial cells) that line the inner walls of the blood vessels, particularly those of the glomeruli [filtering bodies] in the kidneys. Damage to these blood vessels (microangiopathy) leads to complications such as anemia, thrombocytopenia, acute renal failure, and the other symptoms and findings associated with STEC HUS. For example, microangiopathic hemolytic anemia occurs when red blood cells are destroyed or damaged as they pass through the small damaged blood vessels. Circulating platelets are consumed in the small clots in these microscopic blood vessels resulting in thrombocytopenia and the abnormal accumulation of platelets within narrowed blood vessels, causing the formation of small blood clots (microthrombi). As a result, blood flow to organs such as the kidneys, brain, and pancreas variably decreases leading to multiple organ dysfunction or failure.
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Affects of STEC Hemolytic Uremic Syndrome
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STEC HUS affects males and females in equal numbers. Some studies have suggested that the disorder affects females more severely than males. It can affect children or adults, but is more common in children under 10, especially children between 7 months and 6 years of age. STEC HUS is the most common cause of acute renal failure in children. STEC HUS is estimated to occur in 1-3 per 100,000 people in the general population. The incidence rate of E. coli infection in North America is estimated to be 8 in 100,000 people in the general population. Fortunately, only 5 to 15 percent of individuals infected with E. coli progress to develop STEC HUS.
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Affects of STEC Hemolytic Uremic Syndrome. STEC HUS affects males and females in equal numbers. Some studies have suggested that the disorder affects females more severely than males. It can affect children or adults, but is more common in children under 10, especially children between 7 months and 6 years of age. STEC HUS is the most common cause of acute renal failure in children. STEC HUS is estimated to occur in 1-3 per 100,000 people in the general population. The incidence rate of E. coli infection in North America is estimated to be 8 in 100,000 people in the general population. Fortunately, only 5 to 15 percent of individuals infected with E. coli progress to develop STEC HUS.
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Related disorders of STEC Hemolytic Uremic Syndrome
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Symptoms of the following disorders can be similar to those of STEC HUS. Comparisons may be useful for a differential diagnosis.Atypical hemolytic uremic syndrome (aHUS) is an extremely rare disease characterized by hemolytic anemia, low platelet count (thrombocytopenia) and acute renal failure. It is a distinctly different illness from STEC hemolytic uremic syndrome and is not caused by E. coli producing Shiga toxins. Most cases of aHUS are the result of a genetic disorder that results in abnormalities of inhibitors of the alternative pathway of complement. Atypical hemolytic uremic syndrome may become chronic and patients with aHUS may experience repeated attacks of the disorder. Patients with STEC HUS usually recover from the life-threatening initial episode and usually respond well to supportive treatment. Patients with aHUS are much more likely to develop chronic serious complications such as kidney failure and severe high blood pressure. The new agent eculizumab dramatically improves the outcomes of these patients. (For more information on this disorder, choose “atypical hemolytic uremic” as your search term in the Rare Disease Database.)Streptococcal pneumoniae associated HUS [SpHUS] is defined by the occurrence of acute hemolytic anemia, thrombocytopenia and acute kidney injury in a patient a Streptococcal pneumoniae (S. pneumoniae infection). SpHUS occurs in 5-15% of all people with HUS. The majority have pneumonia and a low mortality rate in contrast to those with meningitis who have a more severe clinical course with a mortality rate of 2-12%. SpHUS often may not be diagnosed because of overlapping features with disseminated intravascular coagulation (DIC) and the lack of strict diagnostic criteria. The epidemiology of SpHUS changes with the emergence of different pneumococcal serotypes as newer vaccines are introduced.Thrombotic thrombocytopenia purpura (TTP) is a rare blood disorder characterized by the development of blood clots in small blood vessels (thrombotic microangiopathy). There is considerable overlap between the physical findings of this disorder and those associated with STEC HUS, but there is irrefutable evidence that they are different disorders with variable, yet overlapping findings due to microangiopathy. STEC HUS most commonly occurs in children, while TTP occurs most often in females in the third or fourth decade of life. Findings include low levels of platelets in the blood (thrombocytopenia), a diminished number of circulating red blood cells with red blood cell fragmentation (microangiopathic hemolytic anemia), and/or neurological abnormalities. Thrombocytopenia is associated with a variety of symptoms including the development of purple bruises on the skin, hematuria, and/or small red or purple spots on the skin and/or mucous membranes (petechiae). Neurological abnormalities predominate and may include disorientation, headaches, visual abnormalities, seizures, paralysis (paresis), and/or, in severe cases, coma. In addition, affected individuals may also experience fever, fatigue, weakness, abdominal pain, and/or diarrhea. In some cases, individuals with TTP may have acute renal injury, which may result in diminished excretion of urine; blood appearing in the urine (hematuria); high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (edema); and/or unusually low water content in the body (dehydration). In some cases, acute renal failure may lead to life-threatening complications. There a two main causes of TTP – either a genetic absence of ADAMTS 13 or acquired antibodies against ADAMTS 13. . (For more information on this disorder, choose “Thrombotic Thrombocytopenia Purpura” as your search term in the Rare Disease Database.)
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Related disorders of STEC Hemolytic Uremic Syndrome. Symptoms of the following disorders can be similar to those of STEC HUS. Comparisons may be useful for a differential diagnosis.Atypical hemolytic uremic syndrome (aHUS) is an extremely rare disease characterized by hemolytic anemia, low platelet count (thrombocytopenia) and acute renal failure. It is a distinctly different illness from STEC hemolytic uremic syndrome and is not caused by E. coli producing Shiga toxins. Most cases of aHUS are the result of a genetic disorder that results in abnormalities of inhibitors of the alternative pathway of complement. Atypical hemolytic uremic syndrome may become chronic and patients with aHUS may experience repeated attacks of the disorder. Patients with STEC HUS usually recover from the life-threatening initial episode and usually respond well to supportive treatment. Patients with aHUS are much more likely to develop chronic serious complications such as kidney failure and severe high blood pressure. The new agent eculizumab dramatically improves the outcomes of these patients. (For more information on this disorder, choose “atypical hemolytic uremic” as your search term in the Rare Disease Database.)Streptococcal pneumoniae associated HUS [SpHUS] is defined by the occurrence of acute hemolytic anemia, thrombocytopenia and acute kidney injury in a patient a Streptococcal pneumoniae (S. pneumoniae infection). SpHUS occurs in 5-15% of all people with HUS. The majority have pneumonia and a low mortality rate in contrast to those with meningitis who have a more severe clinical course with a mortality rate of 2-12%. SpHUS often may not be diagnosed because of overlapping features with disseminated intravascular coagulation (DIC) and the lack of strict diagnostic criteria. The epidemiology of SpHUS changes with the emergence of different pneumococcal serotypes as newer vaccines are introduced.Thrombotic thrombocytopenia purpura (TTP) is a rare blood disorder characterized by the development of blood clots in small blood vessels (thrombotic microangiopathy). There is considerable overlap between the physical findings of this disorder and those associated with STEC HUS, but there is irrefutable evidence that they are different disorders with variable, yet overlapping findings due to microangiopathy. STEC HUS most commonly occurs in children, while TTP occurs most often in females in the third or fourth decade of life. Findings include low levels of platelets in the blood (thrombocytopenia), a diminished number of circulating red blood cells with red blood cell fragmentation (microangiopathic hemolytic anemia), and/or neurological abnormalities. Thrombocytopenia is associated with a variety of symptoms including the development of purple bruises on the skin, hematuria, and/or small red or purple spots on the skin and/or mucous membranes (petechiae). Neurological abnormalities predominate and may include disorientation, headaches, visual abnormalities, seizures, paralysis (paresis), and/or, in severe cases, coma. In addition, affected individuals may also experience fever, fatigue, weakness, abdominal pain, and/or diarrhea. In some cases, individuals with TTP may have acute renal injury, which may result in diminished excretion of urine; blood appearing in the urine (hematuria); high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (edema); and/or unusually low water content in the body (dehydration). In some cases, acute renal failure may lead to life-threatening complications. There a two main causes of TTP – either a genetic absence of ADAMTS 13 or acquired antibodies against ADAMTS 13. . (For more information on this disorder, choose “Thrombotic Thrombocytopenia Purpura” as your search term in the Rare Disease Database.)
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Diagnosis of STEC Hemolytic Uremic Syndrome
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A diagnosis of STEC HUS may be suspected upon identification of characteristic findings. STEC HUS should be suspected in anyone, especially young children who develop sudden acute renal failure, anemia and thrombocytopenia after an episode of gastroenteritis with bloody diarrhea.The diagnosis of STEC HUS is confirmed by a thorough clinical evaluation, a detailed patient history, and laboratory tests, particularly stool, blood and urine tests. Stool samples may contain Shiga-toxin producing E. Coli. Blood tests may reveal low levels of circulating red blood cells with fragmented cells called schistocytes, and decreased levels of platelets and elevated levels of white blood cells and immature red blood cells (reticulocytes); stool antibodies against shiga toxin: and higher than normal concentrations of creatinine, a waste product of normal muscle breakdown that is excreted by the kidneys. Testing of the urine (urinalysis) will reveal blood (hematuria) and/or protein (proteinuria). The bilirubin levels and liver enzymes may also be elevated.In some people, additional diagnostic tests may include microscopic examination of samples of kidney tissue (renal biopsy) and electroencephalography (EEG). Microscopic examination of the kidney glomeruli (organelles) that filter the blood passing through the kidneys may reveal characteristic changes that occur in STEC HUS such as narrowing of the glomerular capillaries and arterioles, formation of microthrombi, and cell death (necrosis). Renal biopsies are rarely needed in these patients. An EEG may reveal brain wave patterns that are characteristic of certain types of seizure activity.
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Diagnosis of STEC Hemolytic Uremic Syndrome. A diagnosis of STEC HUS may be suspected upon identification of characteristic findings. STEC HUS should be suspected in anyone, especially young children who develop sudden acute renal failure, anemia and thrombocytopenia after an episode of gastroenteritis with bloody diarrhea.The diagnosis of STEC HUS is confirmed by a thorough clinical evaluation, a detailed patient history, and laboratory tests, particularly stool, blood and urine tests. Stool samples may contain Shiga-toxin producing E. Coli. Blood tests may reveal low levels of circulating red blood cells with fragmented cells called schistocytes, and decreased levels of platelets and elevated levels of white blood cells and immature red blood cells (reticulocytes); stool antibodies against shiga toxin: and higher than normal concentrations of creatinine, a waste product of normal muscle breakdown that is excreted by the kidneys. Testing of the urine (urinalysis) will reveal blood (hematuria) and/or protein (proteinuria). The bilirubin levels and liver enzymes may also be elevated.In some people, additional diagnostic tests may include microscopic examination of samples of kidney tissue (renal biopsy) and electroencephalography (EEG). Microscopic examination of the kidney glomeruli (organelles) that filter the blood passing through the kidneys may reveal characteristic changes that occur in STEC HUS such as narrowing of the glomerular capillaries and arterioles, formation of microthrombi, and cell death (necrosis). Renal biopsies are rarely needed in these patients. An EEG may reveal brain wave patterns that are characteristic of certain types of seizure activity.
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Therapies of STEC Hemolytic Uremic Syndrome
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TreatmentThe treatment of STEC HUS is aimed at managing existing symptoms and preventing further complications. Early diagnosis is essential for appropriate acute, aggressive care. Intravenous volume expansion may decrease the frequency of oligoanuric renal failure in patients with E. coli 0157:H7 gastroenteritis who are at risk for progressing to HUS. Treatment requires the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), intensive care physicians, nurses, nutritionists and social workers need to work in teams to treat patients.Specific treatment includes control of hypertension and seizures.Red blood cell transfusions are needed if the hemoglobin concentration falls below 7 gm/dl. Some patients require many blood transfusions. Platelet transfusions are indicated for active bleeding or before surgical procedures.Monitoring fluid and electrolyte balance is essential to prevent fluid overload and dangerous complications such as elevated potassium and acid levels. In order to maintain proper fluid and electrolyte levels, intravenous fluid and/or nutritional supplementation may be required. Some affected individuals with kidney impairment may require treatment that involves using a special medical procedure to remove wastes from the blood (dialysis) until the kidneys can recover and function on their own.Most infants and young children with STEC HUS tend to recover with immediate, appropriate, aggressive supportive therapy. Recovery time may be longer in affected adults, since kidney complications tend to be more extensive. Long-term follow-up and observation are usually recommended to monitor for potential chronic kidney disease and hypertension.Antibiotic therapy for the E. coli gastroenteritis should be avoided in STEC HUS because antibiotics may increase the release of toxins into the intestine. However large, randomized clinical trials have not been performed to confirm these findings.
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Therapies of STEC Hemolytic Uremic Syndrome. TreatmentThe treatment of STEC HUS is aimed at managing existing symptoms and preventing further complications. Early diagnosis is essential for appropriate acute, aggressive care. Intravenous volume expansion may decrease the frequency of oligoanuric renal failure in patients with E. coli 0157:H7 gastroenteritis who are at risk for progressing to HUS. Treatment requires the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), intensive care physicians, nurses, nutritionists and social workers need to work in teams to treat patients.Specific treatment includes control of hypertension and seizures.Red blood cell transfusions are needed if the hemoglobin concentration falls below 7 gm/dl. Some patients require many blood transfusions. Platelet transfusions are indicated for active bleeding or before surgical procedures.Monitoring fluid and electrolyte balance is essential to prevent fluid overload and dangerous complications such as elevated potassium and acid levels. In order to maintain proper fluid and electrolyte levels, intravenous fluid and/or nutritional supplementation may be required. Some affected individuals with kidney impairment may require treatment that involves using a special medical procedure to remove wastes from the blood (dialysis) until the kidneys can recover and function on their own.Most infants and young children with STEC HUS tend to recover with immediate, appropriate, aggressive supportive therapy. Recovery time may be longer in affected adults, since kidney complications tend to be more extensive. Long-term follow-up and observation are usually recommended to monitor for potential chronic kidney disease and hypertension.Antibiotic therapy for the E. coli gastroenteritis should be avoided in STEC HUS because antibiotics may increase the release of toxins into the intestine. However large, randomized clinical trials have not been performed to confirm these findings.
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Overview of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
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Summary Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent opposite ends of a spectrum of disease that results from an adverse reaction, most often to certain medications. SJS is the less severe end, but still represents a serious condition and potential medical emergency. TEN is a severe, life-threatening disorder. These disorders are differentiated by the degree of skin detachment. The consensus definition published in 1993 states that SJS affects less than 10% of the body surface area; TEN affects more than 30% of the body surface area. The term SJS/TEN-overlap syndrome is used to describe cases in which 10%-30% of the body surface area is detached. The reaction may start with a persistent fever and nonspecific, flu-like symptoms followed by appearance of erythematous macules (red spots) that may cover a large part of the body, and painful blistering of the skin and mucous membranes. The eyes are often involved. Numerous drugs have been reported to cause SJS and TEN and the following have shown an increased risk in larger studies: antibacterial sulfonamides, non-steroidal anti-inflammatory drugs of the oxicam type, certain anti-seizure drugs (antiepileptics), allopurinol and nevirapine. However, approximately one quarter (25%) of cases are not caused by drugs, but potentially by infections or have to be considered as idiopathic (of unknown cause).Individuals suspected of SJS or TEN should immediately stop taking the offending drug if it is known and all nonessential medications if it is not. Prompt recognition and early treatment are essential. It is also important to note that these disorders represent a spectrum of disease ranging from mild cases to those with severe, life-threatening complications. Consequently, every case is unique and the description of symptoms below will not apply to all individuals. Introduction SJS and TEN are classified as severe cutaneous adverse reactions (SCAR), a subcategory of adverse drug reactions (ADR). Unlike individuals with SJS and TEN, most individuals with a reactive skin disease have a mild and self-limiting condition. For years, confusing and contradictory terminology has been used to describe these disorders and controversy still exists as to the best way to classify them. In the past, erythema multiforme (EM) was considered part of this disease spectrum, but is now considered a distinct disorder. NORD has a separate report on erythema multiforme. These disorders are generally broken down into SJS, SJS/TEN overlap, and TEN. SJS was first described in the medical literature in 1922 by doctors A.M. Stevens and F.C. Johnson. The term toxic epidermal necrolysis was introduced in the medical literature in 1956 by Dr. A. Lyell and is also known as Lyell syndrome.
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Overview of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Summary Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent opposite ends of a spectrum of disease that results from an adverse reaction, most often to certain medications. SJS is the less severe end, but still represents a serious condition and potential medical emergency. TEN is a severe, life-threatening disorder. These disorders are differentiated by the degree of skin detachment. The consensus definition published in 1993 states that SJS affects less than 10% of the body surface area; TEN affects more than 30% of the body surface area. The term SJS/TEN-overlap syndrome is used to describe cases in which 10%-30% of the body surface area is detached. The reaction may start with a persistent fever and nonspecific, flu-like symptoms followed by appearance of erythematous macules (red spots) that may cover a large part of the body, and painful blistering of the skin and mucous membranes. The eyes are often involved. Numerous drugs have been reported to cause SJS and TEN and the following have shown an increased risk in larger studies: antibacterial sulfonamides, non-steroidal anti-inflammatory drugs of the oxicam type, certain anti-seizure drugs (antiepileptics), allopurinol and nevirapine. However, approximately one quarter (25%) of cases are not caused by drugs, but potentially by infections or have to be considered as idiopathic (of unknown cause).Individuals suspected of SJS or TEN should immediately stop taking the offending drug if it is known and all nonessential medications if it is not. Prompt recognition and early treatment are essential. It is also important to note that these disorders represent a spectrum of disease ranging from mild cases to those with severe, life-threatening complications. Consequently, every case is unique and the description of symptoms below will not apply to all individuals. Introduction SJS and TEN are classified as severe cutaneous adverse reactions (SCAR), a subcategory of adverse drug reactions (ADR). Unlike individuals with SJS and TEN, most individuals with a reactive skin disease have a mild and self-limiting condition. For years, confusing and contradictory terminology has been used to describe these disorders and controversy still exists as to the best way to classify them. In the past, erythema multiforme (EM) was considered part of this disease spectrum, but is now considered a distinct disorder. NORD has a separate report on erythema multiforme. These disorders are generally broken down into SJS, SJS/TEN overlap, and TEN. SJS was first described in the medical literature in 1922 by doctors A.M. Stevens and F.C. Johnson. The term toxic epidermal necrolysis was introduced in the medical literature in 1956 by Dr. A. Lyell and is also known as Lyell syndrome.
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Symptoms of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
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Most cases involve the development of general, nonspecific symptoms including a persistent fever, burning or stinging eyes, body aches, and discomfort or difficulty swallowing. Additional nonspecific symptoms include headaches, chills, joint paint, and a general feeling of poor health (malaise). A pus-producing (purulent) cough that also brings up mucous, phlegm and saliva (sputum) may also occur. Such symptoms may precede the development of skin involvement by a few days.The initial skin symptom is often the development of a superficial reddening of the skin (erythema) or reddish spots on the skins (macules) that rapidly spread and come together (coalesce) to form a rash. In some cases, these lesions may resemble a target or bull’s eye, so-called “target” lesions. A rash often first develops on the upper chest, face, and the palms and soles. The rash may remain limited to these areas or it may spread, within a few hours or days, to cover a significant portion of the body. The rash may be itchy (pruritic) or painful. Blisters appear on the confluent eruption leading to detachment of the skin and leaving erosions.Blisters may form on various external and internal mucous membranes of the body including the lining inside of the mouth (stomatitis), nose and genitals. Blisters can cause pain and lead to erosions and bleeding. The lips and the inside of the mouth may develop mucosal lesions that are extremely painful and may make eating difficult. Lesions in the genitourinary tract can cause diminished urine flow (dysuria) or an inability to pass urine due to pain. Mucous membrane involvement can precede or follow skin symptoms and often begins with soreness, then little blisters or “bumps” that rupture and leave erosions.The eyes may also be affected. Affected individuals may experience pain and reddish discoloration in the whites of the eyes. Conjunctivitis, which is inflammation of the thin, clear membrane that lines the inner surface of the eyelids and the outer surface of the eye (conjunctiva), is common. Swelling due to fluid accumulation (eyelid edema) may also occur. Eye crusts may form and there may be a sensation of sand or grit in the eyes. Affected individuals may be abnormally sensitive to light (photophobia) and experience inflammation of the eyelids (blepharitis).Skin and mucous membrane involvement initially can be mild or it can rapidly progress. Some individuals may have severe skin symptoms and mild mucosal involvement while others have mild skin involvement and severe mucosal symptoms. Eventually, the upper layer of the skin (epidermis) may pull away (detach) from the underlying layers. In SJS, this affects less than 10% of the body surface area. Patients with TEN have more widespread skin detachment (more than 30% of body surface area) and large areas of skin may shed off (slough) exposing the underlying layers of skin. Scarring and secondary infection may occur in the affected areas if not treated appropriately. Affected individuals can potentially develop sepsis, a widespread, life-threatening infection of the blood and body tissues. Individuals with TEN may resemble patients with severe burns.Late ComplicationsIf untreated, these disorders can cause significant, disabling symptoms and even death. Some individuals who survive the initial, acute episode of SJS or TEN may experience severe, chronic symptoms.Long-term skin issues can include itching (pruritus), excessive sweating (hyperhidrosis), and abnormal dryness of the skin. Abnormal lightening or darkness of affected areas of skin (hypopigmentation and hyperpigmentation) may occur and take years to get better. Permanent loss of nail beds may occur, or the fingernails and toenails may grow back abnormally (onychodystrophy).Chronic eye abnormalities can include chronic inflammation, abnormal dryness of the cornea (corneal xerosis), dry eye syndrome, folding inward of one or both of the eyelids (entropion), eyelashes that are inverted so that they grow back toward the eyeball (trichiasis), and one or both eyelids may become stuck to the eyeballs (symblepharon). Eye tissue can be significantly damaged resulting in scarring, vision loss and, in rare cases, blindness.Involvement of the mucous membranes lining the respiratory tract can lead to lung damage, bronchitis, chronic obstructive pulmonary disease, and scarring of the esophagus. Dental complications including dry mouth (xerostomia), inflammation of the gums, and gum disease have been observed due to changes in the quantity and quality of saliva.Genitourinary abnormalities can include urethral erosions and inflammation of the head of the penis (balanitis) in males and narrowing of the opening of the vagina and abnormal sticking together (adhesion) of the vaginal lips (labia) so that the vagina appears closed (vaginal synechia) in females.
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Symptoms of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Most cases involve the development of general, nonspecific symptoms including a persistent fever, burning or stinging eyes, body aches, and discomfort or difficulty swallowing. Additional nonspecific symptoms include headaches, chills, joint paint, and a general feeling of poor health (malaise). A pus-producing (purulent) cough that also brings up mucous, phlegm and saliva (sputum) may also occur. Such symptoms may precede the development of skin involvement by a few days.The initial skin symptom is often the development of a superficial reddening of the skin (erythema) or reddish spots on the skins (macules) that rapidly spread and come together (coalesce) to form a rash. In some cases, these lesions may resemble a target or bull’s eye, so-called “target” lesions. A rash often first develops on the upper chest, face, and the palms and soles. The rash may remain limited to these areas or it may spread, within a few hours or days, to cover a significant portion of the body. The rash may be itchy (pruritic) or painful. Blisters appear on the confluent eruption leading to detachment of the skin and leaving erosions.Blisters may form on various external and internal mucous membranes of the body including the lining inside of the mouth (stomatitis), nose and genitals. Blisters can cause pain and lead to erosions and bleeding. The lips and the inside of the mouth may develop mucosal lesions that are extremely painful and may make eating difficult. Lesions in the genitourinary tract can cause diminished urine flow (dysuria) or an inability to pass urine due to pain. Mucous membrane involvement can precede or follow skin symptoms and often begins with soreness, then little blisters or “bumps” that rupture and leave erosions.The eyes may also be affected. Affected individuals may experience pain and reddish discoloration in the whites of the eyes. Conjunctivitis, which is inflammation of the thin, clear membrane that lines the inner surface of the eyelids and the outer surface of the eye (conjunctiva), is common. Swelling due to fluid accumulation (eyelid edema) may also occur. Eye crusts may form and there may be a sensation of sand or grit in the eyes. Affected individuals may be abnormally sensitive to light (photophobia) and experience inflammation of the eyelids (blepharitis).Skin and mucous membrane involvement initially can be mild or it can rapidly progress. Some individuals may have severe skin symptoms and mild mucosal involvement while others have mild skin involvement and severe mucosal symptoms. Eventually, the upper layer of the skin (epidermis) may pull away (detach) from the underlying layers. In SJS, this affects less than 10% of the body surface area. Patients with TEN have more widespread skin detachment (more than 30% of body surface area) and large areas of skin may shed off (slough) exposing the underlying layers of skin. Scarring and secondary infection may occur in the affected areas if not treated appropriately. Affected individuals can potentially develop sepsis, a widespread, life-threatening infection of the blood and body tissues. Individuals with TEN may resemble patients with severe burns.Late ComplicationsIf untreated, these disorders can cause significant, disabling symptoms and even death. Some individuals who survive the initial, acute episode of SJS or TEN may experience severe, chronic symptoms.Long-term skin issues can include itching (pruritus), excessive sweating (hyperhidrosis), and abnormal dryness of the skin. Abnormal lightening or darkness of affected areas of skin (hypopigmentation and hyperpigmentation) may occur and take years to get better. Permanent loss of nail beds may occur, or the fingernails and toenails may grow back abnormally (onychodystrophy).Chronic eye abnormalities can include chronic inflammation, abnormal dryness of the cornea (corneal xerosis), dry eye syndrome, folding inward of one or both of the eyelids (entropion), eyelashes that are inverted so that they grow back toward the eyeball (trichiasis), and one or both eyelids may become stuck to the eyeballs (symblepharon). Eye tissue can be significantly damaged resulting in scarring, vision loss and, in rare cases, blindness.Involvement of the mucous membranes lining the respiratory tract can lead to lung damage, bronchitis, chronic obstructive pulmonary disease, and scarring of the esophagus. Dental complications including dry mouth (xerostomia), inflammation of the gums, and gum disease have been observed due to changes in the quantity and quality of saliva.Genitourinary abnormalities can include urethral erosions and inflammation of the head of the penis (balanitis) in males and narrowing of the opening of the vagina and abnormal sticking together (adhesion) of the vaginal lips (labia) so that the vagina appears closed (vaginal synechia) in females.
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Causes of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
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An abnormal reaction to various medications is the cause of most cases of SJS and TEN. Approximately 75% of SJS and TEN cases are caused by medications, but this percentage varies according to age, with a higher percentage in adults and a lower percentage in children. The drugs most commonly associated with these disorders include antibacterial sulfa drugs, anti-epileptics including phenytoin, carbamazepine, lamotrigine, and phenobarbital; allopurinol, a drug commonly used to treat gout or kidney stones; nonsteroidal anti-inflammatory drugs (NSAIDs) of the oxicam such as piroxicam, and nevirapine (an anti-HIV drug). Drug groups with a much lower, but still substantial risk are antibiotics and NSAIDs of the acetic acid type such as diclofenac.Less often, infections, especially bacterial or viral infection can cause SJS or TEN. A bacterial infection known as Mycoplasma pneumoniae has been linked to these disorders. However, more frequently unspecific viral infections affecting the airways have been observed with SJS and TEN. Individuals with human immunodeficiency virus, vaccination or who have graft-versus-host disease can also develop the disorders. In other cases, no underlying cause can be identified (idiopathic cases).Most likely, SJS and TEN develop due to multiple factors (multifactorial) including various genetic, environmental, and immunologic factors. Individuals may have a genetic predisposition to developing these disorders. A genetic predisposition means an individual carries a gene (or genes) for a disorder, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors. Researchers have determined that certain Asian populations have a particular genetically-determined human leukocyte antigen or HLA types. HLAs are proteins that play an important role in the body’s immune system. HLA B*1502 appears to convey a risk of developing these disorders in persons of Chinese or Southeast Asian ancestry when taking the drug carbamazepine.In recent years, additional HLA associations have been identified, including HLA B*3101 and HLA B*1511 with carbamazepine, although not restricted to SJS and TEN and more likely relevant for milder types of cutaneous adverse reactions; HLA B*5801 with allopurinol (mainly in Chinese but also in 55% of Europeans with SJS/TEN); HLA B*38 with sulfamethoxazole or lamotrigine; and HLA B*73 with oxicam-NSAIDs. The exact role these HLAs play in the development of SJS and TEN is not fully understood.The exact, underlying mechanisms that lead to the symptoms of SJS and TEN are not fully understood. It is unknown how individual drugs specifically cause the symptoms of the disorder. Researchers believe that the immune system intervenes in the process of breaking down (metabolizing) the drug to which the body is reacting. The improper immune response against the drug results in damage to healthy cells of the body. Keratinocytes, which are the precursor cells that develop within the five layers of the outer skin (epidermis), are affected in these disorders and are destroyed during the disease process. Keratinocytes are the major cell of the outer layer of the skin (epidermis) and they stick (adhere) together to form the barrier that is the epidermis and they serve as an anchor to the underlying skin layer (dermis). One theory suggests that improper activation of certain white blood cells (T-cells) ultimately leads to keratinocyte death (apoptosis) although the exact method how is unknown. Keratinocyte death, in turn, causes the epidermis to become damaged and pull away (detach) from the underlying layers of the skin. Certain substances that are known to regulate (mediate) cell death such as FasL, granulysin, and annexin A1 have also been proposed as probably playing a role in the development of SJS and TEN. Studies have shown that granulysin is the most important molecule in widespread keratinocyte death.Recent studies have also indicated other factors that may contribute to keratinocyte death such as perforin/granzyme B, nitric oxide, tumor necrosis factor-alpha, and highly reactive molecules known as reactive oxygen stress. Research is ongoing to determine the underlying mechanisms that occur in the development of these disorders.
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Causes of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. An abnormal reaction to various medications is the cause of most cases of SJS and TEN. Approximately 75% of SJS and TEN cases are caused by medications, but this percentage varies according to age, with a higher percentage in adults and a lower percentage in children. The drugs most commonly associated with these disorders include antibacterial sulfa drugs, anti-epileptics including phenytoin, carbamazepine, lamotrigine, and phenobarbital; allopurinol, a drug commonly used to treat gout or kidney stones; nonsteroidal anti-inflammatory drugs (NSAIDs) of the oxicam such as piroxicam, and nevirapine (an anti-HIV drug). Drug groups with a much lower, but still substantial risk are antibiotics and NSAIDs of the acetic acid type such as diclofenac.Less often, infections, especially bacterial or viral infection can cause SJS or TEN. A bacterial infection known as Mycoplasma pneumoniae has been linked to these disorders. However, more frequently unspecific viral infections affecting the airways have been observed with SJS and TEN. Individuals with human immunodeficiency virus, vaccination or who have graft-versus-host disease can also develop the disorders. In other cases, no underlying cause can be identified (idiopathic cases).Most likely, SJS and TEN develop due to multiple factors (multifactorial) including various genetic, environmental, and immunologic factors. Individuals may have a genetic predisposition to developing these disorders. A genetic predisposition means an individual carries a gene (or genes) for a disorder, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors. Researchers have determined that certain Asian populations have a particular genetically-determined human leukocyte antigen or HLA types. HLAs are proteins that play an important role in the body’s immune system. HLA B*1502 appears to convey a risk of developing these disorders in persons of Chinese or Southeast Asian ancestry when taking the drug carbamazepine.In recent years, additional HLA associations have been identified, including HLA B*3101 and HLA B*1511 with carbamazepine, although not restricted to SJS and TEN and more likely relevant for milder types of cutaneous adverse reactions; HLA B*5801 with allopurinol (mainly in Chinese but also in 55% of Europeans with SJS/TEN); HLA B*38 with sulfamethoxazole or lamotrigine; and HLA B*73 with oxicam-NSAIDs. The exact role these HLAs play in the development of SJS and TEN is not fully understood.The exact, underlying mechanisms that lead to the symptoms of SJS and TEN are not fully understood. It is unknown how individual drugs specifically cause the symptoms of the disorder. Researchers believe that the immune system intervenes in the process of breaking down (metabolizing) the drug to which the body is reacting. The improper immune response against the drug results in damage to healthy cells of the body. Keratinocytes, which are the precursor cells that develop within the five layers of the outer skin (epidermis), are affected in these disorders and are destroyed during the disease process. Keratinocytes are the major cell of the outer layer of the skin (epidermis) and they stick (adhere) together to form the barrier that is the epidermis and they serve as an anchor to the underlying skin layer (dermis). One theory suggests that improper activation of certain white blood cells (T-cells) ultimately leads to keratinocyte death (apoptosis) although the exact method how is unknown. Keratinocyte death, in turn, causes the epidermis to become damaged and pull away (detach) from the underlying layers of the skin. Certain substances that are known to regulate (mediate) cell death such as FasL, granulysin, and annexin A1 have also been proposed as probably playing a role in the development of SJS and TEN. Studies have shown that granulysin is the most important molecule in widespread keratinocyte death.Recent studies have also indicated other factors that may contribute to keratinocyte death such as perforin/granzyme B, nitric oxide, tumor necrosis factor-alpha, and highly reactive molecules known as reactive oxygen stress. Research is ongoing to determine the underlying mechanisms that occur in the development of these disorders.
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Affects of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
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SJS and TEN can affect individuals of any age including children, but the incidence is much higher in the elderly population. Individuals of every race and ethnicity can develop these disorders. Some reports suggest that females are affected slightly more often than males. The incidence is western societies is 1-2 per 1,000,000 people in the general population. These adverse reactions usually do not occur again, unless the culprit drug is taken again, but even then often not.
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Affects of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. SJS and TEN can affect individuals of any age including children, but the incidence is much higher in the elderly population. Individuals of every race and ethnicity can develop these disorders. Some reports suggest that females are affected slightly more often than males. The incidence is western societies is 1-2 per 1,000,000 people in the general population. These adverse reactions usually do not occur again, unless the culprit drug is taken again, but even then often not.
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Related disorders of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
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Symptoms of the following disorders can be similar to those of SJS and TEN. Comparisons may be useful for a differential diagnosis.Erythema multiforme (EM) is a general term for a group of hypersensitivity disorders, affecting mostly children and young adults. Affected individuals develop a rash that is characterized by red, patchy lesions that most often appear on the arms and legs. The rash develops on both sides of the body (symmetric). The lesions may resemble targets or bull’s eyes. In some cases, the lesions may blister or scab. Additional symptoms that may occur include mouth sores, fever, and mild aching of joints and muscles. Erythema multiforme most often develops following an infection, especially herpes simplex eruptions in adults and mycoplasma pneumoniae infections in children. Erythema multiforme is divided into a major and a minor form; the major form includes mucous membrane involvement and, potentially, high-grade fever in children, while the minor form does not have mucous membrane involvement or only mild symptoms. (For more information on this disorder, choose “erythema multiforme” as your search term in the Rare Disease Database.)Autoimmune blistering diseases are a group of disorders in which the body mistakenly attacks healthy tissue, causing blistering lesions that primarily affect the skin and mucous and membranes. In autoimmune blistering diseases, antibodies mistakenly attack proteins that are essential for the layers of skin to stick (adhere) together. The specific symptoms and severity of blistering diseases vary from one person to another, even among individuals with the same disorder. In some cases, blistering lesions can cover a significant portion of the skin. Although there is no cure for autoimmune blistering diseases, they can most often be controlled with treatment. In other cases, autoimmune blistering diseases if left untreated can eventually cause life-threatening complications. In recent years, new insight into the causes and development of these disorders has led to research into new therapies such as the development of drugs that target the specific antibodies which cause the symptoms of these diseases. NORD has individual reports on many of the specific disorders classified as autoimmune blistering diseases. For more information, choose the specific disease name as your search term in the Rare Disease Database. (For more information on this disorder, choose “autoimmune blistering diseases” as your search term in the Rare Disease Database.)Staphylococcal scalded skin syndrome (SSSS) is a rare disorder that develops because of a toxin produced by a staphylococcal infection. A toxin is a harmful substance that causes disease when it enters tissues of the body. Staphylococcal scalded skin syndrome is characterized by reddened skin that may form blisters, eventually resembling skin that has been burned or scalded. The top layer of the skin may peel off and shed. Affected individuals may also experience fever, chills, and weakness. Unlike similar disorders, the mucous membranes are rarely affected. Infants and younger children are most susceptible to this disorder, but the disorder can also occur in certain older children or adults such as those with compromised immune systems or insufficient kidney (renal) function. Staphylococcal scalded skin syndrome is caused by toxins produced by certain strains of Staphylococcus aureus, a type of bacterial infection. (For more information on this disorder, choose “staphylococcal scalded skin syndrome” as your search term in the Rare Disease Database.)Additional disorders may need to be distinguished from SJS and TEN including generalized morbilliform drug reaction, generalized bullous fixed-drug eruption (GBFDE), acute generalized exanthematous pustulosis (AGEP), drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS), drug-induced linear immunoglobulin A dermatosis, toxic shock syndrome, and exfoliative erythroderma. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Symptoms of the following disorders can be similar to those of SJS and TEN. Comparisons may be useful for a differential diagnosis.Erythema multiforme (EM) is a general term for a group of hypersensitivity disorders, affecting mostly children and young adults. Affected individuals develop a rash that is characterized by red, patchy lesions that most often appear on the arms and legs. The rash develops on both sides of the body (symmetric). The lesions may resemble targets or bull’s eyes. In some cases, the lesions may blister or scab. Additional symptoms that may occur include mouth sores, fever, and mild aching of joints and muscles. Erythema multiforme most often develops following an infection, especially herpes simplex eruptions in adults and mycoplasma pneumoniae infections in children. Erythema multiforme is divided into a major and a minor form; the major form includes mucous membrane involvement and, potentially, high-grade fever in children, while the minor form does not have mucous membrane involvement or only mild symptoms. (For more information on this disorder, choose “erythema multiforme” as your search term in the Rare Disease Database.)Autoimmune blistering diseases are a group of disorders in which the body mistakenly attacks healthy tissue, causing blistering lesions that primarily affect the skin and mucous and membranes. In autoimmune blistering diseases, antibodies mistakenly attack proteins that are essential for the layers of skin to stick (adhere) together. The specific symptoms and severity of blistering diseases vary from one person to another, even among individuals with the same disorder. In some cases, blistering lesions can cover a significant portion of the skin. Although there is no cure for autoimmune blistering diseases, they can most often be controlled with treatment. In other cases, autoimmune blistering diseases if left untreated can eventually cause life-threatening complications. In recent years, new insight into the causes and development of these disorders has led to research into new therapies such as the development of drugs that target the specific antibodies which cause the symptoms of these diseases. NORD has individual reports on many of the specific disorders classified as autoimmune blistering diseases. For more information, choose the specific disease name as your search term in the Rare Disease Database. (For more information on this disorder, choose “autoimmune blistering diseases” as your search term in the Rare Disease Database.)Staphylococcal scalded skin syndrome (SSSS) is a rare disorder that develops because of a toxin produced by a staphylococcal infection. A toxin is a harmful substance that causes disease when it enters tissues of the body. Staphylococcal scalded skin syndrome is characterized by reddened skin that may form blisters, eventually resembling skin that has been burned or scalded. The top layer of the skin may peel off and shed. Affected individuals may also experience fever, chills, and weakness. Unlike similar disorders, the mucous membranes are rarely affected. Infants and younger children are most susceptible to this disorder, but the disorder can also occur in certain older children or adults such as those with compromised immune systems or insufficient kidney (renal) function. Staphylococcal scalded skin syndrome is caused by toxins produced by certain strains of Staphylococcus aureus, a type of bacterial infection. (For more information on this disorder, choose “staphylococcal scalded skin syndrome” as your search term in the Rare Disease Database.)Additional disorders may need to be distinguished from SJS and TEN including generalized morbilliform drug reaction, generalized bullous fixed-drug eruption (GBFDE), acute generalized exanthematous pustulosis (AGEP), drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS), drug-induced linear immunoglobulin A dermatosis, toxic shock syndrome, and exfoliative erythroderma. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
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A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a skin biopsy. The appearance of the lesions and their rapid progression may enable a physician to make a diagnosis of SJS or TEN. In all cases, a skin biopsy, in which a tiny piece of affected skin is removed and studied under a microscope, should be performed. A biopsy can reveal the layer of skin blistering (subepidermal in SJS/TEN) and dead (necrotic), thickened epithelial tissue, which is indicative of SJS and TEN.A skin biopsy is crucial and should always be performed. Whether a skin biopsy for immunofluorescence test is done may be decided in each case individually, although it is highly recommended. An immunofluorescence test uses antibodies chemically linked to fluorescent dyes to identify or quantify antigens in a tissue sample and is used to rule out other conditions.A disease severity scoring system called SCORTEN (Score of TEN) has been established to help physicians assess the severity of illness in people with SJS and TEN. This scoring system includes seven distinct factors: age; malignancy; percentage of body surface area detached; heart rate, serum urea; serum glucose; and serum bicarbonate levels. For each prognostic factor that is present in an affected individual, one point is scored. The more points a patient has, the higher is the risk of fatality.
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Diagnosis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a skin biopsy. The appearance of the lesions and their rapid progression may enable a physician to make a diagnosis of SJS or TEN. In all cases, a skin biopsy, in which a tiny piece of affected skin is removed and studied under a microscope, should be performed. A biopsy can reveal the layer of skin blistering (subepidermal in SJS/TEN) and dead (necrotic), thickened epithelial tissue, which is indicative of SJS and TEN.A skin biopsy is crucial and should always be performed. Whether a skin biopsy for immunofluorescence test is done may be decided in each case individually, although it is highly recommended. An immunofluorescence test uses antibodies chemically linked to fluorescent dyes to identify or quantify antigens in a tissue sample and is used to rule out other conditions.A disease severity scoring system called SCORTEN (Score of TEN) has been established to help physicians assess the severity of illness in people with SJS and TEN. This scoring system includes seven distinct factors: age; malignancy; percentage of body surface area detached; heart rate, serum urea; serum glucose; and serum bicarbonate levels. For each prognostic factor that is present in an affected individual, one point is scored. The more points a patient has, the higher is the risk of fatality.
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Therapies of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
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TreatmentTreatment is primarily symptomatic and supportive and may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, ophthalmologists, urologists, and other healthcare professionals may need to systematically and comprehensively plan an affected individual’s treatment. Psychosocial support for the entire family is essential as well. Prompt recognition and treatment of these disorders is critical. Treatment may require a highly specialized skin (dermatological) center. Severe cases with large areas of skin detachment and high SCORTEN values may require treatment in an ICU or burn-care center.In cases caused by drug hypersensitivity, immediately stopping and avoiding the offending medication(s) is required. In some cases, determining which medication is causing the reaction may be difficult. If the offending medication is unknown, all suspected and unnecessary medications should be stopped. Generally, the earlier the offending drug is removed, the better the overall prognosis. In case of infection being identified as the most likely cause, this has to be treated appropriately.Fluid replacement with electrolytes is critical and should be administered immediately. Blood products and supplemental nutrition are given as needed. Topical care can include antiseptic solutions or ointments that act as disinfectants, including chlorhexidine, octenidin, polyhexanide, or silver nitrate. Silver sulfadiazine is not recommended. Affected individuals must be monitored for infection and antibiotics may be given to control infection. Protective (prophylactic) systemic antibiotic treatment is not recommended. Pain medications (analgesics) may be used as needed.Wound treatment should be conservative; aggressive surgical removal of affected skin (debridement), which is often performed at burn centers, is not recommended. Intact blisters may serve as a protective “biologic” dressing. The use of non-adhesive dressings is helpful, especially in cases with large areas of skin detachment, e.g. Suprathel®.The lips and mouth may require special care. Oral hygiene is necessary and a disinfectant mouthwash is beneficial. Lips may be treated with appropriate ointments. In severe cases, affected individuals may not be able to eat, requiring the use of a gastric tube, which is a small thin tube inserted directly into the stomach through a small surgical opening, or a nasogastric tube.Individuals with eye involvement should receive a consultation by an ophthalmologist as soon as possible. Treatment may require continued lubrication of the eyes, topical antibiotics, and surgically separating adhesions. Regular ophthalmologic care is needed by many patients on a daily or every-other-day basis. In recent years, the application of a cryopreserved amniotic membrane to the eyes and eyelids during the acute phase of these disorders has been effective in preventing some of the eye complications.PreventionIndividuals who have a history of SJS or TEN due to a specific medication must avoid the causative drug and any potential cross-reacting medications.The U.S. Food and Drug Administration (FDA) recommends screening for HLA B*1502 in individuals of Chinese and Southeast Asian ethnicity before beginning treatment with the drug carbamazepine.
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Therapies of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. TreatmentTreatment is primarily symptomatic and supportive and may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, ophthalmologists, urologists, and other healthcare professionals may need to systematically and comprehensively plan an affected individual’s treatment. Psychosocial support for the entire family is essential as well. Prompt recognition and treatment of these disorders is critical. Treatment may require a highly specialized skin (dermatological) center. Severe cases with large areas of skin detachment and high SCORTEN values may require treatment in an ICU or burn-care center.In cases caused by drug hypersensitivity, immediately stopping and avoiding the offending medication(s) is required. In some cases, determining which medication is causing the reaction may be difficult. If the offending medication is unknown, all suspected and unnecessary medications should be stopped. Generally, the earlier the offending drug is removed, the better the overall prognosis. In case of infection being identified as the most likely cause, this has to be treated appropriately.Fluid replacement with electrolytes is critical and should be administered immediately. Blood products and supplemental nutrition are given as needed. Topical care can include antiseptic solutions or ointments that act as disinfectants, including chlorhexidine, octenidin, polyhexanide, or silver nitrate. Silver sulfadiazine is not recommended. Affected individuals must be monitored for infection and antibiotics may be given to control infection. Protective (prophylactic) systemic antibiotic treatment is not recommended. Pain medications (analgesics) may be used as needed.Wound treatment should be conservative; aggressive surgical removal of affected skin (debridement), which is often performed at burn centers, is not recommended. Intact blisters may serve as a protective “biologic” dressing. The use of non-adhesive dressings is helpful, especially in cases with large areas of skin detachment, e.g. Suprathel®.The lips and mouth may require special care. Oral hygiene is necessary and a disinfectant mouthwash is beneficial. Lips may be treated with appropriate ointments. In severe cases, affected individuals may not be able to eat, requiring the use of a gastric tube, which is a small thin tube inserted directly into the stomach through a small surgical opening, or a nasogastric tube.Individuals with eye involvement should receive a consultation by an ophthalmologist as soon as possible. Treatment may require continued lubrication of the eyes, topical antibiotics, and surgically separating adhesions. Regular ophthalmologic care is needed by many patients on a daily or every-other-day basis. In recent years, the application of a cryopreserved amniotic membrane to the eyes and eyelids during the acute phase of these disorders has been effective in preventing some of the eye complications.PreventionIndividuals who have a history of SJS or TEN due to a specific medication must avoid the causative drug and any potential cross-reacting medications.The U.S. Food and Drug Administration (FDA) recommends screening for HLA B*1502 in individuals of Chinese and Southeast Asian ethnicity before beginning treatment with the drug carbamazepine.
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Overview of Stickler Syndrome
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Stickler syndrome refers to a group of disorders of connective tissue. Connective tissue, which is distributed throughout the body, can affect multiple organ systems. The specific symptoms present in Stickler syndrome often vary greatly from one individual to another. Affected individuals may not have all of the symptoms .The eyes, ears, skeleton and joints are most often affected. Affected individuals may also have distinctive facial features and palate abnormalities.One of the first signs in Stickler syndrome is nearsightedness (myopia), in which objects close by are seen clearly but objects that are far away appear blurry. Myopia may vary from mild to severe in Stickler syndrome, but generally is not progressive (does not get worse). Myopia may be detectable shortly after birth, but the onset varies and may not develop until adolescence or even adulthood in some cases.Stickler syndrome is characterized by the following clinical features: vitreoretinal degeneration, myopia, cataracts, retinal holes and detachments, sensorineural hearing loss, a characteristic facial appearance with mid-facial flatness, small chin, long upper lip (philtrum); palatal abnormalities, including cleft palate, bifid uvula or high arched palate; musculoskeletal problems including loose joints, scoliosis, chest deformities, a hip disorder of childhood (Legg-Calve-Perthe’s disease); early onset degenerative osteoarthritis (onset before age 40 years by X-ray); and mitral valve prolapse. An affected person does not need to have all of these features. In fact, the clinical picture is typically variable even among affected people in the same family.Four distinct forms of Stickler syndrome have been identified in the medical literature based on the location of the mutated gene and inheritance pattern and at least one other form exists with an as yet unknown mutation location.Stickler syndrome was first described in the medical literature in 1965 by Gunnar Stickler et al., who called the disorder hereditary progressive arthro-ophthalmopathy. Stickler syndrome refers to a group of disorders of connective tissue. Connective tissue, which is the material between cells of the body that gives the tissue form and strength, is found all over the body. Connective tissue is made up of a protein known as collagen of which there are several different varieties found in the body. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor), the specialized tissue that serves as a buffer or cushion for bones at joints (cartilage) and the ends of the bones that make up the joints of the body (epiphysis).
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Overview of Stickler Syndrome. Stickler syndrome refers to a group of disorders of connective tissue. Connective tissue, which is distributed throughout the body, can affect multiple organ systems. The specific symptoms present in Stickler syndrome often vary greatly from one individual to another. Affected individuals may not have all of the symptoms .The eyes, ears, skeleton and joints are most often affected. Affected individuals may also have distinctive facial features and palate abnormalities.One of the first signs in Stickler syndrome is nearsightedness (myopia), in which objects close by are seen clearly but objects that are far away appear blurry. Myopia may vary from mild to severe in Stickler syndrome, but generally is not progressive (does not get worse). Myopia may be detectable shortly after birth, but the onset varies and may not develop until adolescence or even adulthood in some cases.Stickler syndrome is characterized by the following clinical features: vitreoretinal degeneration, myopia, cataracts, retinal holes and detachments, sensorineural hearing loss, a characteristic facial appearance with mid-facial flatness, small chin, long upper lip (philtrum); palatal abnormalities, including cleft palate, bifid uvula or high arched palate; musculoskeletal problems including loose joints, scoliosis, chest deformities, a hip disorder of childhood (Legg-Calve-Perthe’s disease); early onset degenerative osteoarthritis (onset before age 40 years by X-ray); and mitral valve prolapse. An affected person does not need to have all of these features. In fact, the clinical picture is typically variable even among affected people in the same family.Four distinct forms of Stickler syndrome have been identified in the medical literature based on the location of the mutated gene and inheritance pattern and at least one other form exists with an as yet unknown mutation location.Stickler syndrome was first described in the medical literature in 1965 by Gunnar Stickler et al., who called the disorder hereditary progressive arthro-ophthalmopathy. Stickler syndrome refers to a group of disorders of connective tissue. Connective tissue, which is the material between cells of the body that gives the tissue form and strength, is found all over the body. Connective tissue is made up of a protein known as collagen of which there are several different varieties found in the body. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor), the specialized tissue that serves as a buffer or cushion for bones at joints (cartilage) and the ends of the bones that make up the joints of the body (epiphysis).
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Stickler Syndrome
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Symptoms of Stickler Syndrome
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Stickler syndrome type I (STL1) is responsible for approximately 70% of reported cases and presents with a wide variety of symptoms affecting the eye, ear, facial appearance, palate and musculoskeletal system and occurs due to mutations over the entire COL2A1 gene on chromosome 12q13.11. These mutations cause loss of function of the COL2A1 gene. The majority of these mutations are associated with normal stature and early onset osteoarthritis. Only a few non-glycine missense mutations have been reported and among these, the arginine to cysteine substitutions predominate and these mutations cause some unusual disorders which may be described as Stickler-like but have short stature and brachydactyly. The inheritance pattern for Stickler syndrome type I is autosomal dominant.Stickler syndrome type II (STL2) occurs due to mutations of the COL11A1 gene on chromosome 1p21. Patients with another condition, called Marshall syndrome, can have mutations of COL11A1 also, but patients with Stickler syndrome type II have a milder phenotype with less prominent facial dysmorphism than patients with Marshall syndrome. Patients with Stickler syndrome type II have less pronounced midfacial flattening and the nasal bridge better developed than seen in patients with Marshall syndrome. Myopia and retinal degeneration are not always present. Cataracts and more severe early onset hearing loss are more common in Stickler type II than in patients with Stickler type I. The inheritance pattern is autosomal dominant.Stickler syndrome type III (STL3) has been described as the non-ocular form of Stickler syndrome, affecting the joints and hearing without involving the eyes. Stickler syndrome type III is caused by mutations of the COL11A2 gene on chromosome 6p21.3. The inheritance pattern is autosomal dominant. This form is now considered the same disorder as heterozygous oto-spondylo-megaepiphyseal dysplasia (OSMED). For more information on heterozygous OSMED see the NORD report on this disorder.A mutation in a fourth gene, COL9A1, located on chromosome 6q13, has been identified in three reported intermarried families in Turkey and Morocco with Stickler syndrome type IV or STL4.The inheritance pattern is autosomal recessive.Stickler syndrome type V (STL5) is thought to be caused by COL9A2, located on chromosome 1p33. This has been described in one intermarried family in India. The inheritance pattern is autosomal recessive.Mutations of COL9A3 have recently been reported in three brothers in an intermarried Moroccan family with features of Stickler syndrome and intellectual disability.Stickler syndrome has also been subdivided based on the vitreous phenotype resulting from mutations in the various loci. However, it has been reported that it is difficult for most ophthalmologists to classify the type of vitreous anomalies in the patients with Stickler syndrome.Clinical Features of Stickler SyndromeOphthalmologic FeaturesAffected individuals may also develop degeneration of the thick, jelly-like fluid (vitreous) that fills the center of the eyes and the thin layer of nerve cells (retina) that lines the back of the eye (vitreoretinal degeneration). The retina senses light and converts it into nerve signals, which are then relayed to brain through the optic nerve. Vitreoretinal degeneration may cause tiny specks (floaters) that seem to float around obstructing a person’s field of vision. Vitreoretinal degeneration also places individuals with Stickler syndrome at risk for retinal detachment, which can affect one or both eyes.Retinal detachment occurs when the retina pulls away or is separated (detaches) from the underlying tissue. In some cases, small tears may occur in the retina as well. Symptoms of retinal detachment include an increase in the number of floaters in the eye, increased blurriness of vision, sudden flashes of light and a sudden decrease in vision as if a curtain or veil is pulled over a portion of a person’s field of vision. Retinal detachment can cause significant loss of vision or blindness if left untreated. Retinal detachment can occur at any age.Additional eye abnormalities associated with Stickler syndrome include clouding (opacity) of the lenses of the eyes (cataracts), crossed eyes (strabismus), and abnormal curvature to the cornea (the clear portion of the eye through which light passes) or lens of the eye (astigmatism), which can contribute to blurred vision. A small percentage of individuals with Stickler syndrome, approximately 5-10 percent, may develop glaucoma, a condition in which increased pressure within the eye causes characteristic damage to the optic nerve, which relays signals from the retina to the brain.Otolaryngologic FeaturesHearing loss may also occur in Stickler syndrome and may be progressive. The degree of hearing loss may vary greatly from one individual to another and can range from mild to significant. Hearing loss can occur due to failure of sound waves to be conducted through the middle ear (conductive hearing loss) or the impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss) or from both (mixed hearing loss). Hearing loss is usually less severe and minimally progressive in Stickler syndrome type I as opposed to type II. Chronic (recurrent) infection of the middle ear (otitis media) may occur and can contribute to conductive hearing loss. Some individuals may develop the accumulation of thick, sticky fluid behind the eardrum (glue ear). People with Stickler syndrome can have hypermobility of the middle ear bones.Individuals with Stickler syndrome often have distinctive facial features including mid-facial hypoplasia with abnormally flat cheek bones and nasal bridge, small nose, long upper lip (philtrum), prominent eyes, and small chin.Affected individuals may also have Pierre-Robin sequence, an assortment of abnormalities that may occur as a distinct syndrome or as part of another underlying disorder. Pierre-Robin sequence is characterized by an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate, sub-mucous cleft palate or bifid uvula). Often babies with Pierre-Robin sequence and glossoptosis obstruct their airway when placed on their backs, and it may be recommended that they sleep prone due to this risk. Patients with very small jaws might be recommended to have surgery to extend their jaw forward.Cleft palate may also occur as an isolated finding. The various craniofacial features may give the face a flattened appearance, but these features usually become less distinctive as affected children grow older. Certain facial features such as cleft palate can cause feeding or breathing difficulties in some children.Dental anomalies such as failure of the upper and lower teeth to meet when biting down (malocclusion) may also occur.Skeletal FeaturesSkeletal malformations are a common finding in individuals with Stickler syndrome. Affected individuals may have abnormally flexible or lax (hypermobile) joints (double jointedness) that may make them prone to joint dislocation. As affected individuals age, such flexibility becomes reduced. Joint pain and stiffness upon rest are frequent findings, and many individuals develop inflammation of the joints during the third or fourth decade of life (early-onset osteoarthritis).Chest deformities such as pectus excavatum (depression of the chest bone) and carinatum (prominent chest bone) can occur. Spinal abnormalities are also common in individuals with Stickler syndrome including abnormal sideways curvature of the spine (scoliosis), front-to-back curvature of the spine (kyphosis), and forward displacement of one vertebra over another, usually the 4th lumbar vertebra over the 5th or the 5th over the sacrum (spondylolisthesis). Spinal abnormalities associated with Stickler may become progressively worse and may be associated with back pain.Additional findings may occur in some cases including diminished muscle tone
(hypotonia), abnormally long, slender fingers (arachnodactyly), flat feet (pes planus), and osteochondritis deformans of the hips (Legg-Calve-Perthes disease), a degenerative hip disorder with childhood onset.Other Features of Stickler syndrome
Intelligence is unaffected in children with Stickler syndrome, but some children may develop learning disabilities because of hearing and vision abnormalities.Some studies have seemed to indicate that the prevalence of mitral valve prolapse (MVP) is greater in individuals with Stickler syndrome (4%) than in the general population (2%). However, other studies seem to show that this is not the case.The mitral valve is located between the left upper and left lower chambers (left atrium and left ventricle) of the heart. Mitral valve prolapse occurs when one or both of the flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left upper chamber (atrium) of the heart. In some cases, this may allow leakage or the backward flow of blood from the left lower chamber of the heart (ventricle) back into the left atrium (mitral regurgitation). In some cases, no associated symptoms are apparent (asymptomatic). However, in other cases, mitral valve prolapse can result in chest pain, abnormal heart rhythms (arrhythmias), fatigue, and dizziness.
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Symptoms of Stickler Syndrome. Stickler syndrome type I (STL1) is responsible for approximately 70% of reported cases and presents with a wide variety of symptoms affecting the eye, ear, facial appearance, palate and musculoskeletal system and occurs due to mutations over the entire COL2A1 gene on chromosome 12q13.11. These mutations cause loss of function of the COL2A1 gene. The majority of these mutations are associated with normal stature and early onset osteoarthritis. Only a few non-glycine missense mutations have been reported and among these, the arginine to cysteine substitutions predominate and these mutations cause some unusual disorders which may be described as Stickler-like but have short stature and brachydactyly. The inheritance pattern for Stickler syndrome type I is autosomal dominant.Stickler syndrome type II (STL2) occurs due to mutations of the COL11A1 gene on chromosome 1p21. Patients with another condition, called Marshall syndrome, can have mutations of COL11A1 also, but patients with Stickler syndrome type II have a milder phenotype with less prominent facial dysmorphism than patients with Marshall syndrome. Patients with Stickler syndrome type II have less pronounced midfacial flattening and the nasal bridge better developed than seen in patients with Marshall syndrome. Myopia and retinal degeneration are not always present. Cataracts and more severe early onset hearing loss are more common in Stickler type II than in patients with Stickler type I. The inheritance pattern is autosomal dominant.Stickler syndrome type III (STL3) has been described as the non-ocular form of Stickler syndrome, affecting the joints and hearing without involving the eyes. Stickler syndrome type III is caused by mutations of the COL11A2 gene on chromosome 6p21.3. The inheritance pattern is autosomal dominant. This form is now considered the same disorder as heterozygous oto-spondylo-megaepiphyseal dysplasia (OSMED). For more information on heterozygous OSMED see the NORD report on this disorder.A mutation in a fourth gene, COL9A1, located on chromosome 6q13, has been identified in three reported intermarried families in Turkey and Morocco with Stickler syndrome type IV or STL4.The inheritance pattern is autosomal recessive.Stickler syndrome type V (STL5) is thought to be caused by COL9A2, located on chromosome 1p33. This has been described in one intermarried family in India. The inheritance pattern is autosomal recessive.Mutations of COL9A3 have recently been reported in three brothers in an intermarried Moroccan family with features of Stickler syndrome and intellectual disability.Stickler syndrome has also been subdivided based on the vitreous phenotype resulting from mutations in the various loci. However, it has been reported that it is difficult for most ophthalmologists to classify the type of vitreous anomalies in the patients with Stickler syndrome.Clinical Features of Stickler SyndromeOphthalmologic FeaturesAffected individuals may also develop degeneration of the thick, jelly-like fluid (vitreous) that fills the center of the eyes and the thin layer of nerve cells (retina) that lines the back of the eye (vitreoretinal degeneration). The retina senses light and converts it into nerve signals, which are then relayed to brain through the optic nerve. Vitreoretinal degeneration may cause tiny specks (floaters) that seem to float around obstructing a person’s field of vision. Vitreoretinal degeneration also places individuals with Stickler syndrome at risk for retinal detachment, which can affect one or both eyes.Retinal detachment occurs when the retina pulls away or is separated (detaches) from the underlying tissue. In some cases, small tears may occur in the retina as well. Symptoms of retinal detachment include an increase in the number of floaters in the eye, increased blurriness of vision, sudden flashes of light and a sudden decrease in vision as if a curtain or veil is pulled over a portion of a person’s field of vision. Retinal detachment can cause significant loss of vision or blindness if left untreated. Retinal detachment can occur at any age.Additional eye abnormalities associated with Stickler syndrome include clouding (opacity) of the lenses of the eyes (cataracts), crossed eyes (strabismus), and abnormal curvature to the cornea (the clear portion of the eye through which light passes) or lens of the eye (astigmatism), which can contribute to blurred vision. A small percentage of individuals with Stickler syndrome, approximately 5-10 percent, may develop glaucoma, a condition in which increased pressure within the eye causes characteristic damage to the optic nerve, which relays signals from the retina to the brain.Otolaryngologic FeaturesHearing loss may also occur in Stickler syndrome and may be progressive. The degree of hearing loss may vary greatly from one individual to another and can range from mild to significant. Hearing loss can occur due to failure of sound waves to be conducted through the middle ear (conductive hearing loss) or the impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss) or from both (mixed hearing loss). Hearing loss is usually less severe and minimally progressive in Stickler syndrome type I as opposed to type II. Chronic (recurrent) infection of the middle ear (otitis media) may occur and can contribute to conductive hearing loss. Some individuals may develop the accumulation of thick, sticky fluid behind the eardrum (glue ear). People with Stickler syndrome can have hypermobility of the middle ear bones.Individuals with Stickler syndrome often have distinctive facial features including mid-facial hypoplasia with abnormally flat cheek bones and nasal bridge, small nose, long upper lip (philtrum), prominent eyes, and small chin.Affected individuals may also have Pierre-Robin sequence, an assortment of abnormalities that may occur as a distinct syndrome or as part of another underlying disorder. Pierre-Robin sequence is characterized by an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate, sub-mucous cleft palate or bifid uvula). Often babies with Pierre-Robin sequence and glossoptosis obstruct their airway when placed on their backs, and it may be recommended that they sleep prone due to this risk. Patients with very small jaws might be recommended to have surgery to extend their jaw forward.Cleft palate may also occur as an isolated finding. The various craniofacial features may give the face a flattened appearance, but these features usually become less distinctive as affected children grow older. Certain facial features such as cleft palate can cause feeding or breathing difficulties in some children.Dental anomalies such as failure of the upper and lower teeth to meet when biting down (malocclusion) may also occur.Skeletal FeaturesSkeletal malformations are a common finding in individuals with Stickler syndrome. Affected individuals may have abnormally flexible or lax (hypermobile) joints (double jointedness) that may make them prone to joint dislocation. As affected individuals age, such flexibility becomes reduced. Joint pain and stiffness upon rest are frequent findings, and many individuals develop inflammation of the joints during the third or fourth decade of life (early-onset osteoarthritis).Chest deformities such as pectus excavatum (depression of the chest bone) and carinatum (prominent chest bone) can occur. Spinal abnormalities are also common in individuals with Stickler syndrome including abnormal sideways curvature of the spine (scoliosis), front-to-back curvature of the spine (kyphosis), and forward displacement of one vertebra over another, usually the 4th lumbar vertebra over the 5th or the 5th over the sacrum (spondylolisthesis). Spinal abnormalities associated with Stickler may become progressively worse and may be associated with back pain.Additional findings may occur in some cases including diminished muscle tone
(hypotonia), abnormally long, slender fingers (arachnodactyly), flat feet (pes planus), and osteochondritis deformans of the hips (Legg-Calve-Perthes disease), a degenerative hip disorder with childhood onset.Other Features of Stickler syndrome
Intelligence is unaffected in children with Stickler syndrome, but some children may develop learning disabilities because of hearing and vision abnormalities.Some studies have seemed to indicate that the prevalence of mitral valve prolapse (MVP) is greater in individuals with Stickler syndrome (4%) than in the general population (2%). However, other studies seem to show that this is not the case.The mitral valve is located between the left upper and left lower chambers (left atrium and left ventricle) of the heart. Mitral valve prolapse occurs when one or both of the flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left upper chamber (atrium) of the heart. In some cases, this may allow leakage or the backward flow of blood from the left lower chamber of the heart (ventricle) back into the left atrium (mitral regurgitation). In some cases, no associated symptoms are apparent (asymptomatic). However, in other cases, mitral valve prolapse can result in chest pain, abnormal heart rhythms (arrhythmias), fatigue, and dizziness.
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Causes of Stickler Syndrome
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Most cases of Stickler syndrome occur in families with other members that also have Stickler syndrome, due to a familial mutation of a gene inherited as an autosomal dominant trait. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.In some cases, Stickler syndrome occurs randomly as a result of a de novo genetic change (i.e., new mutation in the affected individual) that occurs for no known reason. The affected individual with Stickler syndrome would have 50% risk of having an affected pregnancy due to autosomal dominant inheritance (see above). Parents of a child with a de novo mutation causing Stickler syndrome would have a slightly increased risk of having another child with Stickler syndrome than the general population due to the possibility of gonadal mosaicism, which means carrying the mutation in the ovaries or testes but not in the blood.Very, very rarely in a few families where both parents are relatives of each other, Stickler syndrome is due to an autosomal recessive pattern of inheritance. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child with Stickler syndrome is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females. The researchers were able to determine that Stickler syndrome in this family occurred due to mutations of the COL9A1 gene located on the long arm (q) of chromosome 6 (6q13), COL9A2 on the short arm (p) of chromosome 1 (1p33), and possibly COL9A3 on the long (q) arm of chromosome 20 (20q13).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, chromosome 12q13.11 refers to band 13.11 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The genes involved in Stickler syndrome contain instructions for creating (encoding) proteins that are essential for the proper development and function of collagen, one of the most abundant proteins in the body and a major building block of connective tissue, which is the material between cells of the body that gives the tissue form and strength.There are many different types of collagen, which are indicated by Roman numerals. The COL2A1 gene encodes for collagen type II; the COL11A1 and COL11A2 genes encode for collagen type XI; the COL9A1, COL9A2 and COL9A3 genes encode collagen IX.These specific collagens are most prevalent in the specialized tissue that serves as a buffer or cushion for bones at joints (cartilage) and the jelly-like fluid that fills the center of the eye (vitreous). Collagen is also found in bone.
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Causes of Stickler Syndrome. Most cases of Stickler syndrome occur in families with other members that also have Stickler syndrome, due to a familial mutation of a gene inherited as an autosomal dominant trait. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.In some cases, Stickler syndrome occurs randomly as a result of a de novo genetic change (i.e., new mutation in the affected individual) that occurs for no known reason. The affected individual with Stickler syndrome would have 50% risk of having an affected pregnancy due to autosomal dominant inheritance (see above). Parents of a child with a de novo mutation causing Stickler syndrome would have a slightly increased risk of having another child with Stickler syndrome than the general population due to the possibility of gonadal mosaicism, which means carrying the mutation in the ovaries or testes but not in the blood.Very, very rarely in a few families where both parents are relatives of each other, Stickler syndrome is due to an autosomal recessive pattern of inheritance. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child with Stickler syndrome is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females. The researchers were able to determine that Stickler syndrome in this family occurred due to mutations of the COL9A1 gene located on the long arm (q) of chromosome 6 (6q13), COL9A2 on the short arm (p) of chromosome 1 (1p33), and possibly COL9A3 on the long (q) arm of chromosome 20 (20q13).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, chromosome 12q13.11 refers to band 13.11 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The genes involved in Stickler syndrome contain instructions for creating (encoding) proteins that are essential for the proper development and function of collagen, one of the most abundant proteins in the body and a major building block of connective tissue, which is the material between cells of the body that gives the tissue form and strength.There are many different types of collagen, which are indicated by Roman numerals. The COL2A1 gene encodes for collagen type II; the COL11A1 and COL11A2 genes encode for collagen type XI; the COL9A1, COL9A2 and COL9A3 genes encode collagen IX.These specific collagens are most prevalent in the specialized tissue that serves as a buffer or cushion for bones at joints (cartilage) and the jelly-like fluid that fills the center of the eye (vitreous). Collagen is also found in bone.
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Affects of Stickler Syndrome
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Stickler syndrome affects males as well as females. Prevalence rates have been estimated at 1-3 per 10,000 births and at 1 per 7,500 births. Most investigators believe that the disorder is highly under-diagnosed, making it difficult to determine the true prevalence of Stickler syndrome in the general population. Stickler syndrome is one of the most common connective tissue disorders in the United States.
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Affects of Stickler Syndrome. Stickler syndrome affects males as well as females. Prevalence rates have been estimated at 1-3 per 10,000 births and at 1 per 7,500 births. Most investigators believe that the disorder is highly under-diagnosed, making it difficult to determine the true prevalence of Stickler syndrome in the general population. Stickler syndrome is one of the most common connective tissue disorders in the United States.
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Related disorders of Stickler Syndrome
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Symptoms of the following disorders can be similar to those of Stickler syndrome.COL2A1-related disorders are a group of disorders (including Stickler syndrome type I) which are due to mutations of the COL2A1 gene (allelic disorders). This group of disorders includes spondyloepiphyseal dysplasia congenital (SEDC), achondrogenesis type II, spondyloepimetaphyseal dysplasia, and Kneist dysplasia. These disorders are characterized by distinctive facial features, skeletal malformations, abnormal curvature of the spine (kyphoscoliosis), nearsightedness (myopia), and degeneration of the thick, jellylike fluid (vitreous) that fills the center of the eyes and the thin layer of nerve cells (retina) that lines the back of the eye (vitreoretinal degeneration). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)OSMED (oto-spondyl-megaepiphyseal dysplasia) is a rare genetic disorder characterized by skeletal malformations resulting in shortening of the upper limbs and thighs and short stature (rhizomelic dwarfism). Additional symptoms include distinctive facial features and delays in psychomotor development. After the initial period of growth deficiency, affected individuals experience gradual improvement in bone growth that leads to normal physical development by early childhood. Mental and motor development is also normal by early childhood. In some cases, affected individuals develop hearing loss.Heterozygous OSMED occurs because of disruptions or changes (mutations) to the
COL11A2 gene, the same gene that causes Weissenbacher-Zweymuller syndrome and non-ocular Stickler syndrome or Stickler syndrome type III. Some researchers consider these three disorders separate entities; others believe that they are the same disorder or different manifestations of the same disorder. Recently, some researchers have suggested that the name OSMED be used as a general heading to consist of “heterozygous OSMED,” which encompasses Weissenbacher-Zweymuller syndrome and Stickler syndrome type III and is inherited as an autosomal dominant trait and “homozygous OSMED,” which encompasses autosomal recessive cases of oto-spondylo-megaepiphyseal dysplasia. (For more information on this disorder, choose “OSMED” as your search term in the Rare Disease Database.)Marshall syndrome is a rare genetic disorder. Major symptoms may include a distinctive face with a flattened nasal bridge and nostrils that are tilted upward, widely spaced eyes (hyperterlorism), nearsightedness, cataracts and moderate to severe hearing loss. Affected individuals may experience degeneration of the thick fluid that fills the center of the eye and the membrane (retina) that lines the back of the eye (vitreoretinal degeneration). Malformation of certain bones of the arms (e.g., bowing of the arm bones) may also occur. Affected individuals may also have Pierre-Robin sequence. Pierre-Robin sequence consists of an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and, in some cases, incomplete closure of the roof of the mouth (cleft palate). Cleft palate may also occur as an isolated finding. Marshall syndrome is inherited as an autosomal dominant trait. The gene that causes Marshall syndrome (i.e., COL11A1) is the same gene that causes Stickler syndrome type II. Some researchers believe these two disorders are the same disorder or different expressions of the same disorder. Others believe that the two disorders are distinct. Most recent studies show that the mutations in COL11A1 associated with the Marshall Syndrome phenotype are splicing mutations in the exons in the c-terminal region of COL11A1, with a hot spot in exon 50. (For more information choose “Marshall syndrome” as your search term in the Rare Disease Database).Wagner syndrome is a rare progressive genetic disorder characterized by mild nearsightedness (myopia), degeneration of the thick, jelly-like fluid (vitreous) that fills the center of the eyes and the thin layer of nerve cells (retina) that lines the back of the eye (vitreoretinal degeneration), and distinctive facial features. Retinal detachment, cataracts and glaucoma have also been reported in individuals with Wagner syndrome. For years, some researchers believed that Wagner and Stickler syndromes were the same disorder. However, it has now been determined that Wagner syndrome is caused by mutations to a gene on the long arm (q) on chromosome 5 (5q13-q14). Wagner syndrome is inherited as an autosomal dominant trait.
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Related disorders of Stickler Syndrome. Symptoms of the following disorders can be similar to those of Stickler syndrome.COL2A1-related disorders are a group of disorders (including Stickler syndrome type I) which are due to mutations of the COL2A1 gene (allelic disorders). This group of disorders includes spondyloepiphyseal dysplasia congenital (SEDC), achondrogenesis type II, spondyloepimetaphyseal dysplasia, and Kneist dysplasia. These disorders are characterized by distinctive facial features, skeletal malformations, abnormal curvature of the spine (kyphoscoliosis), nearsightedness (myopia), and degeneration of the thick, jellylike fluid (vitreous) that fills the center of the eyes and the thin layer of nerve cells (retina) that lines the back of the eye (vitreoretinal degeneration). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)OSMED (oto-spondyl-megaepiphyseal dysplasia) is a rare genetic disorder characterized by skeletal malformations resulting in shortening of the upper limbs and thighs and short stature (rhizomelic dwarfism). Additional symptoms include distinctive facial features and delays in psychomotor development. After the initial period of growth deficiency, affected individuals experience gradual improvement in bone growth that leads to normal physical development by early childhood. Mental and motor development is also normal by early childhood. In some cases, affected individuals develop hearing loss.Heterozygous OSMED occurs because of disruptions or changes (mutations) to the
COL11A2 gene, the same gene that causes Weissenbacher-Zweymuller syndrome and non-ocular Stickler syndrome or Stickler syndrome type III. Some researchers consider these three disorders separate entities; others believe that they are the same disorder or different manifestations of the same disorder. Recently, some researchers have suggested that the name OSMED be used as a general heading to consist of “heterozygous OSMED,” which encompasses Weissenbacher-Zweymuller syndrome and Stickler syndrome type III and is inherited as an autosomal dominant trait and “homozygous OSMED,” which encompasses autosomal recessive cases of oto-spondylo-megaepiphyseal dysplasia. (For more information on this disorder, choose “OSMED” as your search term in the Rare Disease Database.)Marshall syndrome is a rare genetic disorder. Major symptoms may include a distinctive face with a flattened nasal bridge and nostrils that are tilted upward, widely spaced eyes (hyperterlorism), nearsightedness, cataracts and moderate to severe hearing loss. Affected individuals may experience degeneration of the thick fluid that fills the center of the eye and the membrane (retina) that lines the back of the eye (vitreoretinal degeneration). Malformation of certain bones of the arms (e.g., bowing of the arm bones) may also occur. Affected individuals may also have Pierre-Robin sequence. Pierre-Robin sequence consists of an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and, in some cases, incomplete closure of the roof of the mouth (cleft palate). Cleft palate may also occur as an isolated finding. Marshall syndrome is inherited as an autosomal dominant trait. The gene that causes Marshall syndrome (i.e., COL11A1) is the same gene that causes Stickler syndrome type II. Some researchers believe these two disorders are the same disorder or different expressions of the same disorder. Others believe that the two disorders are distinct. Most recent studies show that the mutations in COL11A1 associated with the Marshall Syndrome phenotype are splicing mutations in the exons in the c-terminal region of COL11A1, with a hot spot in exon 50. (For more information choose “Marshall syndrome” as your search term in the Rare Disease Database).Wagner syndrome is a rare progressive genetic disorder characterized by mild nearsightedness (myopia), degeneration of the thick, jelly-like fluid (vitreous) that fills the center of the eyes and the thin layer of nerve cells (retina) that lines the back of the eye (vitreoretinal degeneration), and distinctive facial features. Retinal detachment, cataracts and glaucoma have also been reported in individuals with Wagner syndrome. For years, some researchers believed that Wagner and Stickler syndromes were the same disorder. However, it has now been determined that Wagner syndrome is caused by mutations to a gene on the long arm (q) on chromosome 5 (5q13-q14). Wagner syndrome is inherited as an autosomal dominant trait.
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Diagnosis of Stickler Syndrome
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A diagnosis of Stickler syndrome is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. As yet, no universally agreed upon criteria for the diagnosis of Stickler syndrome exists. A variety of tests such as x-ray studies and eye examinations may be used to detect the presence or evaluate the severity of certain abnormalities potentially associated with Stickler syndrome.
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Diagnosis of Stickler Syndrome. A diagnosis of Stickler syndrome is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. As yet, no universally agreed upon criteria for the diagnosis of Stickler syndrome exists. A variety of tests such as x-ray studies and eye examinations may be used to detect the presence or evaluate the severity of certain abnormalities potentially associated with Stickler syndrome.
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Therapies of Stickler Syndrome
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Treatment
The treatment of Stickler syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists including: geneticist, pediatrician and/or internist, orthopedic surgeon, rheumatologist, ophthalmologist and retina specialist, otolaryngologist, audiologist, plastic surgeon, orthodontist and other healthcare professionals may need to systematically and comprehensively plan an affected patient’s treatment.Early identification of Stickler syndrome is important because it allows for surveillance and prompt treatment of associated abnormalities such as retinal detachment or skeletal malformations. Patients with ocular forms of Stickler syndrome are restricted from contact sports due to the risk of retinal detachment. Retinal detachment requires prompt surgery to preserve vision. Retinal detachment can recur even after successful surgery. Some physicians recommend prophylactic cryotherapy in certain cases to reduce the risk of developing retinal detachment.Affected individuals should be made aware of the symptoms of retinal detachment so they can immediately have their eyes evaluated (ophthalmologic assessment) and treated if necessary. Surgery may also be necessary to remove cataracts.Corrective lenses (glasses or contact lenses) are used to treat myopia.Individuals with Stickler syndrome and Pierre-Robin sequence may require a tracheostomy (a procedure in which a tube is placed through a surgical opening in the neck) to prevent breathing (respiratory) difficulties. Surgery may also be required to fix various craniofacial abnormalities (e.g., cleft palate. micrognathia) that can contribute to breathing difficulties.Orthodonture may be necessary to correct dental malalignment.Patients with sensorineural or mixed hearing loss may require hearing aids. Hearing aids may be of benefit for certain individuals. A myringotomy, a surgical procedure in which a small incision is made in the eardrum and small tubes are inserted, may be used to treat glue ear. Various anti-inflammatory medications and sometimes prescription pain medications may be used to treat joint disease in individuals with Stickler syndrome. In mild cases, short-term relief may be provided from cortisone injections. Surgical correction of joint abnormalities may be necessary including joint replacement surgery such as a total hip or knee replacement. Surgery may also be necessary for skeletal malformations including abnormal curvature of the spine.Physical therapy may prove beneficial in some cases.Special education and other services may be helpful for children with learning disabilities due to hearing or vision problems.Genetic counseling may be of benefit for affected individuals and their families.
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Therapies of Stickler Syndrome. Treatment
The treatment of Stickler syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists including: geneticist, pediatrician and/or internist, orthopedic surgeon, rheumatologist, ophthalmologist and retina specialist, otolaryngologist, audiologist, plastic surgeon, orthodontist and other healthcare professionals may need to systematically and comprehensively plan an affected patient’s treatment.Early identification of Stickler syndrome is important because it allows for surveillance and prompt treatment of associated abnormalities such as retinal detachment or skeletal malformations. Patients with ocular forms of Stickler syndrome are restricted from contact sports due to the risk of retinal detachment. Retinal detachment requires prompt surgery to preserve vision. Retinal detachment can recur even after successful surgery. Some physicians recommend prophylactic cryotherapy in certain cases to reduce the risk of developing retinal detachment.Affected individuals should be made aware of the symptoms of retinal detachment so they can immediately have their eyes evaluated (ophthalmologic assessment) and treated if necessary. Surgery may also be necessary to remove cataracts.Corrective lenses (glasses or contact lenses) are used to treat myopia.Individuals with Stickler syndrome and Pierre-Robin sequence may require a tracheostomy (a procedure in which a tube is placed through a surgical opening in the neck) to prevent breathing (respiratory) difficulties. Surgery may also be required to fix various craniofacial abnormalities (e.g., cleft palate. micrognathia) that can contribute to breathing difficulties.Orthodonture may be necessary to correct dental malalignment.Patients with sensorineural or mixed hearing loss may require hearing aids. Hearing aids may be of benefit for certain individuals. A myringotomy, a surgical procedure in which a small incision is made in the eardrum and small tubes are inserted, may be used to treat glue ear. Various anti-inflammatory medications and sometimes prescription pain medications may be used to treat joint disease in individuals with Stickler syndrome. In mild cases, short-term relief may be provided from cortisone injections. Surgical correction of joint abnormalities may be necessary including joint replacement surgery such as a total hip or knee replacement. Surgery may also be necessary for skeletal malformations including abnormal curvature of the spine.Physical therapy may prove beneficial in some cases.Special education and other services may be helpful for children with learning disabilities due to hearing or vision problems.Genetic counseling may be of benefit for affected individuals and their families.
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Stickler Syndrome
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Overview of Stiff Person Syndrome
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Stiff person syndrome (SPS) is a rare acquired neurological disorder that most often causes progressive muscle stiffness (rigidity) and repeated episodes of painful muscle spasms. Muscular rigidity often fluctuates (i.e., grows worse and then improves) and usually occurs along with the muscle spasms. Spasms may occur randomly or can be triggered by a variety of different events or circumstances including a sudden noise, light physical contact or when exposed to cold. The severity and progression of SPS varies from one person to another. If left untreated, SPS can potentially progress to cause difficulty walking and significantly impact a person’s ability to perform routine, daily tasks. Although the exact cause of SPS is unknown, it is thought to be an autoimmune disorder and sometimes occurs along with other autoimmune disorders (e.g., thyroid disease, diabetes, pernicious anemia [b12 deficiency], and vitiligo).SPS has been described in the medical literature under many different, confusing names. Originally described as stiff man syndrome, the name was changed to reflect that the disorder can affect individuals of any age, race, ethnicity and gender. Like other autoimmune disorders, the majority of individuals with the condition are females. SPS is considered by many clinicians and researchers to be a spectrum of diseases ranging from the involvement of just one area of the body to a widespread, rapidly progressive form that also includes involvement of the brain, brain stem and spinal cord.
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Overview of Stiff Person Syndrome. Stiff person syndrome (SPS) is a rare acquired neurological disorder that most often causes progressive muscle stiffness (rigidity) and repeated episodes of painful muscle spasms. Muscular rigidity often fluctuates (i.e., grows worse and then improves) and usually occurs along with the muscle spasms. Spasms may occur randomly or can be triggered by a variety of different events or circumstances including a sudden noise, light physical contact or when exposed to cold. The severity and progression of SPS varies from one person to another. If left untreated, SPS can potentially progress to cause difficulty walking and significantly impact a person’s ability to perform routine, daily tasks. Although the exact cause of SPS is unknown, it is thought to be an autoimmune disorder and sometimes occurs along with other autoimmune disorders (e.g., thyroid disease, diabetes, pernicious anemia [b12 deficiency], and vitiligo).SPS has been described in the medical literature under many different, confusing names. Originally described as stiff man syndrome, the name was changed to reflect that the disorder can affect individuals of any age, race, ethnicity and gender. Like other autoimmune disorders, the majority of individuals with the condition are females. SPS is considered by many clinicians and researchers to be a spectrum of diseases ranging from the involvement of just one area of the body to a widespread, rapidly progressive form that also includes involvement of the brain, brain stem and spinal cord.
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Symptoms of Stiff Person Syndrome
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The characteristic symptoms associated with SPS are progressive, fluctuating muscular rigidity that occurs along with muscle spasms. The severity and progression of SPS can vary from one person to another. The symptoms usually develop over a period of months to years and may remain stable for many years or slowly worsen. In some people, symptoms can be stabilized or improved through medication and non-medication interventions. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall treatment plan.Affected individuals may initially experience aching discomfort, stiffness, or pain, especially in the lower back, hips, and/or legs (predominantly in the classic type). Early on, stiffness may come and go, but it can gradually become fixed. The shoulders, arms, and/or neck may also be affected and less commonly the face. As the disease progresses, stiffness of the leg muscles (and other body regions) develops and can be more pronounced on one side than the other (asymmetrical). This leads to a slow, stiff manner of walking. As stiffness increases, affected individuals may develop an increasingly arched lower back due to inward curving of the lower spine (hyperlordosis). In addition to muscular rigidity/stiffness, individuals with SPS also develop muscle spasms, which may occur for no apparent reason (spontaneously) or in response to various triggering events (i.e., stimuli). Spasms can be triggered by unexpected or loud noises, minor physical contact, cold environments, stress or situations that cause a heightened emotional response. Muscle spasms are often very painful and usually worsen existing stiffness. The spasms may involve the entire body or only a specific body region. The legs are often involved, which may lead to falls. Spasms of abdominal muscles may lead to individuals feeling bloated and constricted around their torso. Spasms involving the chest and respiratory muscles can be serious, potentially requiring emergency medical treatment with ventilatory support. However, this is uncommon as most people who have respiratory symptoms with spasms just feel short of breath without respiratory compromise. In general, muscle spasms last seconds to several minutes, but occasionally can last for hours. Sudden withdrawal of medication in individuals with SPS may result in a life-threatening situation with overwhelmingly severe muscle spasms. Sleep usually suppresses the frequency of spasms.In some people, SPS becomes severe enough to affect an individual’s ability to perform daily activities and routines. Some individuals may need to use a device such as a cane, walker or wheelchair. Some affected individuals experience intense anxiety when they need to cross large, open areas unassisted (agoraphobia) and become reluctant to go outside. If left untreated, SPS can potentially progress to cause significant disability and result in secondary complications from immobility.Expanding Clinical Spectrum of SPSSeveral sets of characteristics (phenotypes) of SPS have been reported in the medical literature. This suggests that SPS represents a spectrum of diseases ranging from the involvement of one specific, localized body region to widespread involvement. These phenotypes include classic SPS, partial (or focal) SPS, SPS-plus, progressive encephalomyelitis with rigidity and myoclonus (PERM) and overlapping syndromes. Classic SPS is characterized by muscle stiffness and painful spasms involving the torso and legs (more than arms). This phenotype is the most common type and often presents with asymmetrical limb involvement. The onset of symptoms is typically gradual and slow. Not all individuals will have an excessive curvature of the lower spine (hyperlordosis) and early on people with SPS may have normal exams. Partial or focal SPS is characterized by the localized involvement of one limb, usually a leg (stiff limb syndrome) or the torso (stiff torso [trunk] syndrome). The stiffness and muscle spasms are similar to those found in classic SPS. Partial SPS may progress to classic SPS (affecting both legs and torso) leading to increased difficulty walking and subsequent falls. SPS-plus is characterized by having classic SPS features (limb and back stiffness and spasms) plus brainstem and/or cerebellar involvement. Affected individuals can experience double vision, nystagmus, vertigo, incoordination (ataxia), speech issues (dysarthria) and/or swallowing problems (dysphagia) along with musculoskeletal symptoms. Onset of symptoms vary and often slowly worsen over time. Many individuals with SPS-plus will require help with walking and are at high risk of falling. Progressive encephalomyelitis with rigidity and myoclonus (PERM) is characterized by stiffness and painful muscles that are similar to those seen in individuals with classic SPS. PERM is thought to have a more rapid onset of symptoms (days to several weeks) and progress quicker than other forms of SPS. However, some individuals will develop symptoms over months to years. Stiffness and spasms may occur along with, before or after the development of other symptoms including vertigo, a lack of coordination of voluntary muscles (ataxia), difficulty speaking (dysarthria) and confusion/seizures. In many patients, paralysis of certain eye movements (ophthalmoplegia), nystagmus, difficulty swallowing (dysphagia) and autonomic dysfunction (labile blood pressure and heart rate) occur. Myoclonus also occurs in individuals with PERM. Myoclonus is a general term used to describe the sudden, involuntary jerking of a muscle or group of muscles caused by muscle contractions (positive myoclonus) or muscle relaxation (negative myoclonus). The twitching or jerking of muscles cannot be controlled by the person experiencing it. PERM is considered a distinct disorder from classic SPS and SPS-plus and some think it is a distinct condition all together. There is no evidence that other phenotypes of SPS will inevitably evolve into PERM.There are overlapping syndromes that do not fit perfectly within the other phenotypes. Affected individuals can have a variety of features that are commonly seen in the previously described phenotypes along with other features including predominantly cerebellar symptoms, epilepsy, encephalitis, amongst others.
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Symptoms of Stiff Person Syndrome. The characteristic symptoms associated with SPS are progressive, fluctuating muscular rigidity that occurs along with muscle spasms. The severity and progression of SPS can vary from one person to another. The symptoms usually develop over a period of months to years and may remain stable for many years or slowly worsen. In some people, symptoms can be stabilized or improved through medication and non-medication interventions. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall treatment plan.Affected individuals may initially experience aching discomfort, stiffness, or pain, especially in the lower back, hips, and/or legs (predominantly in the classic type). Early on, stiffness may come and go, but it can gradually become fixed. The shoulders, arms, and/or neck may also be affected and less commonly the face. As the disease progresses, stiffness of the leg muscles (and other body regions) develops and can be more pronounced on one side than the other (asymmetrical). This leads to a slow, stiff manner of walking. As stiffness increases, affected individuals may develop an increasingly arched lower back due to inward curving of the lower spine (hyperlordosis). In addition to muscular rigidity/stiffness, individuals with SPS also develop muscle spasms, which may occur for no apparent reason (spontaneously) or in response to various triggering events (i.e., stimuli). Spasms can be triggered by unexpected or loud noises, minor physical contact, cold environments, stress or situations that cause a heightened emotional response. Muscle spasms are often very painful and usually worsen existing stiffness. The spasms may involve the entire body or only a specific body region. The legs are often involved, which may lead to falls. Spasms of abdominal muscles may lead to individuals feeling bloated and constricted around their torso. Spasms involving the chest and respiratory muscles can be serious, potentially requiring emergency medical treatment with ventilatory support. However, this is uncommon as most people who have respiratory symptoms with spasms just feel short of breath without respiratory compromise. In general, muscle spasms last seconds to several minutes, but occasionally can last for hours. Sudden withdrawal of medication in individuals with SPS may result in a life-threatening situation with overwhelmingly severe muscle spasms. Sleep usually suppresses the frequency of spasms.In some people, SPS becomes severe enough to affect an individual’s ability to perform daily activities and routines. Some individuals may need to use a device such as a cane, walker or wheelchair. Some affected individuals experience intense anxiety when they need to cross large, open areas unassisted (agoraphobia) and become reluctant to go outside. If left untreated, SPS can potentially progress to cause significant disability and result in secondary complications from immobility.Expanding Clinical Spectrum of SPSSeveral sets of characteristics (phenotypes) of SPS have been reported in the medical literature. This suggests that SPS represents a spectrum of diseases ranging from the involvement of one specific, localized body region to widespread involvement. These phenotypes include classic SPS, partial (or focal) SPS, SPS-plus, progressive encephalomyelitis with rigidity and myoclonus (PERM) and overlapping syndromes. Classic SPS is characterized by muscle stiffness and painful spasms involving the torso and legs (more than arms). This phenotype is the most common type and often presents with asymmetrical limb involvement. The onset of symptoms is typically gradual and slow. Not all individuals will have an excessive curvature of the lower spine (hyperlordosis) and early on people with SPS may have normal exams. Partial or focal SPS is characterized by the localized involvement of one limb, usually a leg (stiff limb syndrome) or the torso (stiff torso [trunk] syndrome). The stiffness and muscle spasms are similar to those found in classic SPS. Partial SPS may progress to classic SPS (affecting both legs and torso) leading to increased difficulty walking and subsequent falls. SPS-plus is characterized by having classic SPS features (limb and back stiffness and spasms) plus brainstem and/or cerebellar involvement. Affected individuals can experience double vision, nystagmus, vertigo, incoordination (ataxia), speech issues (dysarthria) and/or swallowing problems (dysphagia) along with musculoskeletal symptoms. Onset of symptoms vary and often slowly worsen over time. Many individuals with SPS-plus will require help with walking and are at high risk of falling. Progressive encephalomyelitis with rigidity and myoclonus (PERM) is characterized by stiffness and painful muscles that are similar to those seen in individuals with classic SPS. PERM is thought to have a more rapid onset of symptoms (days to several weeks) and progress quicker than other forms of SPS. However, some individuals will develop symptoms over months to years. Stiffness and spasms may occur along with, before or after the development of other symptoms including vertigo, a lack of coordination of voluntary muscles (ataxia), difficulty speaking (dysarthria) and confusion/seizures. In many patients, paralysis of certain eye movements (ophthalmoplegia), nystagmus, difficulty swallowing (dysphagia) and autonomic dysfunction (labile blood pressure and heart rate) occur. Myoclonus also occurs in individuals with PERM. Myoclonus is a general term used to describe the sudden, involuntary jerking of a muscle or group of muscles caused by muscle contractions (positive myoclonus) or muscle relaxation (negative myoclonus). The twitching or jerking of muscles cannot be controlled by the person experiencing it. PERM is considered a distinct disorder from classic SPS and SPS-plus and some think it is a distinct condition all together. There is no evidence that other phenotypes of SPS will inevitably evolve into PERM.There are overlapping syndromes that do not fit perfectly within the other phenotypes. Affected individuals can have a variety of features that are commonly seen in the previously described phenotypes along with other features including predominantly cerebellar symptoms, epilepsy, encephalitis, amongst others.
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Stiff Person Syndrome
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Causes of Stiff Person Syndrome
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The exact cause of SPS is not known. Some studies in the medical literature indicate that it is likely an autoimmune disorder. Autoimmune disorders occur when the body’s natural defenses (e.g., antibodies) against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons.Most of those affected with SPS have antibodies to glutamic acid decarboxylase (GAD), a protein in inhibitory nerve cells that is involved in the creation (synthesis) of the main inhibitory neurotransmitter called gamma-aminobutyric acid (GABA). GABA helps control muscle movement and prevents hyperexcitability within the nervous system. The symptoms of SPS may develop when the immune system mistakenly attacks certain nerve cells (neurons) that produce GAD leading to a deficiency of GABA in the body. Nonetheless, the exact role that deficiency of GAD plays in the development of SPS is not fully understood. Less commonly, individuals with SPS have antibodies to amphiphysin, a protein involved in the transmission of signals from one nerve cell to another. In these individuals, breast cancer is quite prevalent. Another less common antibody is the glycine receptor antibody. This antibody appears to have a very close association with PERM and may be directly pathogenic in this phenotype. Other antibodies have been noted within the medical literature, but it is unclear whether they are truly associated with SPS. In some individuals with SPS, no antibodies are detectable. More research is necessary to determine the exact, underlying mechanisms that ultimately cause SPS and the exact role that anti-GAD-65 and other antibodies play in the development and progression of the disorder.Rarely, affected individuals may have an underlying cancer that is associated with their SPS (paraneoplastic SPS). The most common cancers seen are breast and lung cancer. Less commonly associated cancers seen include lymphoma, thymoma, etc. The symptoms and signs of paraneoplastic SPS typically begin weeks to months, and sometimes years before the cancer is found. However, the majority if not all cancers associated with paraneoplastic SPS are found within the first 5 years from SPS symptom onset. (For more information on this disorder, choose “paraneoplastic neurologic syndromes” as your search term in the Rare Disease Database.)
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Causes of Stiff Person Syndrome. The exact cause of SPS is not known. Some studies in the medical literature indicate that it is likely an autoimmune disorder. Autoimmune disorders occur when the body’s natural defenses (e.g., antibodies) against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons.Most of those affected with SPS have antibodies to glutamic acid decarboxylase (GAD), a protein in inhibitory nerve cells that is involved in the creation (synthesis) of the main inhibitory neurotransmitter called gamma-aminobutyric acid (GABA). GABA helps control muscle movement and prevents hyperexcitability within the nervous system. The symptoms of SPS may develop when the immune system mistakenly attacks certain nerve cells (neurons) that produce GAD leading to a deficiency of GABA in the body. Nonetheless, the exact role that deficiency of GAD plays in the development of SPS is not fully understood. Less commonly, individuals with SPS have antibodies to amphiphysin, a protein involved in the transmission of signals from one nerve cell to another. In these individuals, breast cancer is quite prevalent. Another less common antibody is the glycine receptor antibody. This antibody appears to have a very close association with PERM and may be directly pathogenic in this phenotype. Other antibodies have been noted within the medical literature, but it is unclear whether they are truly associated with SPS. In some individuals with SPS, no antibodies are detectable. More research is necessary to determine the exact, underlying mechanisms that ultimately cause SPS and the exact role that anti-GAD-65 and other antibodies play in the development and progression of the disorder.Rarely, affected individuals may have an underlying cancer that is associated with their SPS (paraneoplastic SPS). The most common cancers seen are breast and lung cancer. Less commonly associated cancers seen include lymphoma, thymoma, etc. The symptoms and signs of paraneoplastic SPS typically begin weeks to months, and sometimes years before the cancer is found. However, the majority if not all cancers associated with paraneoplastic SPS are found within the first 5 years from SPS symptom onset. (For more information on this disorder, choose “paraneoplastic neurologic syndromes” as your search term in the Rare Disease Database.)
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Stiff Person Syndrome
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Affects of Stiff Person Syndrome
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SPS is an extremely rare disorder. The exact incidence and prevalence of SPS is unknown, although one estimate places the incidence at approximately 1 in 1,000,000 individuals in the general population. However, this estimate likely does not account for the expanding clinical spectrum. The distribution of SPS between males and females indicates a female predominance. SPS usually becomes apparent sometime between 30-60 years of age. However, SPS has been reported to occur in children and older adults (>60 years old) as well. It appears that SPS can also affect any race and ethnicity.
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Affects of Stiff Person Syndrome. SPS is an extremely rare disorder. The exact incidence and prevalence of SPS is unknown, although one estimate places the incidence at approximately 1 in 1,000,000 individuals in the general population. However, this estimate likely does not account for the expanding clinical spectrum. The distribution of SPS between males and females indicates a female predominance. SPS usually becomes apparent sometime between 30-60 years of age. However, SPS has been reported to occur in children and older adults (>60 years old) as well. It appears that SPS can also affect any race and ethnicity.
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Stiff Person Syndrome
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Related disorders of Stiff Person Syndrome
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Symptoms of the following disorders (not complete list) can be similar to those of SPS. Comparisons may be useful for a differential diagnosis.Tetanus is an infectious disorder that affects the central nervous system (CNS). It is caused by the microorganism Clostridius tetani, a type of bacterium. This microorganism usually enters the body through wounds, injections or skin ulcers. The incubation period of tetanus is usually seven to twenty-one days. Symptoms of this syndrome include muscle stiffness, especially of the jaw (lock jaw) and painful muscle spasms. Affected individuals may also experience low-grade fever, difficulty swallowing (dysphagia), difficulty breathing, alteration in the rhythm of the heartbeat and convulsions. Tetanus can also cause behavioral changes including anxiety and restlessness. The symptoms of tetanus usually last for three to four weeks. Although tetanus is a treatable disease, vaccination is recommended during infancy and every few years thereafter.A wide variety of other disorders can also cause signs and symptoms that are similar to SPS. Usually, these disorders have additional symptoms that can be used to distinguish them from SPS. Such disorders include hyperekplexia, multiple sclerosis, transverse myelitis, occult vascular malformations, neuromyotonia (Isaac’s syndrome), Schwartz-Jampel syndrome, muscular dystrophies and metabolic myopathies. (For more information, choose the specific disorder name as your search term in the Rare Disease Database).
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Related disorders of Stiff Person Syndrome. Symptoms of the following disorders (not complete list) can be similar to those of SPS. Comparisons may be useful for a differential diagnosis.Tetanus is an infectious disorder that affects the central nervous system (CNS). It is caused by the microorganism Clostridius tetani, a type of bacterium. This microorganism usually enters the body through wounds, injections or skin ulcers. The incubation period of tetanus is usually seven to twenty-one days. Symptoms of this syndrome include muscle stiffness, especially of the jaw (lock jaw) and painful muscle spasms. Affected individuals may also experience low-grade fever, difficulty swallowing (dysphagia), difficulty breathing, alteration in the rhythm of the heartbeat and convulsions. Tetanus can also cause behavioral changes including anxiety and restlessness. The symptoms of tetanus usually last for three to four weeks. Although tetanus is a treatable disease, vaccination is recommended during infancy and every few years thereafter.A wide variety of other disorders can also cause signs and symptoms that are similar to SPS. Usually, these disorders have additional symptoms that can be used to distinguish them from SPS. Such disorders include hyperekplexia, multiple sclerosis, transverse myelitis, occult vascular malformations, neuromyotonia (Isaac’s syndrome), Schwartz-Jampel syndrome, muscular dystrophies and metabolic myopathies. (For more information, choose the specific disorder name as your search term in the Rare Disease Database).
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Stiff Person Syndrome
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Diagnosis of Stiff Person Syndrome
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A diagnosis of SPS is made based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical examination. Diagnostic tests are used to help support a clinical diagnosis and very importantly, to help rule out other conditions. Such tests include lab work (blood and spinal fluid) to detect the presence of antibodies against GAD-65, amphiphysin (which is most often associated with paraneoplastic SPS) and glycine receptor. Electromyography (EMG) can be helpful in individuals who have musculoskeletal involvement. This test records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. An EMG can demonstrate continuous muscle activity in stiff muscles along with co-contraction of agonist and antagonist muscles. Muscle relaxers like diazepam will suppress the characteristic findings on EMG.Magnetic resonance imaging (MRI) is useful to rule out the presence of other conditions including spinal stenosis, demyelinating disorders and neurosarcoidosis, amongst others. Body computerized tomography (CT) scan and breast imaging are typically used to evaluate for paraneoplastic SPS. Positron emission tomography (PET) with CT scan is sometimes used to also evaluate for cancer and systemic diseases.
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Diagnosis of Stiff Person Syndrome. A diagnosis of SPS is made based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical examination. Diagnostic tests are used to help support a clinical diagnosis and very importantly, to help rule out other conditions. Such tests include lab work (blood and spinal fluid) to detect the presence of antibodies against GAD-65, amphiphysin (which is most often associated with paraneoplastic SPS) and glycine receptor. Electromyography (EMG) can be helpful in individuals who have musculoskeletal involvement. This test records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. An EMG can demonstrate continuous muscle activity in stiff muscles along with co-contraction of agonist and antagonist muscles. Muscle relaxers like diazepam will suppress the characteristic findings on EMG.Magnetic resonance imaging (MRI) is useful to rule out the presence of other conditions including spinal stenosis, demyelinating disorders and neurosarcoidosis, amongst others. Body computerized tomography (CT) scan and breast imaging are typically used to evaluate for paraneoplastic SPS. Positron emission tomography (PET) with CT scan is sometimes used to also evaluate for cancer and systemic diseases.
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Therapies of Stiff Person Syndrome
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Treatment
The treatment of SPS is directed toward the specific symptoms that are apparent in each individual which often requires a multifaceted approach including non-medication interventions (stretching, heat therapy, aqua therapy, massage therapy, acupuncture, balance training, behavioral therapy, etc.). Medications that are considered GABA-ergic agonists therapies such as benzodiazepines, specifically diazepam and clonazepam, are used to treat muscle stiffness and episodic spasms. Affected individuals may also benefit from baclofen and/or tizanidine, usually given in addition to benzodiazepines. Other medications reported to have benefit include methocarbamol, botulinum toxin and anti-seizure (anticonvulsant) medications (vigabatrin, pregabalin and gabapentin). There are additional symptomatic medications that can be found in the medical literature. Peer-reviewed clinical studies have shown that the most commonly used first-line immune based treatment, intravenous immunoglobulin (IVIG), can be effective in treating symptoms and functions commonly associated with SPS. IVIG, under certain conditions, has been associated with increased risks for blood clots, kidney injury and meningitis. Most common side effects include infusion reactions and headaches. In individuals that are unable to tolerate IVIG, subcutaneous IG (SCIG) has been used. Treatment should be prescribed only after a thorough discussion of the possible risks and benefits. More research is necessary to determine the long-term safety and effectiveness of IVIG for the treatment of individuals with SPS.There are classes of medications that should be avoided in SPS, including serotonin-norepinephrine reuptake inhibitors (SNRIs, i.e., tricyclic antidepressants and duloxetine) and opioids. SNRIs have previously been shown to worsen the EMG activity and clinical symptoms in SPS. Opioids are not recommended for pain control because most individuals with SPS are on benzodiazepines. Mixing these two classes of medications and/or alcohol can lead to severe CNS and respiratory depression followed by death.
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Therapies of Stiff Person Syndrome. Treatment
The treatment of SPS is directed toward the specific symptoms that are apparent in each individual which often requires a multifaceted approach including non-medication interventions (stretching, heat therapy, aqua therapy, massage therapy, acupuncture, balance training, behavioral therapy, etc.). Medications that are considered GABA-ergic agonists therapies such as benzodiazepines, specifically diazepam and clonazepam, are used to treat muscle stiffness and episodic spasms. Affected individuals may also benefit from baclofen and/or tizanidine, usually given in addition to benzodiazepines. Other medications reported to have benefit include methocarbamol, botulinum toxin and anti-seizure (anticonvulsant) medications (vigabatrin, pregabalin and gabapentin). There are additional symptomatic medications that can be found in the medical literature. Peer-reviewed clinical studies have shown that the most commonly used first-line immune based treatment, intravenous immunoglobulin (IVIG), can be effective in treating symptoms and functions commonly associated with SPS. IVIG, under certain conditions, has been associated with increased risks for blood clots, kidney injury and meningitis. Most common side effects include infusion reactions and headaches. In individuals that are unable to tolerate IVIG, subcutaneous IG (SCIG) has been used. Treatment should be prescribed only after a thorough discussion of the possible risks and benefits. More research is necessary to determine the long-term safety and effectiveness of IVIG for the treatment of individuals with SPS.There are classes of medications that should be avoided in SPS, including serotonin-norepinephrine reuptake inhibitors (SNRIs, i.e., tricyclic antidepressants and duloxetine) and opioids. SNRIs have previously been shown to worsen the EMG activity and clinical symptoms in SPS. Opioids are not recommended for pain control because most individuals with SPS are on benzodiazepines. Mixing these two classes of medications and/or alcohol can lead to severe CNS and respiratory depression followed by death.
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Overview of Stomach Cancer
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Stomach cancer is a general term for cancer affecting the stomach. Generally, it refers to cancer that arises from the cells lining the stomach. These cells, like all cancerous cells, exhibit abnormal and rapid growth. Early in the course of the disease there are usually no symptoms (asymptomatic). As the disease progresses, symptoms like indigestion, nausea, vomiting, and feeling full earlier than normal (early satiety) may develop. The cause of stomach cancer is multifactorial, which means that multiple factors that occur together are necessary for the cancer to develop. These factors can include genetic, immunologic, infectious, and environmental factors. Stomach cancer usually develops randomly for unknown reasons (sporadically), and there is usually no family history. There are several different forms of stomach cancer. The most common is called adenocarcinoma, which accounts for about 90-95% of people with stomach cancer. Other types include primary gastric lymphoma, gastrointestinal stromal tumor (GIST), and neuroendocrine (carcinoid) tumors in the stomach. NORD has information on these forms of cancer – for more information choose the specific cancer name as your search term in the Rare Disease Database. In rare instances, other forms of cancer can arise in the stomach including squamous cell carcinoma, small cell carcinoma, and leiomyosarcoma. Malignancies in other organs rarely metastasize to the stomach, although breast cancer is one malignancy that can spread to the stomach in very rare circumstances. This report primarily deals with adenocarcinoma of the stomach or gastroesophageal junction. The stomach is the organ where the main part of digestion occurs. The stomach is connected to the esophagus (a tube that is connected to the throat) at the gastroesophageal junction. After food is chewed and swallowed it travels down the throat, through the esophagus and into the stomach. The bottom part of the stomach is connected to the small intestine called the duodenum. Stomach cancer (adenocarcinoma) can occur anywhere in the stomach, but most often arises from the cells making up the mucus membrane lining the stomach (mucus-producing cells). When cancer forms near the esophagus, it may be referred to as cancer of the gastroesophageal junction.
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Overview of Stomach Cancer. Stomach cancer is a general term for cancer affecting the stomach. Generally, it refers to cancer that arises from the cells lining the stomach. These cells, like all cancerous cells, exhibit abnormal and rapid growth. Early in the course of the disease there are usually no symptoms (asymptomatic). As the disease progresses, symptoms like indigestion, nausea, vomiting, and feeling full earlier than normal (early satiety) may develop. The cause of stomach cancer is multifactorial, which means that multiple factors that occur together are necessary for the cancer to develop. These factors can include genetic, immunologic, infectious, and environmental factors. Stomach cancer usually develops randomly for unknown reasons (sporadically), and there is usually no family history. There are several different forms of stomach cancer. The most common is called adenocarcinoma, which accounts for about 90-95% of people with stomach cancer. Other types include primary gastric lymphoma, gastrointestinal stromal tumor (GIST), and neuroendocrine (carcinoid) tumors in the stomach. NORD has information on these forms of cancer – for more information choose the specific cancer name as your search term in the Rare Disease Database. In rare instances, other forms of cancer can arise in the stomach including squamous cell carcinoma, small cell carcinoma, and leiomyosarcoma. Malignancies in other organs rarely metastasize to the stomach, although breast cancer is one malignancy that can spread to the stomach in very rare circumstances. This report primarily deals with adenocarcinoma of the stomach or gastroesophageal junction. The stomach is the organ where the main part of digestion occurs. The stomach is connected to the esophagus (a tube that is connected to the throat) at the gastroesophageal junction. After food is chewed and swallowed it travels down the throat, through the esophagus and into the stomach. The bottom part of the stomach is connected to the small intestine called the duodenum. Stomach cancer (adenocarcinoma) can occur anywhere in the stomach, but most often arises from the cells making up the mucus membrane lining the stomach (mucus-producing cells). When cancer forms near the esophagus, it may be referred to as cancer of the gastroesophageal junction.
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Symptoms of Stomach Cancer
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The signs and symptoms can vary greatly from one person to another. Specific findings depend on numerous factors including the exact location of the tumor, the extent of the tumor into nearby tissue or organs, the specific organs involved, and whether the disease has remained localized or spread to other areas of the body (metastasized). Stomach cancer is a slow-growing cancer that usually develops over a year or longer. Generally, there are no symptoms in the early stages (asymptomatic). As the disease progresses, a variety of symptoms can develop. These symptoms include indigestion (dyspepsia), which can be severe and persistent, nausea, vomiting, feeling full after eating a small amount of food (early satiety), feeling bloated after eating, and severe, persistent heartburn. Sometimes, stomach discomfort or pain, difficulty swallowing (dysphagia), fatigue, and unintended weight loss can occur. Pain is mild and vague early in the disease, but becomes more severe and constant as the disease progresses. Loss of blood from the stomach can occur and can go unnoticed leading to anemia (low levels of circulating red blood cells). Anemia can lead to fatigue, paleness of skin, and shortness of breath. Although uncommon, in advanced cases, affected individuals may vomit blood (hematemesis) or have dark, sticky feces (melena) due to blood in the stools. Sometimes, the first signs or symptoms of stomach cancer occur after the cancer has spread to other areas of the body. Exact symptoms will depend upon where the cancer spreads to, but common symptoms include inability to tolerate any oral intake due to bowel obstruction, fractures, neurologic changes, and swelling of the abdomen due to the buildup of fluid (ascites). Some other signs of advanced disease include a mass in the upper, center region of the abdomen (epigastric mass) or enlargement of the liver (hepatomegaly).
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Symptoms of Stomach Cancer. The signs and symptoms can vary greatly from one person to another. Specific findings depend on numerous factors including the exact location of the tumor, the extent of the tumor into nearby tissue or organs, the specific organs involved, and whether the disease has remained localized or spread to other areas of the body (metastasized). Stomach cancer is a slow-growing cancer that usually develops over a year or longer. Generally, there are no symptoms in the early stages (asymptomatic). As the disease progresses, a variety of symptoms can develop. These symptoms include indigestion (dyspepsia), which can be severe and persistent, nausea, vomiting, feeling full after eating a small amount of food (early satiety), feeling bloated after eating, and severe, persistent heartburn. Sometimes, stomach discomfort or pain, difficulty swallowing (dysphagia), fatigue, and unintended weight loss can occur. Pain is mild and vague early in the disease, but becomes more severe and constant as the disease progresses. Loss of blood from the stomach can occur and can go unnoticed leading to anemia (low levels of circulating red blood cells). Anemia can lead to fatigue, paleness of skin, and shortness of breath. Although uncommon, in advanced cases, affected individuals may vomit blood (hematemesis) or have dark, sticky feces (melena) due to blood in the stools. Sometimes, the first signs or symptoms of stomach cancer occur after the cancer has spread to other areas of the body. Exact symptoms will depend upon where the cancer spreads to, but common symptoms include inability to tolerate any oral intake due to bowel obstruction, fractures, neurologic changes, and swelling of the abdomen due to the buildup of fluid (ascites). Some other signs of advanced disease include a mass in the upper, center region of the abdomen (epigastric mass) or enlargement of the liver (hepatomegaly).
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Causes of Stomach Cancer
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The exact, underlying cause of stomach cancer is not fully understood. The reason why cancer develops is a complex question and researchers speculate that multiple factors are involved in the development of gastric cancer. These factors can include genetic, environmental, infectious, and immunologic factors. In most people, stomach cancer develops randomly without a family history (sporadically). Often, cancer is associated with different genes, which are linked to cancer’s development. When a variation (mutation of the DNA) of a cancer-associated gene occurs, the protein product created by that gene may be faulty, inefficient, absent, or overproduced. Variations in genes associated with cancer have been shown to increase a person’s risk of developing cancer (genetic predisposition). A genetic predisposition means that a person has a gene or genes for a disease, but the disease will not develop unless additional genetic or environmental factors are also present. These variations are somatic mutations and can occur in any cell of the body except the germ cells (the egg or the sperm). Consequently, these variations are not inherited and are acquired during life. Understanding the underlying genetic factors in stomach cancer is important and can lead to better, more targeted therapies in the future. In rare instances, stomach cancer can run in families. Having a first-degree relative with stomach cancer is considered a risk factor for the disease. In some these families, there may be an associated mutation with known risk factors that accounts for multiple family members being affected. For example, there can be clustering of H. pylori infection within families or there may be a predisposition to chronic inflammation of the mucous membrane lining the stomach (chronic atrophic gastritis). There are hereditary cancer syndromes (genetic disorders) that increase a person’s risk of develop stomach cancer (and often other types of cancer as well). About 1-3% of people with stomach cancer have an inherited cancer predisposition syndrome. These are inherited disorders in which affected individuals have a greater risk than the general population of developing cancer. These syndromes include hereditary diffuse gastric cancer (CDH1 mutations), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), familial intestinal gastric cancer (FIGC), hereditary breast and ovarian cancer (HBOC) syndrome (due to variations in the BRCA1 or BRCA2 gene); Lynch syndrome, which is also called hereditary non-polyposis colorectal cancer; familial adenomatous polyposis; Li-Fraumeni syndrome; and Peutz-Jeghers syndrome. Several different environmental factors have been associated with stomach cancer. Infection with Helicobacter pylori (H. pylori) is strongly associated with stomach cancer, especially cancer of the lower portion of the stomach. H. pylori is a type of bacterial infection that arises in the mucus layer of tissue that lines the stomach. This infection can cause inflammation and ulcers within the stomach. Long-term or chronic H. pylori infection is associated with marked inflammation and precancerous changes in the cells of the lining of the stomach. Most people who have H. pylori infection in the stomach never develop stomach cancer. Individuals who have a rare cancer called mucosa-associated lymphoid tissue (MALT) lymphoma are at a greater risk than the general population of developing adenocarcinoma of the stomach. Individuals with certain disorders including pernicious anemia, combined variable immunodeficiency, or Menetrier disease (hypertrophic gastropathy) are also at an increased risk of stomach cancer. There are noncancerous (benign), small growths (polyps) commonly found in the stomach. Many people have these polyps. A specific type of polyp called an adenoma can change and become cancerous. People who have had previous surgery on the stomach, such as for ulcers, are at an increased risk as well. Some studies suggest that a person’s diet can influence stomach cancer risk and that a diet high in salt and foods smoked or pickled in salt including certain meats or salted fish can increase the risk of stomach cancer. There are studies showing that a diet high in fried food, processed meats, and fish can increase the risk of stomach cancer. There are also studies that have shown that eating fruits and vegetables may help to prevent stomach cancer. The rate of stomach cancer is doubled in people who smoke. Smoking particularly increases the risk of stomach cancer near the esophagus. There is also an increased risk in people who work in certain industries where they are exposed to toxic materials including coal, metal, rubber industries (occupational exposure). Although the reason why is not known, people with type A blood also have a slightly increased risk of stomach cancer. Other potential factors have been suggested including obesity, alcohol consumption, and infection with Epstein-Barr virus, but the evidence is contradictory and such associations remain unproven. Gastroesophageal junction cancer can be associated with gastroesophageal reflux (GERD). GERD is a condition in which the contents of the stomach flow backward into the lower part of the esophagus.
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Causes of Stomach Cancer. The exact, underlying cause of stomach cancer is not fully understood. The reason why cancer develops is a complex question and researchers speculate that multiple factors are involved in the development of gastric cancer. These factors can include genetic, environmental, infectious, and immunologic factors. In most people, stomach cancer develops randomly without a family history (sporadically). Often, cancer is associated with different genes, which are linked to cancer’s development. When a variation (mutation of the DNA) of a cancer-associated gene occurs, the protein product created by that gene may be faulty, inefficient, absent, or overproduced. Variations in genes associated with cancer have been shown to increase a person’s risk of developing cancer (genetic predisposition). A genetic predisposition means that a person has a gene or genes for a disease, but the disease will not develop unless additional genetic or environmental factors are also present. These variations are somatic mutations and can occur in any cell of the body except the germ cells (the egg or the sperm). Consequently, these variations are not inherited and are acquired during life. Understanding the underlying genetic factors in stomach cancer is important and can lead to better, more targeted therapies in the future. In rare instances, stomach cancer can run in families. Having a first-degree relative with stomach cancer is considered a risk factor for the disease. In some these families, there may be an associated mutation with known risk factors that accounts for multiple family members being affected. For example, there can be clustering of H. pylori infection within families or there may be a predisposition to chronic inflammation of the mucous membrane lining the stomach (chronic atrophic gastritis). There are hereditary cancer syndromes (genetic disorders) that increase a person’s risk of develop stomach cancer (and often other types of cancer as well). About 1-3% of people with stomach cancer have an inherited cancer predisposition syndrome. These are inherited disorders in which affected individuals have a greater risk than the general population of developing cancer. These syndromes include hereditary diffuse gastric cancer (CDH1 mutations), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), familial intestinal gastric cancer (FIGC), hereditary breast and ovarian cancer (HBOC) syndrome (due to variations in the BRCA1 or BRCA2 gene); Lynch syndrome, which is also called hereditary non-polyposis colorectal cancer; familial adenomatous polyposis; Li-Fraumeni syndrome; and Peutz-Jeghers syndrome. Several different environmental factors have been associated with stomach cancer. Infection with Helicobacter pylori (H. pylori) is strongly associated with stomach cancer, especially cancer of the lower portion of the stomach. H. pylori is a type of bacterial infection that arises in the mucus layer of tissue that lines the stomach. This infection can cause inflammation and ulcers within the stomach. Long-term or chronic H. pylori infection is associated with marked inflammation and precancerous changes in the cells of the lining of the stomach. Most people who have H. pylori infection in the stomach never develop stomach cancer. Individuals who have a rare cancer called mucosa-associated lymphoid tissue (MALT) lymphoma are at a greater risk than the general population of developing adenocarcinoma of the stomach. Individuals with certain disorders including pernicious anemia, combined variable immunodeficiency, or Menetrier disease (hypertrophic gastropathy) are also at an increased risk of stomach cancer. There are noncancerous (benign), small growths (polyps) commonly found in the stomach. Many people have these polyps. A specific type of polyp called an adenoma can change and become cancerous. People who have had previous surgery on the stomach, such as for ulcers, are at an increased risk as well. Some studies suggest that a person’s diet can influence stomach cancer risk and that a diet high in salt and foods smoked or pickled in salt including certain meats or salted fish can increase the risk of stomach cancer. There are studies showing that a diet high in fried food, processed meats, and fish can increase the risk of stomach cancer. There are also studies that have shown that eating fruits and vegetables may help to prevent stomach cancer. The rate of stomach cancer is doubled in people who smoke. Smoking particularly increases the risk of stomach cancer near the esophagus. There is also an increased risk in people who work in certain industries where they are exposed to toxic materials including coal, metal, rubber industries (occupational exposure). Although the reason why is not known, people with type A blood also have a slightly increased risk of stomach cancer. Other potential factors have been suggested including obesity, alcohol consumption, and infection with Epstein-Barr virus, but the evidence is contradictory and such associations remain unproven. Gastroesophageal junction cancer can be associated with gastroesophageal reflux (GERD). GERD is a condition in which the contents of the stomach flow backward into the lower part of the esophagus.
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Affects of Stomach Cancer
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There are about 28,000 people diagnosed with stomach cancer in the United States each year. It affects men more often than it does women, and about 75% of people are over the age of 50. Most people are diagnosed between 60-80 years of age. By some estimates, stomach cancer is the second most common cancer worldwide. Stomach cancer can affect people of all races and ethnic groups but occurs with greater frequency in individuals of African or Hispanic heritage and Native Americans. Worldwide, stomach cancer is more common in East Asia, Eastern Europe, and South America.
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Affects of Stomach Cancer. There are about 28,000 people diagnosed with stomach cancer in the United States each year. It affects men more often than it does women, and about 75% of people are over the age of 50. Most people are diagnosed between 60-80 years of age. By some estimates, stomach cancer is the second most common cancer worldwide. Stomach cancer can affect people of all races and ethnic groups but occurs with greater frequency in individuals of African or Hispanic heritage and Native Americans. Worldwide, stomach cancer is more common in East Asia, Eastern Europe, and South America.
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Related disorders of Stomach Cancer
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Symptoms of the following disorders can be similar to those of stomach cancer. Comparisons may be useful for a differential diagnosis.There are a variety of conditions that can cause symptoms similar to those seen in stomach cancer. These conditions include forms of inflammation, irritation, or erosion of the lining of the stomach (gastritis) including acute gastritis, atrophic gastritis, and chronic gastritis. Esophageal cancer, narrowing (stricture) of the esophagus, and inflammation of the esophagus (esophagitis), peptic ulcer disease, viral gastroenteritis, and bacterial gastroenteritis can also produce similar symptoms. Gastrointestinal stromal tumors (GISTs) belong to a group of cancers known as soft tissue sarcomas. The number of new cases in the United States annually has been estimated to be 5,000-6,000. Tumors usually arise from the intestinal tract with the most common site being the stomach, followed by the small intestine, and then the colon/rectum with rare cases arising in the esophagus. There are also tumors that appear to arise in the membranous tissue lining the wall of the stomach (peritoneum) or in a fold of such membranous tissue (the omentum). There are also case reports of tumors arising in the appendix and/or pancreas. These tumors most commonly present with abdominal pain, bleeding or signs of intestinal obstruction. They spread most commonly to sites within the abdominal cavity and to the liver, although there are rare cases of spread to the lungs and bone. Some GISTs are noncancerous (benign) and do not spread (indolent); others are aggressive with extensive local invasion as well as distant metastases. Most cases result from a change (mutation) in one of two genes, KIT or PDGFR, which leads to continued growth and division of tumor cells. There are a few reported cases of families in which a gene mutation is inherited; however, the majority of tumors occur randomly for no apparent reason (sporadically) and not inherited (acquired mutation). Most cases arise in older adults. (For more information on this disorder, choose “GIST” as your search term in the Rare Disease Database.)Primary gastric lymphoma is a general term for a type of cancer that originates within the stomach. Approximately 90 percent of patients of primary gastric lymphoma are either mucosa-associated lymphoid tissue (MALT) gastric lymphoma or diffuse large B-cell lymphoma (DLBCL) of the stomach. MALT gastric lymphoma is often associated with infection with the Helicobacter pylori bacterium. Within the medical literature, significant controversy exists regarding the exact definition, classification and staging of primary gastric lymphoma. (For more information on this disorder, choose “primary gastric lymphoma” as your search term in the Rare Disease Database.)
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Related disorders of Stomach Cancer. Symptoms of the following disorders can be similar to those of stomach cancer. Comparisons may be useful for a differential diagnosis.There are a variety of conditions that can cause symptoms similar to those seen in stomach cancer. These conditions include forms of inflammation, irritation, or erosion of the lining of the stomach (gastritis) including acute gastritis, atrophic gastritis, and chronic gastritis. Esophageal cancer, narrowing (stricture) of the esophagus, and inflammation of the esophagus (esophagitis), peptic ulcer disease, viral gastroenteritis, and bacterial gastroenteritis can also produce similar symptoms. Gastrointestinal stromal tumors (GISTs) belong to a group of cancers known as soft tissue sarcomas. The number of new cases in the United States annually has been estimated to be 5,000-6,000. Tumors usually arise from the intestinal tract with the most common site being the stomach, followed by the small intestine, and then the colon/rectum with rare cases arising in the esophagus. There are also tumors that appear to arise in the membranous tissue lining the wall of the stomach (peritoneum) or in a fold of such membranous tissue (the omentum). There are also case reports of tumors arising in the appendix and/or pancreas. These tumors most commonly present with abdominal pain, bleeding or signs of intestinal obstruction. They spread most commonly to sites within the abdominal cavity and to the liver, although there are rare cases of spread to the lungs and bone. Some GISTs are noncancerous (benign) and do not spread (indolent); others are aggressive with extensive local invasion as well as distant metastases. Most cases result from a change (mutation) in one of two genes, KIT or PDGFR, which leads to continued growth and division of tumor cells. There are a few reported cases of families in which a gene mutation is inherited; however, the majority of tumors occur randomly for no apparent reason (sporadically) and not inherited (acquired mutation). Most cases arise in older adults. (For more information on this disorder, choose “GIST” as your search term in the Rare Disease Database.)Primary gastric lymphoma is a general term for a type of cancer that originates within the stomach. Approximately 90 percent of patients of primary gastric lymphoma are either mucosa-associated lymphoid tissue (MALT) gastric lymphoma or diffuse large B-cell lymphoma (DLBCL) of the stomach. MALT gastric lymphoma is often associated with infection with the Helicobacter pylori bacterium. Within the medical literature, significant controversy exists regarding the exact definition, classification and staging of primary gastric lymphoma. (For more information on this disorder, choose “primary gastric lymphoma” as your search term in the Rare Disease Database.)
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Diagnosis of Stomach Cancer
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A diagnosis of stomach cancer is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Because stomach cancer does not usually cause symptoms in the early stages of the disease, it is often not diagnosed until the disease is advanced. There is no screening program for stomach cancer in the United States or Europe, although there are programs in other countries including Japan and Korea. Clinical Testing and Workup
A complete blood count is a standard blood test. This test can be ordered if stomach or gastrointestinal cancer is suspected to detect low levels of circulating red blood cells (anemia), which can occur due to blood loss. Another test that can be ordered is a fecal occult blood test. This test examines the stool for the presence of blood that is not visible to the naked eye. Doctors may order an upper endoscopy examination in individuals suspected of stomach cancer. This examination allows doctors to view the upper portion of the digestive tract including the esophagus, stomach, and the duodenum. During this examination, doctors will run a thin, flexible tube down a person’s throat. This tube has a tiny camera attached to it that allows doctors to visually inspect these areas. If an abnormal growth or abnormal tissue is seen, doctors can pass instruments through the tube that allow them to remove a sample of tissue. Any tissue samples that are taken are then viewed under a microscope. The surgical removal and microscopic examination of a tissue sample is called a biopsy. This biopsy sample is then studied by a pathologist, who is a specialist trained in examining tissues and cells to find disease and determine what disease is present.Doctors may also order advancing imaging (x-ray) techniques, specially computed tomography along with endoscopic ultrasonography. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Doctors will examine the chest and abdomen to determine whether stomach cancer has spread (metastasized) to these sites. An endoscopic ultrasonography is performed to determine the depth and exact location of the tumor and determine whether the cancer has spread into the wall of the stomach or is affecting any of the nearby lymph nodes. Ultrasounds use high-frequency radio waves to create a picture or image (sonogram) of specific structures like internal organs. The radio waves bounce off of (echo) internal structures within the body and the echoes are recorded to create a sonogram.Sometimes, a double-contrast gastrointestinal series may be recommended. This examination uses x-rays along with a barium swallow. Barium is a chalky, white, metallic element. An affected individual will swallow a solution containing barium, which coats the esophagus, stomach, and small intestines. X-rays cannot pass through barium so the x-ray file will be able to outline structures or tissues in these areas. This will help doctors determine the presence and extent of the disease. In some instances, doctors may recommend laparoscopy or laparotomy to obtain biopsy samples and help stage the cancer. Laparoscopy involves examination of the abdominal cavity with an illuminated viewing tube (laparoscope) inserted through incisions in the abdominal wall. Laparotomy is a surgical procedure in which the abdomen is opened, organs are carefully examined to detect signs of disease, and samples of tissue are removed for microscopic examination. Sometimes, fluid samples are taken and studied. This can include fluid from the abdomen when ascites is present. Staging
When an individual is diagnosed with stomach cancer, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging stomach carcinoma (e.g., blood tests, CT scanning,). Stomach cancer can be staged by the American Joint Committee on Cancer (AJCC)/the Union for International Cancer Control (UICC) system, which is based on the Tumor, Node, Metastasis (TNM) classification system. Information on this staging system for stomach cancer is available from the American Cancer Society at: https://www.cancer.org/cancer/stomach-cancer/detection-diagnosis-staging/staging.html
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Diagnosis of Stomach Cancer. A diagnosis of stomach cancer is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Because stomach cancer does not usually cause symptoms in the early stages of the disease, it is often not diagnosed until the disease is advanced. There is no screening program for stomach cancer in the United States or Europe, although there are programs in other countries including Japan and Korea. Clinical Testing and Workup
A complete blood count is a standard blood test. This test can be ordered if stomach or gastrointestinal cancer is suspected to detect low levels of circulating red blood cells (anemia), which can occur due to blood loss. Another test that can be ordered is a fecal occult blood test. This test examines the stool for the presence of blood that is not visible to the naked eye. Doctors may order an upper endoscopy examination in individuals suspected of stomach cancer. This examination allows doctors to view the upper portion of the digestive tract including the esophagus, stomach, and the duodenum. During this examination, doctors will run a thin, flexible tube down a person’s throat. This tube has a tiny camera attached to it that allows doctors to visually inspect these areas. If an abnormal growth or abnormal tissue is seen, doctors can pass instruments through the tube that allow them to remove a sample of tissue. Any tissue samples that are taken are then viewed under a microscope. The surgical removal and microscopic examination of a tissue sample is called a biopsy. This biopsy sample is then studied by a pathologist, who is a specialist trained in examining tissues and cells to find disease and determine what disease is present.Doctors may also order advancing imaging (x-ray) techniques, specially computed tomography along with endoscopic ultrasonography. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Doctors will examine the chest and abdomen to determine whether stomach cancer has spread (metastasized) to these sites. An endoscopic ultrasonography is performed to determine the depth and exact location of the tumor and determine whether the cancer has spread into the wall of the stomach or is affecting any of the nearby lymph nodes. Ultrasounds use high-frequency radio waves to create a picture or image (sonogram) of specific structures like internal organs. The radio waves bounce off of (echo) internal structures within the body and the echoes are recorded to create a sonogram.Sometimes, a double-contrast gastrointestinal series may be recommended. This examination uses x-rays along with a barium swallow. Barium is a chalky, white, metallic element. An affected individual will swallow a solution containing barium, which coats the esophagus, stomach, and small intestines. X-rays cannot pass through barium so the x-ray file will be able to outline structures or tissues in these areas. This will help doctors determine the presence and extent of the disease. In some instances, doctors may recommend laparoscopy or laparotomy to obtain biopsy samples and help stage the cancer. Laparoscopy involves examination of the abdominal cavity with an illuminated viewing tube (laparoscope) inserted through incisions in the abdominal wall. Laparotomy is a surgical procedure in which the abdomen is opened, organs are carefully examined to detect signs of disease, and samples of tissue are removed for microscopic examination. Sometimes, fluid samples are taken and studied. This can include fluid from the abdomen when ascites is present. Staging
When an individual is diagnosed with stomach cancer, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging stomach carcinoma (e.g., blood tests, CT scanning,). Stomach cancer can be staged by the American Joint Committee on Cancer (AJCC)/the Union for International Cancer Control (UICC) system, which is based on the Tumor, Node, Metastasis (TNM) classification system. Information on this staging system for stomach cancer is available from the American Cancer Society at: https://www.cancer.org/cancer/stomach-cancer/detection-diagnosis-staging/staging.html
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Therapies of Stomach Cancer
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Treatment
The therapeutic management of individuals with stomach cancer may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of diseases of the digestive system (gastroenterologists), physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who specialize in the diagnosis and treatment of cancer with surgery (surgical oncologists), physicians who specialize in the use of radiation therapy for treatment of cancer (radiation oncologists), oncology nurses, psychiatrists, nutritionists, and other healthcare specialists. Psychosocial support for the entire family is essential as well. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific stomach cancer subtype; whether the cancer has spread; the presence or absence of certain symptoms; an individual's age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Surgery is a main therapeutic option for stomach cancer. The exact surgery and extent of surgery depends upon the type and stage of the cancer. Surgery can include endoscopic resection, in which the cancer has not spread to nearby lymph nodes. Surgeons run a thin, flexible tube down the throat to the stomach. They are able to guide tools down the tube that allow them to surgically remove the tumor and any affected tissue from the stomach wall. Gastric cancer diagnosed in the United States is rarely thin and small enough to allow for endoscopic resection. In addition, this technique is dependent upon the expertise of the physician performing the procedure.For most patients with gastric cancer confined to the stomach and adjacent lymph nodes, surgeons need to remove some of the stomach along with the tumor. This is called a subtotal (partial) gastrectomy. If the cancer is in the upper part of the stomach, sometimes some of the esophagus may also need to be removed. If the cancer is in the lower part of the stomach, sometimes some of the upper portion of the lower intestines called the duodenum may need to be removed. Sometimes, surgeons must remove the entire stomach and some of the surrounding tissue. This is called a total gastrectomy. It is most often recommended when cancer has spread throughout the stomach. During this surgery the end of the esophagus is connected directly to the duodenum to allow the passage of food. A common part of the surgery to remove part or all of the stomach is to remove adjacent lymph nodes. This part of surgery may be referred to as lymph node dissection or lymphadenopathy.Sometimes chemotherapy or radiation therapy may be before or after surgery. This is called neoadjuvant or adjuvant therapy. When used along with surgery, chemotherapy may be given before surgery (neoadjuvant) to shrink a tumor or following surgery (adjuvant) to eliminate any remaining cancer cells and lessen the risk of a recurrence. Sometimes, chemotherapy may be given before and after surgery (perioperative). Different combinations of medications may be used; this is called a chemotherapy regimen. When chemotherapy is given, the specific chemotherapy regimen used can vary. Different medical centers may have their own preferences as to the best way to approach treatment and what chemotherapeutic regimen is best for each individual.5FU/leucovorin and oxaliplatin are often used as the first therapy for the treatment of stomach cancer that is locally advanced or has spread to other parts of the body. Docetaxel (Taxotere) is approved for adenocarcinoma of the stomach or gastroesophageal junction that is advanced in people who have not been treated with chemotherapy for advanced disease. Radiation therapy may also be used as an adjuvant therapy. Radiation therapy is the use of high doses of radiation to kill cancer cells and shrink tumors. Radiation therapy preferentially destroys or injures rapidly-dividing cells, primarily cancerous cells. Radiation is passed through affected tissue to destroy cancer cells while minimizing exposure and damage to normal cells. Radiation therapy works to destroy cancer cells by depositing energy that damages the cells’ genetic material, preventing or slowing their growth and replication. Radiation therapy is sometimes given at the same time as chemotherapy (chemoradiotherapy). For example, when treating cancer of the gastroesophageal junction chemoradiotherapy is often given following surgery.The eradication of H. pylori infection with antibacterial medications is important. TARGETED THERAPIES
Targeted therapies target a specific molecule, protein or substance in order to block the growth and spread of cancer rather than destroy cancer cells (cytotoxic treatments) like chemotherapy or radiation therapy. Targeted therapies are less likely to damage healthy cells. There are a few targeted therapies that have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of stomach cancer. In 2010, the FDA approved Herceptin (trastuzumab) along with chemotherapy for the treatment of stomach or gastroesophageal cancer (adenocarcinomas) that produce too much HER2 protein and has spread (metastasized). Affected individuals must have not yet received other treatment for metastatic disease.In 2015, the FDA approved Cyramza (ramucirumab) for the treatment of advanced stomach cancer or gastroesophageal junction cancer that has not responded to other treatments. In 2017, the FDA granted accelerated approval of Keytruda (pembrolizumab) for the treatment of stomach cancer or gastroesophageal junction cancer that is recurrent and locally advanced or has spread (metastatic). It is approved for affected individuals whose cancer has the PD-1 protein and has worsened despite two or more other therapies. Pembrolizumab is a type of new therapy called immunotherapy. This type of treatment aims to enhance the body’s innate ability to fight cancer cells using the immune system. For example, the most common form of immunotherapy called PD-1 or PD-L1 blockade releases the “brakes” on the immune system that some cancers use to try to evade the immune cells.Most recently, in 2021, the FDA approved Opdivo (nivolumab) in combination with certain types of chemotherapy for the initial treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma. This is the first FDA-approved immunotherapy for the first-line treatment of gastric cancer.
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Therapies of Stomach Cancer. Treatment
The therapeutic management of individuals with stomach cancer may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of diseases of the digestive system (gastroenterologists), physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who specialize in the diagnosis and treatment of cancer with surgery (surgical oncologists), physicians who specialize in the use of radiation therapy for treatment of cancer (radiation oncologists), oncology nurses, psychiatrists, nutritionists, and other healthcare specialists. Psychosocial support for the entire family is essential as well. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific stomach cancer subtype; whether the cancer has spread; the presence or absence of certain symptoms; an individual's age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Surgery is a main therapeutic option for stomach cancer. The exact surgery and extent of surgery depends upon the type and stage of the cancer. Surgery can include endoscopic resection, in which the cancer has not spread to nearby lymph nodes. Surgeons run a thin, flexible tube down the throat to the stomach. They are able to guide tools down the tube that allow them to surgically remove the tumor and any affected tissue from the stomach wall. Gastric cancer diagnosed in the United States is rarely thin and small enough to allow for endoscopic resection. In addition, this technique is dependent upon the expertise of the physician performing the procedure.For most patients with gastric cancer confined to the stomach and adjacent lymph nodes, surgeons need to remove some of the stomach along with the tumor. This is called a subtotal (partial) gastrectomy. If the cancer is in the upper part of the stomach, sometimes some of the esophagus may also need to be removed. If the cancer is in the lower part of the stomach, sometimes some of the upper portion of the lower intestines called the duodenum may need to be removed. Sometimes, surgeons must remove the entire stomach and some of the surrounding tissue. This is called a total gastrectomy. It is most often recommended when cancer has spread throughout the stomach. During this surgery the end of the esophagus is connected directly to the duodenum to allow the passage of food. A common part of the surgery to remove part or all of the stomach is to remove adjacent lymph nodes. This part of surgery may be referred to as lymph node dissection or lymphadenopathy.Sometimes chemotherapy or radiation therapy may be before or after surgery. This is called neoadjuvant or adjuvant therapy. When used along with surgery, chemotherapy may be given before surgery (neoadjuvant) to shrink a tumor or following surgery (adjuvant) to eliminate any remaining cancer cells and lessen the risk of a recurrence. Sometimes, chemotherapy may be given before and after surgery (perioperative). Different combinations of medications may be used; this is called a chemotherapy regimen. When chemotherapy is given, the specific chemotherapy regimen used can vary. Different medical centers may have their own preferences as to the best way to approach treatment and what chemotherapeutic regimen is best for each individual.5FU/leucovorin and oxaliplatin are often used as the first therapy for the treatment of stomach cancer that is locally advanced or has spread to other parts of the body. Docetaxel (Taxotere) is approved for adenocarcinoma of the stomach or gastroesophageal junction that is advanced in people who have not been treated with chemotherapy for advanced disease. Radiation therapy may also be used as an adjuvant therapy. Radiation therapy is the use of high doses of radiation to kill cancer cells and shrink tumors. Radiation therapy preferentially destroys or injures rapidly-dividing cells, primarily cancerous cells. Radiation is passed through affected tissue to destroy cancer cells while minimizing exposure and damage to normal cells. Radiation therapy works to destroy cancer cells by depositing energy that damages the cells’ genetic material, preventing or slowing their growth and replication. Radiation therapy is sometimes given at the same time as chemotherapy (chemoradiotherapy). For example, when treating cancer of the gastroesophageal junction chemoradiotherapy is often given following surgery.The eradication of H. pylori infection with antibacterial medications is important. TARGETED THERAPIES
Targeted therapies target a specific molecule, protein or substance in order to block the growth and spread of cancer rather than destroy cancer cells (cytotoxic treatments) like chemotherapy or radiation therapy. Targeted therapies are less likely to damage healthy cells. There are a few targeted therapies that have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of stomach cancer. In 2010, the FDA approved Herceptin (trastuzumab) along with chemotherapy for the treatment of stomach or gastroesophageal cancer (adenocarcinomas) that produce too much HER2 protein and has spread (metastasized). Affected individuals must have not yet received other treatment for metastatic disease.In 2015, the FDA approved Cyramza (ramucirumab) for the treatment of advanced stomach cancer or gastroesophageal junction cancer that has not responded to other treatments. In 2017, the FDA granted accelerated approval of Keytruda (pembrolizumab) for the treatment of stomach cancer or gastroesophageal junction cancer that is recurrent and locally advanced or has spread (metastatic). It is approved for affected individuals whose cancer has the PD-1 protein and has worsened despite two or more other therapies. Pembrolizumab is a type of new therapy called immunotherapy. This type of treatment aims to enhance the body’s innate ability to fight cancer cells using the immune system. For example, the most common form of immunotherapy called PD-1 or PD-L1 blockade releases the “brakes” on the immune system that some cancers use to try to evade the immune cells.Most recently, in 2021, the FDA approved Opdivo (nivolumab) in combination with certain types of chemotherapy for the initial treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma. This is the first FDA-approved immunotherapy for the first-line treatment of gastric cancer.
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Overview of Sturge Weber Syndrome
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SummarySturge-Weber syndrome (SWS) is a rare vascular disorder characterized by the association of a facial birthmark called a port-wine birthmark, abnormal blood vessels in the brain, and eye abnormalities such as glaucoma. SWS can be thought of as a spectrum of disease in which individuals may have abnormalities affecting all three of these systems (i.e. brain, skin and eyes), or only two, or only one. Consequently, the specific symptoms and severity of the disorder can vary dramatically from one person to another. Symptoms are usually present at birth (congenital), yet the disorder is not inherited and does not run in families. Some symptoms may not develop until adulthood. SWS is caused by a somatic mutation, most commonly in the GNAQ gene. This mutation occurs randomly (sporadically) for no known reason.IntroductionSWS may be classified as a neurocutaneous syndrome or one of the phakomatoses. Neurocutaneous syndromes or phakomatoses are broad terms for groups of disorders in which “growths” develop in the skin, brain, spinal cord, bones and sometimes other organs of the body. In the case of SWS, these “growths” are malformations of abnormal blood vessels.Some publications break down SWS into three main subtypes. Type 1 consists of skin and neurological symptoms. These individuals may or may not have glaucoma. Type 2 consists of skin symptoms and possibly glaucoma, but there is no evidence of neurological involvement. Type 3 consists of neurological involvement, but without skin abnormalities. Glaucoma is usually not present. Type 3 may also be known as the isolated neurological variant.
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Overview of Sturge Weber Syndrome. SummarySturge-Weber syndrome (SWS) is a rare vascular disorder characterized by the association of a facial birthmark called a port-wine birthmark, abnormal blood vessels in the brain, and eye abnormalities such as glaucoma. SWS can be thought of as a spectrum of disease in which individuals may have abnormalities affecting all three of these systems (i.e. brain, skin and eyes), or only two, or only one. Consequently, the specific symptoms and severity of the disorder can vary dramatically from one person to another. Symptoms are usually present at birth (congenital), yet the disorder is not inherited and does not run in families. Some symptoms may not develop until adulthood. SWS is caused by a somatic mutation, most commonly in the GNAQ gene. This mutation occurs randomly (sporadically) for no known reason.IntroductionSWS may be classified as a neurocutaneous syndrome or one of the phakomatoses. Neurocutaneous syndromes or phakomatoses are broad terms for groups of disorders in which “growths” develop in the skin, brain, spinal cord, bones and sometimes other organs of the body. In the case of SWS, these “growths” are malformations of abnormal blood vessels.Some publications break down SWS into three main subtypes. Type 1 consists of skin and neurological symptoms. These individuals may or may not have glaucoma. Type 2 consists of skin symptoms and possibly glaucoma, but there is no evidence of neurological involvement. Type 3 consists of neurological involvement, but without skin abnormalities. Glaucoma is usually not present. Type 3 may also be known as the isolated neurological variant.
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Symptoms of Sturge Weber Syndrome
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SWS is a highly variable disorder. Some individuals may develop characteristic skin abnormalities, but no neurological abnormalities. Less often, individuals develop neurological abnormalities without the characteristic skin issues. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every individual patient is unique. Parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.A congenital facial birthmark known as a capillary malformation (port-wine birthmark or nevus flammeus) is often the most notable initial symptom. This birthmark can range from light pink to reddish to dark purple in color. The size of a port-wine birthmark can vary. Usually, at least one eyelid, temple area, and/or the forehead of one side of the face are affected; both sides of the face have been affected less often. In some children, the entire half of one, or both, side of the face may be affected. Sometimes, the discoloration may extend slightly onto the other side of the face or both sides of the face may be extensively involved. Rarely, a port-wine birthmark extends all the way to the trunk and/or arms. The port-wine birthmark that characterizes SWS is caused by an overabundance of capillaries just below the surface of the skin. Capillaries are tiny blood vessels that form a fine network throughout the body connecting arteries and veins and are responsible for the exchange of various substances such as oxygen between cells and tissue. If untreated, port-wine birthmarks may deepen in color with age, thicken, and potentially develop blood blisters (blebs) that can burst causing spontaneously bleeding.The abnormal blood vessels that make up a port-wine birthmark will vary in size, diameter, distribution, and depth from one individual to another and even within the same person in different affected areas. This means that a port-wine birthmark in each individual is unique and can be quite dissimilar from one person to another.Individuals with SWS may also experience a variety of neurological abnormalities. The extent of neurological involvement can vary dramatically from one person to another. Neurological symptoms are caused by the abnormal malformation of blood vessels on the surface of the brain (leptomeningeal angiomas). Seizures, which often begin in infancy or childhood, are a common finding. Seizures usually affect the opposite side of the body as the brain involvement (and the port-wine birthmark), but sometimes affect both sides of the body. Seizures may vary in frequency and intensity and sometimes may worsen in severity and frequency with age. Affected individuals may also experience muscle weakness or paralysis on one side of the body (hemiparesis), usually on the side opposite the brain involvement and the port-wine birthmark. Developmental delays and intellectual disability ranging from mild learning disabilities to severe cognitive deficits may occur in pediatric patients and may lead to lower cognitive function and quality of life; in other children, intelligence and cognition are unaffected. In patients with severe or uncontrolled seizures, cognitive impairments are common. Younger age at seizure onset is associated with lower cognitive function and quality of life. In addition, greater extensive skin involvement, bilateral glaucoma, and greater total Sturge-Weber involvements are associated with lower quality of life. Physical and family histories are associated with neurological and cognitive development in SWS patients as well. Patients with bilateral brain involvement are more likely to have learning disabilities and intellectual disability, while the extent of the port-wine birthmark is associated with epilepsy. Family history of birthmarks is associated with symptomatic strokes, and family history of seizures is associated with earlier seizure onset. Earlier seizure onset is associated with learning disabilities, intellectual disability, stroke-like episodes, symptomatic strokes, hemiparesis, visual field deficit, and brain surgery. Headaches, including migraines, and visual field defects such as the loss of vision in half the visual field in one or both eyes (hemaniopsia) may also occur. There is a risk of stroke, stroke-like episodes or mini-strokes (transient ischemic attacks). Stroke-like episodes can be associated with temporary (transient) weakness or paralysis of half of the body and visual field defects. Behavioral problems such as attention deficit disorder, mood disorders, and poorer social skills have also been seen in some children, particularly those with lower cognitive function and a greater frequency of seizures.Some children are born with, or develop, glaucoma, a condition marked by increased pressure within the eye. Glaucoma usually affects the eye on the same side of the face as the port-wine birthmark. Glaucoma can potentially damage the optic nerve, the main nerve that transmits signals from the eye to the brain, ultimately resulting in progressive vision loss. The same eye also may become enlarged and appear to bulge out or to enlarge its socket (buphthalmos).Other eye abnormalities can occur including the development of angiomas in the membranes that line the inner surface of the eyelids (conjunctiva), the layer of blood vessels and connective tissue (choroid) between the white of the eye and the retina, and the clear, transparent membrane covering the membrane (cornea). An affected individual’s eyes can be two different colors (e.g. one brown and one blue eye). Additional ocular symptoms can include an abnormal accumulation of fluid inside the eyeball causing enlargement of the eyeball (hydrophthalmos), degeneration of the cranial nerve that transmit lights signals to the brain (optic atrophy), clouding or displacement of the lenses, retinal detachment, streaks resembling blood vessels in the retina (angioid streaks), and/or loss of vision due to an organic lesion in the visual cortex (cortical blindness). Individuals who have neurological abnormalities, but do not have a port-wine birthmark generally do not develop eye problems, but can have cortical blindness presenting as visual field deficits.Endocrine disorders have also been reported in some individuals including central hypothyroidism and an increased risk of growth hormone deficiency. Central hypothyroidism is characterized by underactivity of the thyroid gland due to insufficient stimulation of thyroid stimulating hormone in an otherwise healthy thyroid. Central hypothyroidism in SWS may be due to anti-seizure medication.Additional symptoms may occur including an abnormally large head (macrocephaly), overgrowth (hypertrophy) of the certain soft tissues underlying the port-wine birthmark, and lymphatic malformations, which are non-malignant masses consisting of fluid-filled channels or spaces thought to be caused by abnormal development of the lymphatic system. These symptoms are consistent with a related rare disorder known as Klippel-Trenaunay syndrome (KTS) and most children with these findings are classified as having KTS. Patients with these issues or presenting with other atypical features should have genetic testing as several somatic mutations have been associated with SWS and KTS including gene mutations in GNAQ, GNAQ11, PIK3CA and others.
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Symptoms of Sturge Weber Syndrome. SWS is a highly variable disorder. Some individuals may develop characteristic skin abnormalities, but no neurological abnormalities. Less often, individuals develop neurological abnormalities without the characteristic skin issues. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every individual patient is unique. Parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.A congenital facial birthmark known as a capillary malformation (port-wine birthmark or nevus flammeus) is often the most notable initial symptom. This birthmark can range from light pink to reddish to dark purple in color. The size of a port-wine birthmark can vary. Usually, at least one eyelid, temple area, and/or the forehead of one side of the face are affected; both sides of the face have been affected less often. In some children, the entire half of one, or both, side of the face may be affected. Sometimes, the discoloration may extend slightly onto the other side of the face or both sides of the face may be extensively involved. Rarely, a port-wine birthmark extends all the way to the trunk and/or arms. The port-wine birthmark that characterizes SWS is caused by an overabundance of capillaries just below the surface of the skin. Capillaries are tiny blood vessels that form a fine network throughout the body connecting arteries and veins and are responsible for the exchange of various substances such as oxygen between cells and tissue. If untreated, port-wine birthmarks may deepen in color with age, thicken, and potentially develop blood blisters (blebs) that can burst causing spontaneously bleeding.The abnormal blood vessels that make up a port-wine birthmark will vary in size, diameter, distribution, and depth from one individual to another and even within the same person in different affected areas. This means that a port-wine birthmark in each individual is unique and can be quite dissimilar from one person to another.Individuals with SWS may also experience a variety of neurological abnormalities. The extent of neurological involvement can vary dramatically from one person to another. Neurological symptoms are caused by the abnormal malformation of blood vessels on the surface of the brain (leptomeningeal angiomas). Seizures, which often begin in infancy or childhood, are a common finding. Seizures usually affect the opposite side of the body as the brain involvement (and the port-wine birthmark), but sometimes affect both sides of the body. Seizures may vary in frequency and intensity and sometimes may worsen in severity and frequency with age. Affected individuals may also experience muscle weakness or paralysis on one side of the body (hemiparesis), usually on the side opposite the brain involvement and the port-wine birthmark. Developmental delays and intellectual disability ranging from mild learning disabilities to severe cognitive deficits may occur in pediatric patients and may lead to lower cognitive function and quality of life; in other children, intelligence and cognition are unaffected. In patients with severe or uncontrolled seizures, cognitive impairments are common. Younger age at seizure onset is associated with lower cognitive function and quality of life. In addition, greater extensive skin involvement, bilateral glaucoma, and greater total Sturge-Weber involvements are associated with lower quality of life. Physical and family histories are associated with neurological and cognitive development in SWS patients as well. Patients with bilateral brain involvement are more likely to have learning disabilities and intellectual disability, while the extent of the port-wine birthmark is associated with epilepsy. Family history of birthmarks is associated with symptomatic strokes, and family history of seizures is associated with earlier seizure onset. Earlier seizure onset is associated with learning disabilities, intellectual disability, stroke-like episodes, symptomatic strokes, hemiparesis, visual field deficit, and brain surgery. Headaches, including migraines, and visual field defects such as the loss of vision in half the visual field in one or both eyes (hemaniopsia) may also occur. There is a risk of stroke, stroke-like episodes or mini-strokes (transient ischemic attacks). Stroke-like episodes can be associated with temporary (transient) weakness or paralysis of half of the body and visual field defects. Behavioral problems such as attention deficit disorder, mood disorders, and poorer social skills have also been seen in some children, particularly those with lower cognitive function and a greater frequency of seizures.Some children are born with, or develop, glaucoma, a condition marked by increased pressure within the eye. Glaucoma usually affects the eye on the same side of the face as the port-wine birthmark. Glaucoma can potentially damage the optic nerve, the main nerve that transmits signals from the eye to the brain, ultimately resulting in progressive vision loss. The same eye also may become enlarged and appear to bulge out or to enlarge its socket (buphthalmos).Other eye abnormalities can occur including the development of angiomas in the membranes that line the inner surface of the eyelids (conjunctiva), the layer of blood vessels and connective tissue (choroid) between the white of the eye and the retina, and the clear, transparent membrane covering the membrane (cornea). An affected individual’s eyes can be two different colors (e.g. one brown and one blue eye). Additional ocular symptoms can include an abnormal accumulation of fluid inside the eyeball causing enlargement of the eyeball (hydrophthalmos), degeneration of the cranial nerve that transmit lights signals to the brain (optic atrophy), clouding or displacement of the lenses, retinal detachment, streaks resembling blood vessels in the retina (angioid streaks), and/or loss of vision due to an organic lesion in the visual cortex (cortical blindness). Individuals who have neurological abnormalities, but do not have a port-wine birthmark generally do not develop eye problems, but can have cortical blindness presenting as visual field deficits.Endocrine disorders have also been reported in some individuals including central hypothyroidism and an increased risk of growth hormone deficiency. Central hypothyroidism is characterized by underactivity of the thyroid gland due to insufficient stimulation of thyroid stimulating hormone in an otherwise healthy thyroid. Central hypothyroidism in SWS may be due to anti-seizure medication.Additional symptoms may occur including an abnormally large head (macrocephaly), overgrowth (hypertrophy) of the certain soft tissues underlying the port-wine birthmark, and lymphatic malformations, which are non-malignant masses consisting of fluid-filled channels or spaces thought to be caused by abnormal development of the lymphatic system. These symptoms are consistent with a related rare disorder known as Klippel-Trenaunay syndrome (KTS) and most children with these findings are classified as having KTS. Patients with these issues or presenting with other atypical features should have genetic testing as several somatic mutations have been associated with SWS and KTS including gene mutations in GNAQ, GNAQ11, PIK3CA and others.
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Causes of Sturge Weber Syndrome
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SWS is usually caused by a somatic mutation in the GNAQ gene. This genetic mutation is a somatic mutation because it occurs after fertilization of the embryo; in the case of SWS, mutation most likely occurs at an early stage of embryonic development. By definition, a somatic mutation can occur in any cell of the body except the sex cells (sperm and egg). Affected individuals will have some cells with a normal copy of the gene and some cells with the abnormal gene (mosaic pattern). This may be referred to as having two distinct cells lines in the body. The variability of symptoms associated with SWS is due, in part, to the ratio of healthy cells to abnormal cells in the body and the types of cells that are affected. Somatic mutations are not inherited and are not passed on to children. Researchers think that somatic mutations of the GNAQ gene occur randomly for no apparent reason (sporadically).Genes provide instructions for creating proteins that play a critical role in many functions of the body. When there is a gene mutation, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The GNAQ gene creates G protein alpha subunit q (Gaq) that plays an important role in cell function, including the regulation of blood vessels. 90% of SWS patients have R183Q mutations in GNAQ which leads to over-activation of downstream pathways to Gaq. This hyperactivation, in turn, leads to congenital vascular abnormalities. While most SWS patients have an activating mutation in GNAQ, recent research demonstrates that mutations in a similar gene called GNA11 can lead to SWS as well.As discussed above, symptoms are caused, in part, by the abnormal development, growth, and proliferation of certain blood vessels. These blood vessel abnormalities often result in secondary effects to the affected tissue including lack of oxygen in affected body tissue (hypoxia), inadequate blood supply to affected areas (ischemia), obstruction of affected veins (venous occlusion), the formation of blood clots (thrombosis), and/or tissue death caused by lack of oxygen (infarction). Calcification of affected areas of the brain may also occur.A mutation in the GNAQ gene can also cause a form of skin cancer (melanoma) that affects the eye (uveal melanoma). GNAQ mutations associated with uveal melanoma affect specific cells known as melanocytes. The mutation in people with uveal melanoma occurs in adulthood as opposed to before birth as it does in people with SWS. Therefore, the specific cells involved and the age of an individual when a mutation in GNAQ occurs is extremely important and can cause different disorders or physical findings.
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Causes of Sturge Weber Syndrome. SWS is usually caused by a somatic mutation in the GNAQ gene. This genetic mutation is a somatic mutation because it occurs after fertilization of the embryo; in the case of SWS, mutation most likely occurs at an early stage of embryonic development. By definition, a somatic mutation can occur in any cell of the body except the sex cells (sperm and egg). Affected individuals will have some cells with a normal copy of the gene and some cells with the abnormal gene (mosaic pattern). This may be referred to as having two distinct cells lines in the body. The variability of symptoms associated with SWS is due, in part, to the ratio of healthy cells to abnormal cells in the body and the types of cells that are affected. Somatic mutations are not inherited and are not passed on to children. Researchers think that somatic mutations of the GNAQ gene occur randomly for no apparent reason (sporadically).Genes provide instructions for creating proteins that play a critical role in many functions of the body. When there is a gene mutation, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The GNAQ gene creates G protein alpha subunit q (Gaq) that plays an important role in cell function, including the regulation of blood vessels. 90% of SWS patients have R183Q mutations in GNAQ which leads to over-activation of downstream pathways to Gaq. This hyperactivation, in turn, leads to congenital vascular abnormalities. While most SWS patients have an activating mutation in GNAQ, recent research demonstrates that mutations in a similar gene called GNA11 can lead to SWS as well.As discussed above, symptoms are caused, in part, by the abnormal development, growth, and proliferation of certain blood vessels. These blood vessel abnormalities often result in secondary effects to the affected tissue including lack of oxygen in affected body tissue (hypoxia), inadequate blood supply to affected areas (ischemia), obstruction of affected veins (venous occlusion), the formation of blood clots (thrombosis), and/or tissue death caused by lack of oxygen (infarction). Calcification of affected areas of the brain may also occur.A mutation in the GNAQ gene can also cause a form of skin cancer (melanoma) that affects the eye (uveal melanoma). GNAQ mutations associated with uveal melanoma affect specific cells known as melanocytes. The mutation in people with uveal melanoma occurs in adulthood as opposed to before birth as it does in people with SWS. Therefore, the specific cells involved and the age of an individual when a mutation in GNAQ occurs is extremely important and can cause different disorders or physical findings.
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Affects of Sturge Weber Syndrome
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SWS affects males and females in equal numbers. The exact incidence and prevalence is unknown. One estimate places the incidence at 1 in 20,000-50,000 live births. Approximately 3 in 1,000 babies are born with a port-wine birthmark, but only approximately 6% of individuals with a port-wine birthmark on the face develop the neurological abnormalities associated with SWS. The risk increases to 20-50% when the port-wine birthmark is on the forehead, temple region or upper part of the face. SWS can affect individuals of any race or ethnicity.
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Affects of Sturge Weber Syndrome. SWS affects males and females in equal numbers. The exact incidence and prevalence is unknown. One estimate places the incidence at 1 in 20,000-50,000 live births. Approximately 3 in 1,000 babies are born with a port-wine birthmark, but only approximately 6% of individuals with a port-wine birthmark on the face develop the neurological abnormalities associated with SWS. The risk increases to 20-50% when the port-wine birthmark is on the forehead, temple region or upper part of the face. SWS can affect individuals of any race or ethnicity.
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Related disorders of Sturge Weber Syndrome
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Symptoms of the following disorders can be similar to those of SWS. Comparisons may be useful for a differential diagnosis.Klippel-Trenaunay syndrome (KTS) is a rare disorder that is present at birth and is characterized by a triad of cutaneous capillary malformation (port wine birthmark), lymphatic anomalies, and abnormal veins in association with variable overgrowth (hypertrophy) of soft tissue and bone. KTS occurs most frequently in the lower limbs and less commonly in the upper extremities and trunk. KTS equally affects males and females. Mutations in genes such PIK3CA, or rarely RASA1, cause this syndrome. (For more information on this disorder, choose “Klippel-Trenaunay syndrome” as your search term in the Rare Disease Database.)Others disorders included in the classification of neurocutaneous disorders or phakomatoses such as tuberous sclerosis, Von Hippel Lindau syndrome, Wyburn-Mason syndrome, and neurofibromatosis may have signs and symptoms that are similar to those seen in individuals with SWS. Additional disorders that may have similar symptoms include PHACE syndrome, Cobb syndrome, Maffucci syndrome, Gorham-Stout syndrome, and Parkes Weber syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)In addition, some children with megalencephaly-capillary malformation syndrome (MCAP) overlap in features with SWS. Most cases of MCAP are caused by mutations in the PIK3CA gene, and genetic testing of involved skin tissue can be done if this is a question. (For more information on this condition, choose MCAP as your search term in the Rare Disease Database.)
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Related disorders of Sturge Weber Syndrome. Symptoms of the following disorders can be similar to those of SWS. Comparisons may be useful for a differential diagnosis.Klippel-Trenaunay syndrome (KTS) is a rare disorder that is present at birth and is characterized by a triad of cutaneous capillary malformation (port wine birthmark), lymphatic anomalies, and abnormal veins in association with variable overgrowth (hypertrophy) of soft tissue and bone. KTS occurs most frequently in the lower limbs and less commonly in the upper extremities and trunk. KTS equally affects males and females. Mutations in genes such PIK3CA, or rarely RASA1, cause this syndrome. (For more information on this disorder, choose “Klippel-Trenaunay syndrome” as your search term in the Rare Disease Database.)Others disorders included in the classification of neurocutaneous disorders or phakomatoses such as tuberous sclerosis, Von Hippel Lindau syndrome, Wyburn-Mason syndrome, and neurofibromatosis may have signs and symptoms that are similar to those seen in individuals with SWS. Additional disorders that may have similar symptoms include PHACE syndrome, Cobb syndrome, Maffucci syndrome, Gorham-Stout syndrome, and Parkes Weber syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)In addition, some children with megalencephaly-capillary malformation syndrome (MCAP) overlap in features with SWS. Most cases of MCAP are caused by mutations in the PIK3CA gene, and genetic testing of involved skin tissue can be done if this is a question. (For more information on this condition, choose MCAP as your search term in the Rare Disease Database.)
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Diagnosis of Sturge Weber Syndrome
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A diagnosis of SWS is based upon identification of characteristic symptoms (e.g. port-wine birthmark), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be straightforward in an infant with a port-wine birthmark, glaucoma, evidence of cerebral involvement and neuroimaging findings consistent with a diagnosis of SWS. Diagnosis can be more difficult in infants who have a port-wine birthmark, but no neurological symptoms. Early imaging in infants has low sensitivity and needs to be repeated after a year to exclude SWS brain involvement.Clinical Testing and Workup
Various imaging techniques can be used to identify and assess neurological complications including x-rays of the skull (skull radiography) or magnetic resonance imaging (MRI) with gadolinium. A head computed tomography (CT) scan can show intracranial calcification in certain areas of the brain. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Gadolinium is a contrast agent that is used to enhance the scanning results and supply a more detailed picture of tissues such as the brain or blood vessels. MRI with contrast is the preferred way to evaluate and diagnose SWS brain involvement.Newer neuroimaging techniques such as susceptibility-weighted imaging (SWI) have proven useful in evaluating individuals for brain abnormalities potentially associated with SWS. SWI uses a different type of contrast to enhance traditional MRIs and may allow physicians to diagnose brain abnormalities earlier. SWI is particularly effective at evaluating venous structures in the brain.Computerized tomography (CT) scanning may also be used to aid in diagnosing SWS. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A single-photon emission computed tomography scan (SPECT), which is a specialized CT scan, can reveal areas of involvement in the brain that may not show in MRI or traditional CT scans. SPECT scanning may be used in conjunction with other scanning techniques to evaluate the brain of individuals suspected of having SWS.Traditional angiography designed to evaluate the health and function of blood vessels) are not usually recommended for individuals suspected of having SWS, but occasionally may be required to exclude a high flow lesion such as an arterial venous malformation or arterial venous fistula. Usually MRA and MRV imaging is sufficient to exclude these vascular issues. An electroencephalogram (EEG) can be used to evaluate and localize seizure activity. In addition, EEG can be used to screen for brain involvement in young infants where early imaging may fail to detect brain involvement.Transcranial doppler may be used as a noninvasive method to monitor children for progressive changes over time by assessing the severity of blood flow abnormalities. Since the percentage of middle cerebral arteries velocity asymmetry is correlated with the clinical severity score and with seizure frequency, blood flow asymmetry may be used to indicate poor prognosis. A complete ophthalmological exam can reveal glaucoma and other eye abnormalities potentially associated with SWS. Because of the high risk of glaucoma, complete eye examination should be performed regularly, especially in infants and young children. Follow-up examination should continue into adulthood even if results are normal through childhood.Patients with SWS may be at a significantly greater risk of suicide than a control population of other neurologically involved patients. Data from suicidality risk assessment suggests that sex differences may be significant in SWS outcomes. Compared to other patients with neurologic disorder, male sex was associated with increased suicide risk in Sturge-Weber patients, while no such association was found in females. Further study is needed to understand the sex differences in suicide risk for SWS patients.
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Diagnosis of Sturge Weber Syndrome. A diagnosis of SWS is based upon identification of characteristic symptoms (e.g. port-wine birthmark), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be straightforward in an infant with a port-wine birthmark, glaucoma, evidence of cerebral involvement and neuroimaging findings consistent with a diagnosis of SWS. Diagnosis can be more difficult in infants who have a port-wine birthmark, but no neurological symptoms. Early imaging in infants has low sensitivity and needs to be repeated after a year to exclude SWS brain involvement.Clinical Testing and Workup
Various imaging techniques can be used to identify and assess neurological complications including x-rays of the skull (skull radiography) or magnetic resonance imaging (MRI) with gadolinium. A head computed tomography (CT) scan can show intracranial calcification in certain areas of the brain. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Gadolinium is a contrast agent that is used to enhance the scanning results and supply a more detailed picture of tissues such as the brain or blood vessels. MRI with contrast is the preferred way to evaluate and diagnose SWS brain involvement.Newer neuroimaging techniques such as susceptibility-weighted imaging (SWI) have proven useful in evaluating individuals for brain abnormalities potentially associated with SWS. SWI uses a different type of contrast to enhance traditional MRIs and may allow physicians to diagnose brain abnormalities earlier. SWI is particularly effective at evaluating venous structures in the brain.Computerized tomography (CT) scanning may also be used to aid in diagnosing SWS. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A single-photon emission computed tomography scan (SPECT), which is a specialized CT scan, can reveal areas of involvement in the brain that may not show in MRI or traditional CT scans. SPECT scanning may be used in conjunction with other scanning techniques to evaluate the brain of individuals suspected of having SWS.Traditional angiography designed to evaluate the health and function of blood vessels) are not usually recommended for individuals suspected of having SWS, but occasionally may be required to exclude a high flow lesion such as an arterial venous malformation or arterial venous fistula. Usually MRA and MRV imaging is sufficient to exclude these vascular issues. An electroencephalogram (EEG) can be used to evaluate and localize seizure activity. In addition, EEG can be used to screen for brain involvement in young infants where early imaging may fail to detect brain involvement.Transcranial doppler may be used as a noninvasive method to monitor children for progressive changes over time by assessing the severity of blood flow abnormalities. Since the percentage of middle cerebral arteries velocity asymmetry is correlated with the clinical severity score and with seizure frequency, blood flow asymmetry may be used to indicate poor prognosis. A complete ophthalmological exam can reveal glaucoma and other eye abnormalities potentially associated with SWS. Because of the high risk of glaucoma, complete eye examination should be performed regularly, especially in infants and young children. Follow-up examination should continue into adulthood even if results are normal through childhood.Patients with SWS may be at a significantly greater risk of suicide than a control population of other neurologically involved patients. Data from suicidality risk assessment suggests that sex differences may be significant in SWS outcomes. Compared to other patients with neurologic disorder, male sex was associated with increased suicide risk in Sturge-Weber patients, while no such association was found in females. Further study is needed to understand the sex differences in suicide risk for SWS patients.
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Therapies of Sturge Weber Syndrome
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Treatment
The treatment of SWS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, neurosurgeons, dermatologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan a child’s treatment. Psychosocial support for the entire family is essential as well.Laser therapy can lighten or remove the port-wine birthmark in affected individuals, even infants as young as one month old. However, port-wine birthmarks tend to return or darken again, necessitating multiple laser therapy sessions. Pulse dye laser therapy is the most common technique for treating individuals with SWS. However, because each port-wine birthmark is dissimilar (e.g., they vary in size, diameter, distribution and depth), the most effective therapy for one person will not be the same for another person and no one form of laser therapy is effective for all affected individuals. In fact, different laser therapies may be required for different affected areas of the same individual. Topical sirolimus is now being used by some providers in combination with laser treatments to prevent regrowth of abnormal vessels.Seizures are treated with anti-seizure (anti-convulsant) medications. A multicenter research data suggests that levetiracetam, low-dose aspirin, and oxcarbazepine are the most frequently used medications for seizure management. Patients highly affected are more likely to take greater number of anti-seizure medications. The effectiveness of these medications in treating people with SWS is highly variable. Some individuals do not respond to anti-seizure medications (refractory seizures) despite an aggressive treatment regimen. Refractory cases may ultimately require surgery. Surgical techniques that have been used to control seizures in SWS include hemispherectomy, focal cortical resection, and vagal nerve stimulation.Hemispherectomy involves the surgical removal or disabling of half of the brain, specifically the half of the brain which is repeatedly damaged by chronic seizure activity. This surgical procedure can be associated with significant adverse effects including weakness on one side of the body to possibly affect walking (hemiparetic gait), little use of the affected hand, or hemianopsia. In some patients, such abnormalities may already be present before the surgery as a consequence of SWS. In certain patients, hemispherectomy may be recommended for individuals with repeated stroke-like episodes and progressive neurological deficits.Focal cortical resection is used when seizure activity arises from one specific area of the brain. This area of the brain can be isolated through brain mapping, a scientific method of studying brainwave activity. A neurosurgeon will remove the affected piece of the brain (focal resection). This procedure requires removing a small piece of the skull in order to gain access to the brain. A focal resection is less likely to produce neurologic deficits but is also less likely to result in full seizure control.Vagus nerve stimulation is a procedure in which a device called a pulse generator is inserted into the chest and a wire is run underneath the skin to the vagus nerve in the neck. The pulse generator is similar to a pacemaker and transmits mild, electrical impulses to the brain via the vagus nerve. These impulses prevent seizures from occurring. This intensity and timing of the nerve impulses are determined based upon each individual’s needs.The decision to undergo surgery to treat refractory seizures in children with SWS is difficult because of the varied pattern, frequency and severity of seizures in each child. Some children experience clusters of seizures that occur close together only to be followed by a seizure-free period that can last for many months or years. Some physicians advocate earlier surgery for seizures in order to protect against refractory seizures, developmental delays, cognitive dysfunction, and hemiparesis.Decisions concerning the use of particular drug regimens, surgery, and/or other treatments should be made by physicians and other members of the health care team in careful consultation with parents or a patient based upon the specifics of an individual’s case, a thorough discussion of the potential benefits and risks including possible side effects and long-term effects, patient preference, and other appropriate factors.Preventive (prophylactic) treatment of migraines and headaches may be recommended and may include medications such as propranolol or verapamil. Some anti-seizure medications such as gabapentin, topiramate, and valproic acid may also help to treat migraines or headaches.Affected infants and children should receive regular ophthalmological exams in order to promptly detect and treat glaucoma and any increase in intraocular pressure. Certain medications usually delivered as eye drops or orally may be used to treat glaucoma. Ultimately, glaucoma often requires surgery with medications used as a follow up (adjunct) therapy. There are several different surgical techniques used to treat glaucoma in individuals with SWS depending upon the individual’s case such as angle procedures, filtering procedures, device placement, and combination procedures. Combination procedure is widely used because of single procedure failure rate of angle surgery and the complications associated with device placement. SWS patients are encouraged to get life-long monitoring for ocular complications. Additional therapy includes physical therapy for muscle weakness, special education for children with developmental delays or intellectual disability as well as other medical, social or vocational services.
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Therapies of Sturge Weber Syndrome. Treatment
The treatment of SWS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, neurosurgeons, dermatologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan a child’s treatment. Psychosocial support for the entire family is essential as well.Laser therapy can lighten or remove the port-wine birthmark in affected individuals, even infants as young as one month old. However, port-wine birthmarks tend to return or darken again, necessitating multiple laser therapy sessions. Pulse dye laser therapy is the most common technique for treating individuals with SWS. However, because each port-wine birthmark is dissimilar (e.g., they vary in size, diameter, distribution and depth), the most effective therapy for one person will not be the same for another person and no one form of laser therapy is effective for all affected individuals. In fact, different laser therapies may be required for different affected areas of the same individual. Topical sirolimus is now being used by some providers in combination with laser treatments to prevent regrowth of abnormal vessels.Seizures are treated with anti-seizure (anti-convulsant) medications. A multicenter research data suggests that levetiracetam, low-dose aspirin, and oxcarbazepine are the most frequently used medications for seizure management. Patients highly affected are more likely to take greater number of anti-seizure medications. The effectiveness of these medications in treating people with SWS is highly variable. Some individuals do not respond to anti-seizure medications (refractory seizures) despite an aggressive treatment regimen. Refractory cases may ultimately require surgery. Surgical techniques that have been used to control seizures in SWS include hemispherectomy, focal cortical resection, and vagal nerve stimulation.Hemispherectomy involves the surgical removal or disabling of half of the brain, specifically the half of the brain which is repeatedly damaged by chronic seizure activity. This surgical procedure can be associated with significant adverse effects including weakness on one side of the body to possibly affect walking (hemiparetic gait), little use of the affected hand, or hemianopsia. In some patients, such abnormalities may already be present before the surgery as a consequence of SWS. In certain patients, hemispherectomy may be recommended for individuals with repeated stroke-like episodes and progressive neurological deficits.Focal cortical resection is used when seizure activity arises from one specific area of the brain. This area of the brain can be isolated through brain mapping, a scientific method of studying brainwave activity. A neurosurgeon will remove the affected piece of the brain (focal resection). This procedure requires removing a small piece of the skull in order to gain access to the brain. A focal resection is less likely to produce neurologic deficits but is also less likely to result in full seizure control.Vagus nerve stimulation is a procedure in which a device called a pulse generator is inserted into the chest and a wire is run underneath the skin to the vagus nerve in the neck. The pulse generator is similar to a pacemaker and transmits mild, electrical impulses to the brain via the vagus nerve. These impulses prevent seizures from occurring. This intensity and timing of the nerve impulses are determined based upon each individual’s needs.The decision to undergo surgery to treat refractory seizures in children with SWS is difficult because of the varied pattern, frequency and severity of seizures in each child. Some children experience clusters of seizures that occur close together only to be followed by a seizure-free period that can last for many months or years. Some physicians advocate earlier surgery for seizures in order to protect against refractory seizures, developmental delays, cognitive dysfunction, and hemiparesis.Decisions concerning the use of particular drug regimens, surgery, and/or other treatments should be made by physicians and other members of the health care team in careful consultation with parents or a patient based upon the specifics of an individual’s case, a thorough discussion of the potential benefits and risks including possible side effects and long-term effects, patient preference, and other appropriate factors.Preventive (prophylactic) treatment of migraines and headaches may be recommended and may include medications such as propranolol or verapamil. Some anti-seizure medications such as gabapentin, topiramate, and valproic acid may also help to treat migraines or headaches.Affected infants and children should receive regular ophthalmological exams in order to promptly detect and treat glaucoma and any increase in intraocular pressure. Certain medications usually delivered as eye drops or orally may be used to treat glaucoma. Ultimately, glaucoma often requires surgery with medications used as a follow up (adjunct) therapy. There are several different surgical techniques used to treat glaucoma in individuals with SWS depending upon the individual’s case such as angle procedures, filtering procedures, device placement, and combination procedures. Combination procedure is widely used because of single procedure failure rate of angle surgery and the complications associated with device placement. SWS patients are encouraged to get life-long monitoring for ocular complications. Additional therapy includes physical therapy for muscle weakness, special education for children with developmental delays or intellectual disability as well as other medical, social or vocational services.
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Overview of Stuve-Wiedemann Syndrome
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SummaryStuve Wiedemann syndrome (STWS) is a rare genetic disorder that has been diagnosed in very few patients. It is characterized by short stature, bowing of the long bones of the arms and legs (campomelia) and fingers or toes that are permanently flexed (camptodactyly) outward away from the thumb (ulnar deviation). Affected infants are often unable to survive past one year due to life-threatening complications, including respiratory distress and episodes during which there is a sudden rise in body temperature (hyperthermia). Those who do survive will develop severe spinal deformities, spontaneous bone fractures, temperature instability (from dysautonomia) and some general developmental delays, though no intellectual deficits have been found. STWS is inherited in an autosomal recessive pattern.In the past, STWS was thought to be a lethal condition in all affected individuals. Today, survival past the first year of life is increasingly common thanks to early diagnosis and proper medical monitoring.
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Overview of Stuve-Wiedemann Syndrome. SummaryStuve Wiedemann syndrome (STWS) is a rare genetic disorder that has been diagnosed in very few patients. It is characterized by short stature, bowing of the long bones of the arms and legs (campomelia) and fingers or toes that are permanently flexed (camptodactyly) outward away from the thumb (ulnar deviation). Affected infants are often unable to survive past one year due to life-threatening complications, including respiratory distress and episodes during which there is a sudden rise in body temperature (hyperthermia). Those who do survive will develop severe spinal deformities, spontaneous bone fractures, temperature instability (from dysautonomia) and some general developmental delays, though no intellectual deficits have been found. STWS is inherited in an autosomal recessive pattern.In the past, STWS was thought to be a lethal condition in all affected individuals. Today, survival past the first year of life is increasingly common thanks to early diagnosis and proper medical monitoring.
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Symptoms of Stuve-Wiedemann Syndrome
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The symptoms of STWS vary from person to person. Most infants develop characteristic skeletal abnormalities including permanent flexion of fingers or toes (camptodactyly) outward away from the thumb (ulnar deviation) and bowing of the long bones of the arms and legs (camptomelia), which results in short stature. Affected infants may also have underdeveloped muscle tone (hypotonia) and/or an elbow that is permanently fixed in a bent or flexed position (elbow contracture). Some children with STWS have distinctive facial features, including a small chin (micrognathia), pursed mouth, and underdeveloped upper jaw, cheekbones, and eye sockets (midface hypoplasia) that sometimes results in protruding eyes.Some infants with STWS may develop episodes where they repeatedly stop breathing during sleep (sleep apnea). Feeding and swallowing difficulties may also occur. In some children, life-threatening complications may develop early during infancy including respiratory distress and repeated episodes where there is a sudden rise in body temperature (hyperthermia).Other symptoms include decreased bone density (osteopenia) and autonomic nervous system dysfunction (dysautonomia) that includes difficulty regulating temperature, smooth tongue and absent corneal (blinking) and patellar reflexes. The absence of a corneal reflex may put children at risk of physical damage to the eye resulting in vision loss. Affected children will also have general developmental delays, though there have been no reports of any intellectual deficits.The specific clinical picture of STWS is unclear due to the small number of cases reported in the medical literature. Some affected individuals develop symptoms similar to those associated with dysautonomia. (For more information on dysautonomia, see the Related Disorders section below). These symptoms may include diminished sensitivity to pain, absence of the knob-like projections that cover the tongue (fungiform papillae), excessive sweating at low temperatures, absent corneal reflexes, multiple fractures and spinal abnormalities.Additional findings have been reported in some children with STWS including high blood pressure of the main artery of the lungs (pulmonary hypertension), liver (hepatic) failure, and a form of clubfoot in which the heel is turned outward away from the midline of the leg (talipes valgus). It is not known whether these are characteristic findings of STWS or coincidental findings. As STWS becomes better recognized, more cases will be identified allowing for a clearer clinical picture to emerge.
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Symptoms of Stuve-Wiedemann Syndrome. The symptoms of STWS vary from person to person. Most infants develop characteristic skeletal abnormalities including permanent flexion of fingers or toes (camptodactyly) outward away from the thumb (ulnar deviation) and bowing of the long bones of the arms and legs (camptomelia), which results in short stature. Affected infants may also have underdeveloped muscle tone (hypotonia) and/or an elbow that is permanently fixed in a bent or flexed position (elbow contracture). Some children with STWS have distinctive facial features, including a small chin (micrognathia), pursed mouth, and underdeveloped upper jaw, cheekbones, and eye sockets (midface hypoplasia) that sometimes results in protruding eyes.Some infants with STWS may develop episodes where they repeatedly stop breathing during sleep (sleep apnea). Feeding and swallowing difficulties may also occur. In some children, life-threatening complications may develop early during infancy including respiratory distress and repeated episodes where there is a sudden rise in body temperature (hyperthermia).Other symptoms include decreased bone density (osteopenia) and autonomic nervous system dysfunction (dysautonomia) that includes difficulty regulating temperature, smooth tongue and absent corneal (blinking) and patellar reflexes. The absence of a corneal reflex may put children at risk of physical damage to the eye resulting in vision loss. Affected children will also have general developmental delays, though there have been no reports of any intellectual deficits.The specific clinical picture of STWS is unclear due to the small number of cases reported in the medical literature. Some affected individuals develop symptoms similar to those associated with dysautonomia. (For more information on dysautonomia, see the Related Disorders section below). These symptoms may include diminished sensitivity to pain, absence of the knob-like projections that cover the tongue (fungiform papillae), excessive sweating at low temperatures, absent corneal reflexes, multiple fractures and spinal abnormalities.Additional findings have been reported in some children with STWS including high blood pressure of the main artery of the lungs (pulmonary hypertension), liver (hepatic) failure, and a form of clubfoot in which the heel is turned outward away from the midline of the leg (talipes valgus). It is not known whether these are characteristic findings of STWS or coincidental findings. As STWS becomes better recognized, more cases will be identified allowing for a clearer clinical picture to emerge.
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Causes of Stuve-Wiedemann Syndrome
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STWS is caused by changes (variants or mutations) in the leukemia inhibitory factor receptor (LIFR) gene. Variants in this gene may cause the complete absence of the LIFR protein or the production of a non-functional LIFR protein. LIFR gene variants ultimately affect the JAK/STAT 3 signaling pathway. This pathway is one of the many signaling pathways involved in human development, involving many different cytokines and growth factors. Of note, not all reported individuals have a LIFR gene variant, indicating that not all of the STWS-causing genes have been identified.STWS is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Stuve-Wiedemann Syndrome. STWS is caused by changes (variants or mutations) in the leukemia inhibitory factor receptor (LIFR) gene. Variants in this gene may cause the complete absence of the LIFR protein or the production of a non-functional LIFR protein. LIFR gene variants ultimately affect the JAK/STAT 3 signaling pathway. This pathway is one of the many signaling pathways involved in human development, involving many different cytokines and growth factors. Of note, not all reported individuals have a LIFR gene variant, indicating that not all of the STWS-causing genes have been identified.STWS is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Affects of Stuve-Wiedemann Syndrome
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STWS has a very low prevalence of <1 out of 1,000,000. However, the disease is relatively common in the United Arab Emirates with a prevalence of 1 out of 20,000 births. STWS affects males and females in equal numbers. Patients with STWS often go unrecognized, making it difficult to determine the true frequency of the disorder in the general population. STWS was first described in the medical literature in 1971.
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Affects of Stuve-Wiedemann Syndrome. STWS has a very low prevalence of <1 out of 1,000,000. However, the disease is relatively common in the United Arab Emirates with a prevalence of 1 out of 20,000 births. STWS affects males and females in equal numbers. Patients with STWS often go unrecognized, making it difficult to determine the true frequency of the disorder in the general population. STWS was first described in the medical literature in 1971.
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Related disorders of Stuve-Wiedemann Syndrome
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Symptoms of the following disorders can be similar to those of STWS. Comparisons may be useful for a differential diagnosis:Crisponi syndrome is a rare autosomal recessive genetic disorder and is characterized by muscular contractions, episodic or continuous hyperthermia, abnormal facial features and camptodactyly. Facial differences include large, round faces with a broad nose and long philtrum. Patients also have hypotonia. Children affected with this syndrome start to exhibit symptoms at birth. Infants have shortness of breath, periods of no breathing (apnea), decreased oxygen causing the babies to turn blue-ish (cyanosis) and continuous hyperthermia, which differs from a fever in that there is no infection. These factors can lead to sudden death. Crisponi syndrome has only been documented in 30 patients, all from Italian families.Occipital horn syndrome (OHS) is an X-linked recessive genetic disorder. It is extremely rare, with only 20 cases reported to date. OHS is characterized by untreatable diarrhea, outpouchings of the bladder wall (diverticulae) or recurrent urinary tract infections. Delayed motor development due to hypotonia may also be seen. Symptoms of OHS may occur anywhere from infancy to early adulthood.Larsen syndrome (LS) is a rare, non-life threatening autosomal dominant genetic disorder affecting skeletal development in infants. LS is characterized by congenital large joint dislocation, foot deformities, scoliosis, neck bone abnormalities (cervical spine dysplasia), spatula-shaped finger and toe bones (phalanges) and other cranial abnormalities.Schwartz-Jampel syndrome is a rare genetic disorder characterized by abnormalities of the skeletal muscles, including muscle weakness and stiffness (myotonic myopathy); abnormal bone development (bone dysplasia); permanent bending or extension of certain joints in a fixed position (joint contractures) and/or growth delays resulting in short stature (dwarfism). Affected individuals may also have small, fixed facial features and various abnormalities of the eyes, some of which may cause impaired vision. The range and severity of symptoms may vary from person to person. (For more information on this disorder, choose “Schwartz-Jampel” as your search term in the Rare Disease Database.)Campomelic dysplasia is a rare congenital skeletal disorder characterized by short stature along with bowing and an unusual angular shape of the long bones of the legs. The bones of the shoulders and pelvic area are often abnormal. Affected individuals may have 11 pairs of ribs instead of the usual 12. There are two forms of this disorder, the long-limbed form and the short-limbed form. Additional symptoms of campomelic dysplasia include characteristic facial features, congenital heart defects, and severe respiratory distress. Campomelic dysplasia is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Campomelic” as your search term in the Rare Disease Database.)Kyphomelic dysplasia is a rare genetic skeletal disorder characterized by bowing of the long bones of the arms and legs that is present at birth, resulting in short stature. The thighbone is most often affected. Some affected infants may have an abnormally small jaw, cleft palate and cleft lip. Affected infants may also have a narrow chest and short ribs. Kyphomelic dysplasia is inherited in an autosomal recessive pattern.Familial dysautonomia is a rare genetic disorder of the autonomic nervous system that controls vital involuntary body functions. It is characterized by diminished sensitivity to pain, lack of overflow tearing in the eyes, a decrease in the number of knob-like projections that cover the tongue (fungiform papillae), unusual fluctuations of body temperature and unstable blood pressure. Symptoms of this disorder are apparent at birth. Familial dysautonomia is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “dysautonomia” as your search term in the Rare Disease Database.)
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Related disorders of Stuve-Wiedemann Syndrome. Symptoms of the following disorders can be similar to those of STWS. Comparisons may be useful for a differential diagnosis:Crisponi syndrome is a rare autosomal recessive genetic disorder and is characterized by muscular contractions, episodic or continuous hyperthermia, abnormal facial features and camptodactyly. Facial differences include large, round faces with a broad nose and long philtrum. Patients also have hypotonia. Children affected with this syndrome start to exhibit symptoms at birth. Infants have shortness of breath, periods of no breathing (apnea), decreased oxygen causing the babies to turn blue-ish (cyanosis) and continuous hyperthermia, which differs from a fever in that there is no infection. These factors can lead to sudden death. Crisponi syndrome has only been documented in 30 patients, all from Italian families.Occipital horn syndrome (OHS) is an X-linked recessive genetic disorder. It is extremely rare, with only 20 cases reported to date. OHS is characterized by untreatable diarrhea, outpouchings of the bladder wall (diverticulae) or recurrent urinary tract infections. Delayed motor development due to hypotonia may also be seen. Symptoms of OHS may occur anywhere from infancy to early adulthood.Larsen syndrome (LS) is a rare, non-life threatening autosomal dominant genetic disorder affecting skeletal development in infants. LS is characterized by congenital large joint dislocation, foot deformities, scoliosis, neck bone abnormalities (cervical spine dysplasia), spatula-shaped finger and toe bones (phalanges) and other cranial abnormalities.Schwartz-Jampel syndrome is a rare genetic disorder characterized by abnormalities of the skeletal muscles, including muscle weakness and stiffness (myotonic myopathy); abnormal bone development (bone dysplasia); permanent bending or extension of certain joints in a fixed position (joint contractures) and/or growth delays resulting in short stature (dwarfism). Affected individuals may also have small, fixed facial features and various abnormalities of the eyes, some of which may cause impaired vision. The range and severity of symptoms may vary from person to person. (For more information on this disorder, choose “Schwartz-Jampel” as your search term in the Rare Disease Database.)Campomelic dysplasia is a rare congenital skeletal disorder characterized by short stature along with bowing and an unusual angular shape of the long bones of the legs. The bones of the shoulders and pelvic area are often abnormal. Affected individuals may have 11 pairs of ribs instead of the usual 12. There are two forms of this disorder, the long-limbed form and the short-limbed form. Additional symptoms of campomelic dysplasia include characteristic facial features, congenital heart defects, and severe respiratory distress. Campomelic dysplasia is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Campomelic” as your search term in the Rare Disease Database.)Kyphomelic dysplasia is a rare genetic skeletal disorder characterized by bowing of the long bones of the arms and legs that is present at birth, resulting in short stature. The thighbone is most often affected. Some affected infants may have an abnormally small jaw, cleft palate and cleft lip. Affected infants may also have a narrow chest and short ribs. Kyphomelic dysplasia is inherited in an autosomal recessive pattern.Familial dysautonomia is a rare genetic disorder of the autonomic nervous system that controls vital involuntary body functions. It is characterized by diminished sensitivity to pain, lack of overflow tearing in the eyes, a decrease in the number of knob-like projections that cover the tongue (fungiform papillae), unusual fluctuations of body temperature and unstable blood pressure. Symptoms of this disorder are apparent at birth. Familial dysautonomia is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “dysautonomia” as your search term in the Rare Disease Database.)
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Diagnosis of Stuve-Wiedemann Syndrome
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STWS is usually diagnosed based on clinical and radiological findings after birth. A detailed patient history is taken into account. Radiological images show the telltale congenital contractures, bowed long bones, decreased bone density and other abnormal patterns. Genetic testing for variants in the LIFR gene can confirm a STWS diagnosis. At least one child with STWS was diagnosed before birth (antenatally) by fetal ultrasound during the late second or third trimester. In fetal ultrasound, sound waves are used to create an image of the developing fetus.
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Diagnosis of Stuve-Wiedemann Syndrome. STWS is usually diagnosed based on clinical and radiological findings after birth. A detailed patient history is taken into account. Radiological images show the telltale congenital contractures, bowed long bones, decreased bone density and other abnormal patterns. Genetic testing for variants in the LIFR gene can confirm a STWS diagnosis. At least one child with STWS was diagnosed before birth (antenatally) by fetal ultrasound during the late second or third trimester. In fetal ultrasound, sound waves are used to create an image of the developing fetus.
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Therapies of Stuve-Wiedemann Syndrome
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TreatmentThe treatment of STWS currently involves treatment of the symptoms of each patient. This might include prevention of choking while eating via a tube that connects the nose to the stomach for feeding (nasogastric tube), prevention of inhaling food on accident (lung aspiration) or physiotherapy and/or surgery to correct bone malformations. However, it should be noted that due to the tendency of affected individuals to have episodes of hyperthermia, use of anesthesia for procedures should be treated with extreme caution. Other treatment considerations include eye protection to prevent vision loss in the absence of a corneal reflex.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Stuve-Wiedemann Syndrome. TreatmentThe treatment of STWS currently involves treatment of the symptoms of each patient. This might include prevention of choking while eating via a tube that connects the nose to the stomach for feeding (nasogastric tube), prevention of inhaling food on accident (lung aspiration) or physiotherapy and/or surgery to correct bone malformations. However, it should be noted that due to the tendency of affected individuals to have episodes of hyperthermia, use of anesthesia for procedures should be treated with extreme caution. Other treatment considerations include eye protection to prevent vision loss in the absence of a corneal reflex.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of STXBP1 Disorders
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Summary STXBP1-related disorders comprise a spectrum of rare autosomal dominant neurodevelopmental conditions caused by changes in the STXBP1 gene. STXBP1-related epileptic encephalopathy was initially discovered in 2008 in individuals with a severe, neonatal epilepsy termed Ohtahara syndrome (Saitsu et al, 2008). In the years following, the spectrum of patient presentations expanded significantly. Individuals with STXBP1-related disorders experience a broad range of symptoms including early-onset seizures, developmental delays, intellectual disability, muscular hypotonia, spasticity and ataxia. Affected individuals may also exhibit some features of autism spectrum disorder. Individuals with STXBP1-related disorders may be also described as having a developmental and epileptic encephalopathy since most experience both developmental delay and epilepsy.The STXBP1 gene encodes the syntaxin-binding protein 1, which is integral to communication between nerve cells, facilitating the release of neurotransmitter into the synapse. Individuals with a pathogenic variant in the STXBP1 gene do not produce enough syntaxin-binding protein 1. The estimated incidence rate for STXBP1-related disorders is approximately 1 in 30,000 (Lopez-Rivera et al, 2020).Seizures typically develop in the first year of life and may be the first symptom to bring children to medical attention. Epilepsy onset may occur after infancy, generally in early childhood, though onset has been reported in adolescence (Stamberger et al, 2016, Ambramov et al, 2020). Individuals are typically treated with anti-seizure medications (ASMs) to control seizures; however, seizures are not controlled in 25% of patients treated with ASMs. Other treatment options include ketogenic diet, steroids and adrenocorticotropin hormone (ACTH) for infantile spasms and epilepsy surgery including vagal nerve stimulation.
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Overview of STXBP1 Disorders. Summary STXBP1-related disorders comprise a spectrum of rare autosomal dominant neurodevelopmental conditions caused by changes in the STXBP1 gene. STXBP1-related epileptic encephalopathy was initially discovered in 2008 in individuals with a severe, neonatal epilepsy termed Ohtahara syndrome (Saitsu et al, 2008). In the years following, the spectrum of patient presentations expanded significantly. Individuals with STXBP1-related disorders experience a broad range of symptoms including early-onset seizures, developmental delays, intellectual disability, muscular hypotonia, spasticity and ataxia. Affected individuals may also exhibit some features of autism spectrum disorder. Individuals with STXBP1-related disorders may be also described as having a developmental and epileptic encephalopathy since most experience both developmental delay and epilepsy.The STXBP1 gene encodes the syntaxin-binding protein 1, which is integral to communication between nerve cells, facilitating the release of neurotransmitter into the synapse. Individuals with a pathogenic variant in the STXBP1 gene do not produce enough syntaxin-binding protein 1. The estimated incidence rate for STXBP1-related disorders is approximately 1 in 30,000 (Lopez-Rivera et al, 2020).Seizures typically develop in the first year of life and may be the first symptom to bring children to medical attention. Epilepsy onset may occur after infancy, generally in early childhood, though onset has been reported in adolescence (Stamberger et al, 2016, Ambramov et al, 2020). Individuals are typically treated with anti-seizure medications (ASMs) to control seizures; however, seizures are not controlled in 25% of patients treated with ASMs. Other treatment options include ketogenic diet, steroids and adrenocorticotropin hormone (ACTH) for infantile spasms and epilepsy surgery including vagal nerve stimulation.
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Symptoms of STXBP1 Disorders
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Children with STXBP1-related disorders typically present with seizures and/or delays in meeting early developmental milestones. Epilepsy is diagnosed in up to 85% of individuals with STXBP1-related disorders, often developing very early in life; the median age of seizure onset is as early as six weeks, though onset may range from the immediate postnatal period to adolescence (Abramov et al, 2020, Stamberger et al, 2016). A broad spectrum of seizure types has been reported, including infantile or epileptic spasms, focal-onset seizures, and tonic seizures; up to 40% of children with STXBPI-related disorders develop infantile spasms. Epilepsy in children with STXBP1-related disorders is unpredictable and may prove difficult to treat, especially early in the course, often requiring concurrent use of multiple ASMs. More than a third of children with STXBP1-related disorders achieve seizure freedom during childhood. In some children, delays in achieving early developmental milestones may be the first sign of a STXBP1-related disorder. This may manifest as a failure to achieve head control, roll over or crawl within the expected timeframe. Low muscle tone (hypotonia) may be an early indication of delayed motor development in children with this disorder; in a subset of children, hypotonia may be the first indication of spasticity. All children with a STXBP1-related disorder have some degree of neurodevelopmental delays and/or intellectual disability (Stamberger et al, 2016). Independent walking is achieved in less than half of children with STXBP1-related disorders, often several years after typically expected. The development of expressive language skills (e.g., ability to speak more than 2-3 words) is observed in only a small minority of children diagnosed with STXBP1-related disorders (more than 90% of children will not acquire expressive language); however, children may have relatively spared receptive language and develop other means of communication. Features of autism spectrum disorder have been reported as well (reports ranging from 16-31%; Stamberger et al, 2016). A variety of movement disorders and muscle tone abnormalities are also associated with STXBP1-related disorders, including hypotonia; spasticity (i.e., stiff muscle tone); dystonia (i.e., repetitive muscle contractures causing twisting movements); ataxia (e.g., motor incoordination, unsteady gait); tremor and dyskinesias (involuntary, erratic movements). These signs may emerge or evolve in terms of severity at any point during infancy or childhood. However, new-onset neurological symptoms beyond the first three years of life are not common. Cortical visual impairment is seen in some children with STXBP1-related disorders.
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Symptoms of STXBP1 Disorders. Children with STXBP1-related disorders typically present with seizures and/or delays in meeting early developmental milestones. Epilepsy is diagnosed in up to 85% of individuals with STXBP1-related disorders, often developing very early in life; the median age of seizure onset is as early as six weeks, though onset may range from the immediate postnatal period to adolescence (Abramov et al, 2020, Stamberger et al, 2016). A broad spectrum of seizure types has been reported, including infantile or epileptic spasms, focal-onset seizures, and tonic seizures; up to 40% of children with STXBPI-related disorders develop infantile spasms. Epilepsy in children with STXBP1-related disorders is unpredictable and may prove difficult to treat, especially early in the course, often requiring concurrent use of multiple ASMs. More than a third of children with STXBP1-related disorders achieve seizure freedom during childhood. In some children, delays in achieving early developmental milestones may be the first sign of a STXBP1-related disorder. This may manifest as a failure to achieve head control, roll over or crawl within the expected timeframe. Low muscle tone (hypotonia) may be an early indication of delayed motor development in children with this disorder; in a subset of children, hypotonia may be the first indication of spasticity. All children with a STXBP1-related disorder have some degree of neurodevelopmental delays and/or intellectual disability (Stamberger et al, 2016). Independent walking is achieved in less than half of children with STXBP1-related disorders, often several years after typically expected. The development of expressive language skills (e.g., ability to speak more than 2-3 words) is observed in only a small minority of children diagnosed with STXBP1-related disorders (more than 90% of children will not acquire expressive language); however, children may have relatively spared receptive language and develop other means of communication. Features of autism spectrum disorder have been reported as well (reports ranging from 16-31%; Stamberger et al, 2016). A variety of movement disorders and muscle tone abnormalities are also associated with STXBP1-related disorders, including hypotonia; spasticity (i.e., stiff muscle tone); dystonia (i.e., repetitive muscle contractures causing twisting movements); ataxia (e.g., motor incoordination, unsteady gait); tremor and dyskinesias (involuntary, erratic movements). These signs may emerge or evolve in terms of severity at any point during infancy or childhood. However, new-onset neurological symptoms beyond the first three years of life are not common. Cortical visual impairment is seen in some children with STXBP1-related disorders.
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Causes of STXBP1 Disorders
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STXBP1-related disorders are caused by changes, or pathogenic variants in the STXBP1 gene, which is located on chromosome 9. These are autosomal dominant disorders, meaning that the symptoms manifest when one of two copies (alleles) of the STXBP1 gene are affected by a pathogenic change. These pathogenic variants are typically de novo, meaning that they are unique to the child, and not inherited from either parent. The risk of disease is the same for males and females. Disease-causing variants in the STXBP1 gene may be due to missense, nonsense, frameshift, and splice-site alterations as well as whole gene deletions; identified pathogenic variants are distributed throughout the gene (Abramov et al, 2020). The STXBP1 protein, also known as Munc-18, plays a role in synaptic vesicle release, a key aspect of communication between neurons. The STXBP1 protein is part of the SNARE complex, which mediates vesicle fusion to release neurotransmitter into the synapse (Deak et al, 2009). Pathogenic STXBP1 variants result in haploinsufficiency, where not enough STXBP1 protein is produced. There is also emerging evidence that certain types of STXBP1 mutations may also create some aggregation of the mutant STXBP1 protein, which may hint at additional disease mechanisms that are not fully understood yet.
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Causes of STXBP1 Disorders. STXBP1-related disorders are caused by changes, or pathogenic variants in the STXBP1 gene, which is located on chromosome 9. These are autosomal dominant disorders, meaning that the symptoms manifest when one of two copies (alleles) of the STXBP1 gene are affected by a pathogenic change. These pathogenic variants are typically de novo, meaning that they are unique to the child, and not inherited from either parent. The risk of disease is the same for males and females. Disease-causing variants in the STXBP1 gene may be due to missense, nonsense, frameshift, and splice-site alterations as well as whole gene deletions; identified pathogenic variants are distributed throughout the gene (Abramov et al, 2020). The STXBP1 protein, also known as Munc-18, plays a role in synaptic vesicle release, a key aspect of communication between neurons. The STXBP1 protein is part of the SNARE complex, which mediates vesicle fusion to release neurotransmitter into the synapse (Deak et al, 2009). Pathogenic STXBP1 variants result in haploinsufficiency, where not enough STXBP1 protein is produced. There is also emerging evidence that certain types of STXBP1 mutations may also create some aggregation of the mutant STXBP1 protein, which may hint at additional disease mechanisms that are not fully understood yet.
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Affects of STXBP1 Disorders
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STXBP1-related disorders are rare, affecting males and females equally. Approximately 282 individuals have been described in the literature, and there are an estimated 750 cases known worldwide. Estimated incidence rate is between 3.3 – 3.8 per 100,000 births (Lopez-Rivera et al, 2020). Individuals with STXBP1-related disorders are from families with various ethnic backgrounds in North America, South America, Europe, Africa and Asia.
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Affects of STXBP1 Disorders. STXBP1-related disorders are rare, affecting males and females equally. Approximately 282 individuals have been described in the literature, and there are an estimated 750 cases known worldwide. Estimated incidence rate is between 3.3 – 3.8 per 100,000 births (Lopez-Rivera et al, 2020). Individuals with STXBP1-related disorders are from families with various ethnic backgrounds in North America, South America, Europe, Africa and Asia.
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Related disorders of STXBP1 Disorders
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Physicians often use different frameworks when describing an individual’s symptoms and may use distinct terminology to refer to the presentation of the epilepsy and the underlying cause. For example, a child may be diagnosed with West syndrome (epilepsy syndrome) due to a disease-causing change in STXBP1 (underlying genetic cause).The following epilepsy syndromes have been associated with STXBP1-related disorders. Note that the following epilepsy syndromes share overlapping features, and that it is possible for an individual with STXBP1-related disorder to receive one or more of the following diagnoses over the course of their childhood.Ohtahara syndrome, sometimes referred to as early infantile epileptic encephalopathy (EIEE) is a rare type of epilepsy that typically becomes apparent during the first 1-3 months of life. It is characterized by frequent tonic seizures that are difficult to treat. Tonic seizures appear as stiffening of a limb or the body. The disorder is also characterized by a severely abnormal electroencephalogram (EEG) called “burst-suppression” in which short periods of abnormal brain activity are separated by several seconds of quiet. Ohtahara syndrome is considered an epileptic encephalopathy because this abnormal brain activity is thought to contribute to the cognitive and behavioral impairments associated with the disorder. Most children will go on to develop additional seizure types such as infantile spasms or Lennox-Gastaut syndrome as they grow older. There are many causes of this epilepsy syndrome including metabolic disorders, genetic and structural brain malformations or injuries.West syndrome is an epilepsy syndrome that comprises three clinical features: infantile/epileptic spasms (a specific seizure type), hypsarrhythmia (a specific abnormal brain wave pattern diagnosed by electroencephalogram (EEG)), and intellectual disability. Infantile spasms can vary in appearance, but typically involve repeated clusters of sudden, brief (1-5 second duration), tonic contractions of the trunk and limbs. Spasms occur most commonly just before sleep or upon wakening, and are frequently accompanied by fussiness. These spasms usually develop within the first year of life and can result from a variety of causes (genetic disorders, hypoxic ischemic encephalopathy, brain malformations, etc.). Infants with West syndrome also have an abnormal EEG pattern marked by high amplitude, chaotic spike waves, and referred to as hypsarrhythmia. Children with the diagnosis of West syndrome demonstrate regression of skills or delays in acquiring motor and language milestones. Not all infants with spasms will share all three features. (For more information on this condition, search for “West syndrome” in the Rare Disease Database.) Dravet syndrome is an epilepsy syndrome marked by frequent, often prolonged seizures, commonly triggered by high body temperature (hyperthermia) in addition to developmental delays, speech/language impairment, ataxia, hypotonia and sleep disturbances. It is primarily associated with changes within SCN1A gene, which encodes subunits of the sodium ion channels found within the central nervous system. Dravet syndrome generally appears in the first year of life in an otherwise healthy-appearing infant, typically following a generalized tonic-clonic or hemiclonic seizure. Status epilepticus (i.e., a seizure lasting longer than 5 minutes) is not uncommon among children with Dravet syndrome, especially in the early years. Additional seizure types including myoclonic, atypical absence, and complex partial seizures may appear, generally prior to five years of age. (For more information on this condition, search for “Dravet syndrome” in the Rare Disease Database.) Lennox-Gastaut syndrome is a rare type of epilepsy that typically becomes apparent during infancy or early childhood. The disorder is characterized by frequent seizures, psychomotor delays, and intellectual disability. Individuals with the disorder may experience several different types of seizures including drop attacks, tonic seizures, absence and convulsions. Lennox-Gastaut syndrome may be due to—or occur in association with—numerous different underlying disorders and genetic alterations. (For more information on this condition, search for “Lennox-Gastaut syndrome” in the Rare Disease Database.)
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Related disorders of STXBP1 Disorders. Physicians often use different frameworks when describing an individual’s symptoms and may use distinct terminology to refer to the presentation of the epilepsy and the underlying cause. For example, a child may be diagnosed with West syndrome (epilepsy syndrome) due to a disease-causing change in STXBP1 (underlying genetic cause).The following epilepsy syndromes have been associated with STXBP1-related disorders. Note that the following epilepsy syndromes share overlapping features, and that it is possible for an individual with STXBP1-related disorder to receive one or more of the following diagnoses over the course of their childhood.Ohtahara syndrome, sometimes referred to as early infantile epileptic encephalopathy (EIEE) is a rare type of epilepsy that typically becomes apparent during the first 1-3 months of life. It is characterized by frequent tonic seizures that are difficult to treat. Tonic seizures appear as stiffening of a limb or the body. The disorder is also characterized by a severely abnormal electroencephalogram (EEG) called “burst-suppression” in which short periods of abnormal brain activity are separated by several seconds of quiet. Ohtahara syndrome is considered an epileptic encephalopathy because this abnormal brain activity is thought to contribute to the cognitive and behavioral impairments associated with the disorder. Most children will go on to develop additional seizure types such as infantile spasms or Lennox-Gastaut syndrome as they grow older. There are many causes of this epilepsy syndrome including metabolic disorders, genetic and structural brain malformations or injuries.West syndrome is an epilepsy syndrome that comprises three clinical features: infantile/epileptic spasms (a specific seizure type), hypsarrhythmia (a specific abnormal brain wave pattern diagnosed by electroencephalogram (EEG)), and intellectual disability. Infantile spasms can vary in appearance, but typically involve repeated clusters of sudden, brief (1-5 second duration), tonic contractions of the trunk and limbs. Spasms occur most commonly just before sleep or upon wakening, and are frequently accompanied by fussiness. These spasms usually develop within the first year of life and can result from a variety of causes (genetic disorders, hypoxic ischemic encephalopathy, brain malformations, etc.). Infants with West syndrome also have an abnormal EEG pattern marked by high amplitude, chaotic spike waves, and referred to as hypsarrhythmia. Children with the diagnosis of West syndrome demonstrate regression of skills or delays in acquiring motor and language milestones. Not all infants with spasms will share all three features. (For more information on this condition, search for “West syndrome” in the Rare Disease Database.) Dravet syndrome is an epilepsy syndrome marked by frequent, often prolonged seizures, commonly triggered by high body temperature (hyperthermia) in addition to developmental delays, speech/language impairment, ataxia, hypotonia and sleep disturbances. It is primarily associated with changes within SCN1A gene, which encodes subunits of the sodium ion channels found within the central nervous system. Dravet syndrome generally appears in the first year of life in an otherwise healthy-appearing infant, typically following a generalized tonic-clonic or hemiclonic seizure. Status epilepticus (i.e., a seizure lasting longer than 5 minutes) is not uncommon among children with Dravet syndrome, especially in the early years. Additional seizure types including myoclonic, atypical absence, and complex partial seizures may appear, generally prior to five years of age. (For more information on this condition, search for “Dravet syndrome” in the Rare Disease Database.) Lennox-Gastaut syndrome is a rare type of epilepsy that typically becomes apparent during infancy or early childhood. The disorder is characterized by frequent seizures, psychomotor delays, and intellectual disability. Individuals with the disorder may experience several different types of seizures including drop attacks, tonic seizures, absence and convulsions. Lennox-Gastaut syndrome may be due to—or occur in association with—numerous different underlying disorders and genetic alterations. (For more information on this condition, search for “Lennox-Gastaut syndrome” in the Rare Disease Database.)
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Diagnosis of STXBP1 Disorders
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STXBP1-related disorder may be suspected in any child with an unexplained early infantile epileptic encephalopathy or new-onset infantile spasms. The diagnosis of a STXBP1-related disorder is currently made by looking at the DNA sequence of the STXBP1 gene via targeted genetic panels or whole exome sequencing. The STXBP1 gene is included on most epilepsy, neurodevelopmental, and autism/intellectual disability gene panels. In rare cases, a microdeletion containing the STXBP1 gene may be found on a chromosomal microarray.Clinical Testing and Work-Up
In addition to confirming the diagnosis with genetic testing, electroencephalograms (EEGs) and magnetic resonance imaging (MRI) of the brain are generally obtained as part of the initial evaluation.
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Diagnosis of STXBP1 Disorders. STXBP1-related disorder may be suspected in any child with an unexplained early infantile epileptic encephalopathy or new-onset infantile spasms. The diagnosis of a STXBP1-related disorder is currently made by looking at the DNA sequence of the STXBP1 gene via targeted genetic panels or whole exome sequencing. The STXBP1 gene is included on most epilepsy, neurodevelopmental, and autism/intellectual disability gene panels. In rare cases, a microdeletion containing the STXBP1 gene may be found on a chromosomal microarray.Clinical Testing and Work-Up
In addition to confirming the diagnosis with genetic testing, electroencephalograms (EEGs) and magnetic resonance imaging (MRI) of the brain are generally obtained as part of the initial evaluation.
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Therapies of STXBP1 Disorders
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Management
Currently, there are no curative, disease-altering, or specific therapies available for individuals with STXBP1 encephalopathy. Medical management is principally symptomatic and supportive. Given the wide spectrum of symptoms and severity, the specific treatment plan is often highly individualized. In general, a multidisciplinary team approach may be the most effective way to optimize and the individual’s function. Pediatric subspecialists commonly involved in the care of children with STXBP1 encephalopathy include neurologists, physiatrists, dieticians, gastroenterologists, ophthalmologists, physical and occupational therapists and speech pathologists.During certain aspects of the disease course, seizure control may be challenging and may be a difficult health issue to manage. No single anti-seizure medication has been found to be uniformly effective for children with STXBP1 encephalopathy. While some individuals respond well to treatment with a single medication, multiple anti-seizure medications are necessary in other individuals for adequate seizure control. For infantile spasms, a common seizure type among children with this diagnosis, the first line therapies include ACTH, high dose prednisone or vigabatrin. Dietary modifications such as the ketogenic diet (KD) have shown variable improvement in some individuals. Importantly, KD as an adjunctive therapy for seizure control necessitates rigid, often burdensome, dietary changes and must only be implemented under close medical supervision. Vagal nerve stimulation (VNS) has also been used in some patients with STXBP1-related disorders.An emphasis should be placed on early intervention therapies such as physical therapy, occupational therapy and speech and augmentative communication therapy. Important aspects of management include psychosocial support for the family, development of an appropriate education plan and assessment of available community resources.
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Therapies of STXBP1 Disorders. Management
Currently, there are no curative, disease-altering, or specific therapies available for individuals with STXBP1 encephalopathy. Medical management is principally symptomatic and supportive. Given the wide spectrum of symptoms and severity, the specific treatment plan is often highly individualized. In general, a multidisciplinary team approach may be the most effective way to optimize and the individual’s function. Pediatric subspecialists commonly involved in the care of children with STXBP1 encephalopathy include neurologists, physiatrists, dieticians, gastroenterologists, ophthalmologists, physical and occupational therapists and speech pathologists.During certain aspects of the disease course, seizure control may be challenging and may be a difficult health issue to manage. No single anti-seizure medication has been found to be uniformly effective for children with STXBP1 encephalopathy. While some individuals respond well to treatment with a single medication, multiple anti-seizure medications are necessary in other individuals for adequate seizure control. For infantile spasms, a common seizure type among children with this diagnosis, the first line therapies include ACTH, high dose prednisone or vigabatrin. Dietary modifications such as the ketogenic diet (KD) have shown variable improvement in some individuals. Importantly, KD as an adjunctive therapy for seizure control necessitates rigid, often burdensome, dietary changes and must only be implemented under close medical supervision. Vagal nerve stimulation (VNS) has also been used in some patients with STXBP1-related disorders.An emphasis should be placed on early intervention therapies such as physical therapy, occupational therapy and speech and augmentative communication therapy. Important aspects of management include psychosocial support for the family, development of an appropriate education plan and assessment of available community resources.
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Overview of Subacute Cerebellar Degeneration
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SummarySubacute cerebellar degeneration (SCD) is characterized by the deterioration of the area of the brain concerned with muscle coordination and balance (the cerebellum). Less frequently, the area involved may include the region connecting the spinal cord to the brain (the medulla oblongata, the cerebral cortex, and the brain stem). There are two types of SCD: 1) paraneoplastic cerebellar degeneration, which sometimes precedes the diagnosis of cancer, and 2) alcoholic or nutritional cerebellar degeneration, caused by a lack of the vitamin B-1 (thiamine). These two types share symptoms but not the same cause. Hallmark symptoms include weakened muscle coordination (ataxia), difficulty speaking (dysarthria), difficulty swallowing (dysphagia), abnormal walking patterns and dementia.Paraneoplastic cerebellar degeneration may be an autoimmune disorder (diseases where the immune system mistakenly attacks one own body) that affects more females than males and has an average age of onset of 50 years old. It has been associated with certain cancers and production of certain autoimmune antibodies, proteins released by immune cells that mistakenly recognizes and attack proteins in one’s own body instead of foreign substances like bacteria and viruses. Cancers associated with paraneoplastic cerebellar degeneration are Hodgkin’s disease, small-cell lung cancer (SCLC), breast, and gynecologic cancers. The cancers may trigger production of autoimmune antibodies that attack brain cells in the cerebellum called Purkinje cells, leading to cerebellar degeneration. In alcoholic cerebellar degeneration, symptoms usually begin to occur in middle-aged individuals with a history of chronic alcohol abuse. These symptoms are caused by thiamine deficiency, which also occurs in nutritional cerebellar degeneration.If SCD is suspected, magnetic resonance spectroscopy, cerebrospinal fluid analyses, paraneoplastic antibody assays, and imaging studies such as magnetic resonance imaging (MRI) scans and computed tomography (CT) scans, may be performed for a definitive diagnosis. If diagnosed with paraneoplastic cerebellar degeneration, available therapies include treatment of the underlying cancer and associated antibodies. If diagnosed with alcoholic or nutritional cerebellar degeneration, treatment includes receiving thiamine, along with either decreasing alcohol consumption or resuming a normal diet.
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Overview of Subacute Cerebellar Degeneration. SummarySubacute cerebellar degeneration (SCD) is characterized by the deterioration of the area of the brain concerned with muscle coordination and balance (the cerebellum). Less frequently, the area involved may include the region connecting the spinal cord to the brain (the medulla oblongata, the cerebral cortex, and the brain stem). There are two types of SCD: 1) paraneoplastic cerebellar degeneration, which sometimes precedes the diagnosis of cancer, and 2) alcoholic or nutritional cerebellar degeneration, caused by a lack of the vitamin B-1 (thiamine). These two types share symptoms but not the same cause. Hallmark symptoms include weakened muscle coordination (ataxia), difficulty speaking (dysarthria), difficulty swallowing (dysphagia), abnormal walking patterns and dementia.Paraneoplastic cerebellar degeneration may be an autoimmune disorder (diseases where the immune system mistakenly attacks one own body) that affects more females than males and has an average age of onset of 50 years old. It has been associated with certain cancers and production of certain autoimmune antibodies, proteins released by immune cells that mistakenly recognizes and attack proteins in one’s own body instead of foreign substances like bacteria and viruses. Cancers associated with paraneoplastic cerebellar degeneration are Hodgkin’s disease, small-cell lung cancer (SCLC), breast, and gynecologic cancers. The cancers may trigger production of autoimmune antibodies that attack brain cells in the cerebellum called Purkinje cells, leading to cerebellar degeneration. In alcoholic cerebellar degeneration, symptoms usually begin to occur in middle-aged individuals with a history of chronic alcohol abuse. These symptoms are caused by thiamine deficiency, which also occurs in nutritional cerebellar degeneration.If SCD is suspected, magnetic resonance spectroscopy, cerebrospinal fluid analyses, paraneoplastic antibody assays, and imaging studies such as magnetic resonance imaging (MRI) scans and computed tomography (CT) scans, may be performed for a definitive diagnosis. If diagnosed with paraneoplastic cerebellar degeneration, available therapies include treatment of the underlying cancer and associated antibodies. If diagnosed with alcoholic or nutritional cerebellar degeneration, treatment includes receiving thiamine, along with either decreasing alcohol consumption or resuming a normal diet.
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Symptoms of Subacute Cerebellar Degeneration
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Common symptoms of SCD include:1) Weakened muscle coordination (ataxia) of the limbs (especially of the arms in paraneoplastic cerebellar degeneration, and of the legs in alcoholic or nutritional cerebellar degeneration);
(2) Problems in articulation of speech (dysarthria), which are especially noticeable in paraneoplastic cerebellar degeneration;
(3) Difficulty in swallowing (dysphagia);
(4) Loss of reason (dementia); this occurs in approximately half the patients with paraneoplastic cerebellar degeneration;
(5) Involuntary rapid movements of the eyeball in a horizontal or vertical direction (nystagmus); as well as double-vision (diplopia), vertigo (dizziness), and paralysis of the eye muscles (ophthalmoplegia) if the patient has alcoholic/nutritional cerebellar degeneration;
(6) Cell loss localized to the midline structures of the cerebellum contributes to poor motor coordination of the head, such as head bobbing and loss of limb movements
(7) Tremors (shaking) related to complex motor tasks or purposeful movements due to abnormal Purkinje cells (a particular kind of nerve cell) throughout the cerebellum;
(8) Repetitive behaviors in children (hand clapping, rhythmic rocking, twirling of objects) associated with cerebellar vermis damage;
(9) Problems with cognitive and emotional regulation (autism, schizophrenia, attention deficit-hyperactivity disorder)In addition, patients with SCD lose many Purkinje cells throughout the cerebellum. Computerized axial tomography (CAT) scans may show enlargement of the area of the brain between the spinal cord and the rest of the brain (fourth ventricle) as well as areas of the cerebellum. Examination of cerebrospinal fluid may show a high volume of lymph cells (white blood cells formed in lymphoid tissue) and an elevated protein level.
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Symptoms of Subacute Cerebellar Degeneration. Common symptoms of SCD include:1) Weakened muscle coordination (ataxia) of the limbs (especially of the arms in paraneoplastic cerebellar degeneration, and of the legs in alcoholic or nutritional cerebellar degeneration);
(2) Problems in articulation of speech (dysarthria), which are especially noticeable in paraneoplastic cerebellar degeneration;
(3) Difficulty in swallowing (dysphagia);
(4) Loss of reason (dementia); this occurs in approximately half the patients with paraneoplastic cerebellar degeneration;
(5) Involuntary rapid movements of the eyeball in a horizontal or vertical direction (nystagmus); as well as double-vision (diplopia), vertigo (dizziness), and paralysis of the eye muscles (ophthalmoplegia) if the patient has alcoholic/nutritional cerebellar degeneration;
(6) Cell loss localized to the midline structures of the cerebellum contributes to poor motor coordination of the head, such as head bobbing and loss of limb movements
(7) Tremors (shaking) related to complex motor tasks or purposeful movements due to abnormal Purkinje cells (a particular kind of nerve cell) throughout the cerebellum;
(8) Repetitive behaviors in children (hand clapping, rhythmic rocking, twirling of objects) associated with cerebellar vermis damage;
(9) Problems with cognitive and emotional regulation (autism, schizophrenia, attention deficit-hyperactivity disorder)In addition, patients with SCD lose many Purkinje cells throughout the cerebellum. Computerized axial tomography (CAT) scans may show enlargement of the area of the brain between the spinal cord and the rest of the brain (fourth ventricle) as well as areas of the cerebellum. Examination of cerebrospinal fluid may show a high volume of lymph cells (white blood cells formed in lymphoid tissue) and an elevated protein level.
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Causes of Subacute Cerebellar Degeneration
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Paraneoplastic cerebellar degeneration may potentially be an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against invading organisms mistakenly attack healthy tissue for unknown reasons. It may also be an abnormal response to cancer. In cases where there is an underlying cancer, the individual’s immune system may react to the cancer by stimulating the body’s natural defense mechanisms. These natural defense mechanisms include producing antibodies, which are proteins that help the immune system detect harmful substances, and increase the number of T-cells, which are white blood cells that destroy infected cells and tumors. These antibodies and T-cells normally target only the cancerous tumors; however, in paraneoplastic cerebellar degeneration, these antibodies bind to and attack normal cells in the nervous systems, such as Purkinje cells in the cerebellum, leading to their death and loss of function. Purkinje cells are cells specifically found in the cerebellum that gather multiple signals throughout the brain to control motor movements.
Some antibodies and cancers appear to have a direct role in causing paraneoplastic cerebellar degeneration. Hodgkin’s disease, small-cell lung cancer (SCLC), breast, and gynecologic cancers are strongly linked to paraneoplastic cerebellar degeneration. In the absence of a detected tumor, some of these antibodies may still be produced in individuals with paraneoplastic cerebellar degeneration. These antibodies react with Purkinje cells, causing inflammation in the brain and cell death.
Alcoholic/nutritional cerebellar degeneration is associated with thiamine deficiency. The human body needs thiamine, also known as vitamin B1, to function properly. Humans need to consume thiamine in their diet because they are unable to produce it within the body. Once consumed, thiamine becomes absorbed in the small intestine and is stored in the liver. Thiamine is an essential vitamin for the brain and other tissues and is important for many cellular processes. This includes glucose metabolism and energy production, which are required for normal brain function. A reduction in thiamine will impair cellular energy production and, therefore, disrupt brain function. In addition, heavy alcohol use and thiamine deficiency will cause inflammation in the brain, leading to brain damage. Secondary thiamine deficiency results from impaired absorption or utilization or from increased requirements for thiamine. Individuals with a history of chronic alcohol abuse tend to eat poorly and may not get enough thiamine-containing foods. They also absorb or utilize the vitamin less efficiently, due to the effect of alcohol on the liver, and therefore, may require larger than normal amounts of thiamine.
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Causes of Subacute Cerebellar Degeneration. Paraneoplastic cerebellar degeneration may potentially be an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against invading organisms mistakenly attack healthy tissue for unknown reasons. It may also be an abnormal response to cancer. In cases where there is an underlying cancer, the individual’s immune system may react to the cancer by stimulating the body’s natural defense mechanisms. These natural defense mechanisms include producing antibodies, which are proteins that help the immune system detect harmful substances, and increase the number of T-cells, which are white blood cells that destroy infected cells and tumors. These antibodies and T-cells normally target only the cancerous tumors; however, in paraneoplastic cerebellar degeneration, these antibodies bind to and attack normal cells in the nervous systems, such as Purkinje cells in the cerebellum, leading to their death and loss of function. Purkinje cells are cells specifically found in the cerebellum that gather multiple signals throughout the brain to control motor movements.
Some antibodies and cancers appear to have a direct role in causing paraneoplastic cerebellar degeneration. Hodgkin’s disease, small-cell lung cancer (SCLC), breast, and gynecologic cancers are strongly linked to paraneoplastic cerebellar degeneration. In the absence of a detected tumor, some of these antibodies may still be produced in individuals with paraneoplastic cerebellar degeneration. These antibodies react with Purkinje cells, causing inflammation in the brain and cell death.
Alcoholic/nutritional cerebellar degeneration is associated with thiamine deficiency. The human body needs thiamine, also known as vitamin B1, to function properly. Humans need to consume thiamine in their diet because they are unable to produce it within the body. Once consumed, thiamine becomes absorbed in the small intestine and is stored in the liver. Thiamine is an essential vitamin for the brain and other tissues and is important for many cellular processes. This includes glucose metabolism and energy production, which are required for normal brain function. A reduction in thiamine will impair cellular energy production and, therefore, disrupt brain function. In addition, heavy alcohol use and thiamine deficiency will cause inflammation in the brain, leading to brain damage. Secondary thiamine deficiency results from impaired absorption or utilization or from increased requirements for thiamine. Individuals with a history of chronic alcohol abuse tend to eat poorly and may not get enough thiamine-containing foods. They also absorb or utilize the vitamin less efficiently, due to the effect of alcohol on the liver, and therefore, may require larger than normal amounts of thiamine.
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Affects of Subacute Cerebellar Degeneration
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In paraneoplastic cerebellar degeneration, the average age of onset is 50 years, with females affected more often than males. This form of cerebellar degeneration may precede cancer, however <1% of patients with cancer have paraneoplastic cerebellar degeneration. Alcoholic or nutritional cerebellar degeneration affects alcoholics and people with thiamine deficiency. In alcoholic cerebellar degeneration, symptoms usually occur in middle aged individuals who have a history of chronic alcohol abuse.
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Affects of Subacute Cerebellar Degeneration. In paraneoplastic cerebellar degeneration, the average age of onset is 50 years, with females affected more often than males. This form of cerebellar degeneration may precede cancer, however <1% of patients with cancer have paraneoplastic cerebellar degeneration. Alcoholic or nutritional cerebellar degeneration affects alcoholics and people with thiamine deficiency. In alcoholic cerebellar degeneration, symptoms usually occur in middle aged individuals who have a history of chronic alcohol abuse.
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Related disorders of Subacute Cerebellar Degeneration
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Symptoms of the following disorders can be similar to those of SCD. Comparisons may be useful for a differential diagnosis:Paraneoplastic neurologic syndromes (PNS) are a group of conditions that affect the nervous system (brain, spinal cord, nerves and/or muscles) in patients with cancer. The term “paraneoplastic” means that the neurological syndrome is not caused by the tumor itself, but by the immunological reactions that the tumor produces. PNS are categorized by the area of the nervous system that is principally affected, the type of symptoms or the type of immunological response. (For more information on these disorders, choose “paraneoplastic neurologic syndromes” as your search term in the Rare Disease Database.)Multiple sclerosis (MS) is a chronic disease of the central nervous system, which may be progressive, relapsing and remitting, or stable. MS is characterized by small lesions called plaques that form randomly throughout the brain and spinal cord. These patches prevent proper transmission of nervous system signals and thus result in a variety of neurological symptoms including visual difficulties (blind spots, double vision, nystagmus), impairment of speech, abnormal skin sensations (paresthesia) or numbness, walking disturbance and difficulties with bladder or bowel function. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)Wernicke encephalopathy is a degenerative brain disorder characterized by a deficiency of thiamine. It is marked by loss of coordination (ataxia) and apathy, confusion, disorientation or delirium. Various vision dysfunctions may also develop. This disorder often occurs in conjunction with Korsakoff syndrome which involves a Vitamin B1 (thiamine) deficiency usually caused by alcoholism. Wernicke encephalopathy can be severely disabling and life threatening if it is not recognized and treated early. (For more information, on this disorder, choose “Korsakoff” or “Wernicke” as your search term in the Rare Disease Database.)Hodgkin’s disease and several other types of cancers, such as lung, ovarian, breast, stomach, and uterine cancers may be associated with paraneoplastic cerebellar degeneration. Hodgkin’s disease is a form of cancer of the lymphatic system, especially the lymph nodes. Tumors occur in the lymph nodes (places where lymphatic vessels unite) and/or the area around the nodes. Fever, night sweats, and weight loss may occur along with swollen lymph nodes. (For more information on this disorder, choose “Hodgkin’s disease” as your search term in the Rare Disease Database.)Spinocerebellar ataxia is a rare, hereditary disease that occurs when a single copy of a non-working gene has been inherited from either parent or has been changed within the affected individual. Spinocerebellar ataxia mainly affects the cerebellum and causes symptoms such as ataxia, abnormal speech, and vision problems. There are about 40 different types of spinocerebellar ataxia. Each type of spinocerebellar ataxia is associated with a different altered gene. (For more information on this disorder, choose “autosomal dominant hereditary ataxia” as your search term in the Rare Disease Database.)
Episodic ataxia is a rare, neurologic condition that affects nerve cell signaling that controls body movement. There are currently 8 types of episodic ataxia. It is a disorder caused by altered genes and occurs when a single copy of a non-working gene has been inherited from either parent or has been changed within the affected individual. Each episode can last a few seconds up to a few hours, and can cause muscle weakness, seizures, or paralysis. (For more information on this disorder, choose “autosomal dominant hereditary ataxia” as your search term in the Rare Disease Database.)
Spinocerebellar ataxia with axonal neuropathy is a rare, hereditary, disease that occurs when a non-working gene has been inherited by each parent. Spinocerebellar ataxia with axonal neuropathy is characterized by the onset of cerebellar ataxia during the late childhood years. The disease progresses slowly and can cause symptoms such as ataxia, dysarthria (abnormal speech), gaze nystagmus (uncontrolled movement of the eyes), and peripheral neuropathy. (For more information on this disorder, choose “spinocerebellar ataxia with axonal neuropathy” as your search term in the Rare Disease Database.)Behcet’s disease is a disorder characterized by inflammation, skin lesions, and ulcers affecting mucous membranes around the mouth and genitals. Behcet’s disease can also cause symptoms affecting the central nervous system and can lead to headaches, impaired muscle movements of the throat and face, ataxia, stroke, or seizures. The exact cause of this disorder is unknown. (For more information on this disorder, choose “Behcet’s” as your search term in the Rare Disease Database.)Creutzfeldt-Jakob disease (CJD) is a rare disorder characterized by the deterioration of the brain and a sudden onset of symptoms, such as confusion, behavior changes, impaired vision, impaired coordination, and muscle weakness. Creutzfeldt-Jakob disease occurs randomly in about 90 percent of cases and the other 10 percent of cases may be associated with a family history of the disease. It may also result from an abnormal prion protein, which is a protein that can cause other normal proteins in the brain to misfold. (For more information on this disorder, choose “Creutzfeldt Jakob disease” as your search term in the Rare Disease Database.)Progressive multifocal leukoencephalopathy is a disorder caused by an infection of the JC virus, a virus named after the initials of its first known patient. The JC virus attacks cells that make myelin, a substance that forms a protective layer around nerve cells in the spinal cord and brain. Symptoms of progressive multifocal leukoencephalopathy may include difficulty speaking, sensory loss, impaired vision, weakness, and ataxia. (For more information on this disorder, choose “progressive multifocal leukoencephalopathy” as your search term in the Rare Disease Database.)
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Related disorders of Subacute Cerebellar Degeneration. Symptoms of the following disorders can be similar to those of SCD. Comparisons may be useful for a differential diagnosis:Paraneoplastic neurologic syndromes (PNS) are a group of conditions that affect the nervous system (brain, spinal cord, nerves and/or muscles) in patients with cancer. The term “paraneoplastic” means that the neurological syndrome is not caused by the tumor itself, but by the immunological reactions that the tumor produces. PNS are categorized by the area of the nervous system that is principally affected, the type of symptoms or the type of immunological response. (For more information on these disorders, choose “paraneoplastic neurologic syndromes” as your search term in the Rare Disease Database.)Multiple sclerosis (MS) is a chronic disease of the central nervous system, which may be progressive, relapsing and remitting, or stable. MS is characterized by small lesions called plaques that form randomly throughout the brain and spinal cord. These patches prevent proper transmission of nervous system signals and thus result in a variety of neurological symptoms including visual difficulties (blind spots, double vision, nystagmus), impairment of speech, abnormal skin sensations (paresthesia) or numbness, walking disturbance and difficulties with bladder or bowel function. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)Wernicke encephalopathy is a degenerative brain disorder characterized by a deficiency of thiamine. It is marked by loss of coordination (ataxia) and apathy, confusion, disorientation or delirium. Various vision dysfunctions may also develop. This disorder often occurs in conjunction with Korsakoff syndrome which involves a Vitamin B1 (thiamine) deficiency usually caused by alcoholism. Wernicke encephalopathy can be severely disabling and life threatening if it is not recognized and treated early. (For more information, on this disorder, choose “Korsakoff” or “Wernicke” as your search term in the Rare Disease Database.)Hodgkin’s disease and several other types of cancers, such as lung, ovarian, breast, stomach, and uterine cancers may be associated with paraneoplastic cerebellar degeneration. Hodgkin’s disease is a form of cancer of the lymphatic system, especially the lymph nodes. Tumors occur in the lymph nodes (places where lymphatic vessels unite) and/or the area around the nodes. Fever, night sweats, and weight loss may occur along with swollen lymph nodes. (For more information on this disorder, choose “Hodgkin’s disease” as your search term in the Rare Disease Database.)Spinocerebellar ataxia is a rare, hereditary disease that occurs when a single copy of a non-working gene has been inherited from either parent or has been changed within the affected individual. Spinocerebellar ataxia mainly affects the cerebellum and causes symptoms such as ataxia, abnormal speech, and vision problems. There are about 40 different types of spinocerebellar ataxia. Each type of spinocerebellar ataxia is associated with a different altered gene. (For more information on this disorder, choose “autosomal dominant hereditary ataxia” as your search term in the Rare Disease Database.)
Episodic ataxia is a rare, neurologic condition that affects nerve cell signaling that controls body movement. There are currently 8 types of episodic ataxia. It is a disorder caused by altered genes and occurs when a single copy of a non-working gene has been inherited from either parent or has been changed within the affected individual. Each episode can last a few seconds up to a few hours, and can cause muscle weakness, seizures, or paralysis. (For more information on this disorder, choose “autosomal dominant hereditary ataxia” as your search term in the Rare Disease Database.)
Spinocerebellar ataxia with axonal neuropathy is a rare, hereditary, disease that occurs when a non-working gene has been inherited by each parent. Spinocerebellar ataxia with axonal neuropathy is characterized by the onset of cerebellar ataxia during the late childhood years. The disease progresses slowly and can cause symptoms such as ataxia, dysarthria (abnormal speech), gaze nystagmus (uncontrolled movement of the eyes), and peripheral neuropathy. (For more information on this disorder, choose “spinocerebellar ataxia with axonal neuropathy” as your search term in the Rare Disease Database.)Behcet’s disease is a disorder characterized by inflammation, skin lesions, and ulcers affecting mucous membranes around the mouth and genitals. Behcet’s disease can also cause symptoms affecting the central nervous system and can lead to headaches, impaired muscle movements of the throat and face, ataxia, stroke, or seizures. The exact cause of this disorder is unknown. (For more information on this disorder, choose “Behcet’s” as your search term in the Rare Disease Database.)Creutzfeldt-Jakob disease (CJD) is a rare disorder characterized by the deterioration of the brain and a sudden onset of symptoms, such as confusion, behavior changes, impaired vision, impaired coordination, and muscle weakness. Creutzfeldt-Jakob disease occurs randomly in about 90 percent of cases and the other 10 percent of cases may be associated with a family history of the disease. It may also result from an abnormal prion protein, which is a protein that can cause other normal proteins in the brain to misfold. (For more information on this disorder, choose “Creutzfeldt Jakob disease” as your search term in the Rare Disease Database.)Progressive multifocal leukoencephalopathy is a disorder caused by an infection of the JC virus, a virus named after the initials of its first known patient. The JC virus attacks cells that make myelin, a substance that forms a protective layer around nerve cells in the spinal cord and brain. Symptoms of progressive multifocal leukoencephalopathy may include difficulty speaking, sensory loss, impaired vision, weakness, and ataxia. (For more information on this disorder, choose “progressive multifocal leukoencephalopathy” as your search term in the Rare Disease Database.)
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Diagnosis of Subacute Cerebellar Degeneration
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The diagnostic criteria for paraneoplastic cerebellar degeneration are:The diagnostic criteria for alcoholic/ nutritional cerebellar degeneration are:Clinical Testing and Work-Up Paraneoplastic Cerebellar Degeneration –Alcoholic/ Nutritional Cerebellar Degeneration –
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Diagnosis of Subacute Cerebellar Degeneration. The diagnostic criteria for paraneoplastic cerebellar degeneration are:The diagnostic criteria for alcoholic/ nutritional cerebellar degeneration are:Clinical Testing and Work-Up Paraneoplastic Cerebellar Degeneration –Alcoholic/ Nutritional Cerebellar Degeneration –
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Therapies of Subacute Cerebellar Degeneration
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Standard therapeutic options for paraneoplastic cerebellar degeneration include diagnosing and treating the underlying cancer. Prompt tumor removal, chemotherapy and/or radiation may be beneficial and help reduce symptoms in patients. Adjuvant therapy with glucocorticoids such as methylprednisolone and immunotherapy with potent T cell inhibition, such as rituximab and tacrolimus may be elusive. However, small cases have shown both rituximab and tacrolimus may help to stabilize symptom progression in patients with paraneoplastic cerebellar degeneration only. For alcoholic/nutritional cerebellar degeneration, thiamine is given along with other B vitamins, usually relieving the condition if the patient stops drinking alcohol and resumes a normal diet. Physical therapy with focus areas on strengthening, balance and gait balance can help to restore function and prevent long term disability in patients with progressive symptoms. Occupational therapy may focus mainly on activities of daily living and dysphagia rehabilitation.
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Therapies of Subacute Cerebellar Degeneration. Standard therapeutic options for paraneoplastic cerebellar degeneration include diagnosing and treating the underlying cancer. Prompt tumor removal, chemotherapy and/or radiation may be beneficial and help reduce symptoms in patients. Adjuvant therapy with glucocorticoids such as methylprednisolone and immunotherapy with potent T cell inhibition, such as rituximab and tacrolimus may be elusive. However, small cases have shown both rituximab and tacrolimus may help to stabilize symptom progression in patients with paraneoplastic cerebellar degeneration only. For alcoholic/nutritional cerebellar degeneration, thiamine is given along with other B vitamins, usually relieving the condition if the patient stops drinking alcohol and resumes a normal diet. Physical therapy with focus areas on strengthening, balance and gait balance can help to restore function and prevent long term disability in patients with progressive symptoms. Occupational therapy may focus mainly on activities of daily living and dysphagia rehabilitation.
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Overview of Subacute Sclerosing Panencephalitis
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Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder characterized by inflammation of the brain (encephalitis). The disease may develop due to reactivation of the measles virus or an inappropriate immune response to the measles virus. SSPE usually develops 2 to 10 years after the original viral attack. Initial symptoms may include memory loss, irritability, seizures, involuntary muscle movements, and/or behavioral changes, leading to neurological deterioration.
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Overview of Subacute Sclerosing Panencephalitis. Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder characterized by inflammation of the brain (encephalitis). The disease may develop due to reactivation of the measles virus or an inappropriate immune response to the measles virus. SSPE usually develops 2 to 10 years after the original viral attack. Initial symptoms may include memory loss, irritability, seizures, involuntary muscle movements, and/or behavioral changes, leading to neurological deterioration.
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Symptoms of Subacute Sclerosing Panencephalitis
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Subacute sclerosing panencephalitis is a rare neurological disease of childhood or young adulthood. The first signs are usually behavioral changes such as failing schoolwork, memory loss, and/or irritability. Involuntary muscle movements (myoclonic jerks) and generalized seizures follow. Subacute sclerosing panencephalitis is a progressive disease which results in personality changes, outbursts of temper, sleeplessness, disorientation, stupor, spasticity, loss of previously acquired intellectual skills, poor memory and judgment (dementia), and general neurological deterioration. Blindness may develop because of a lesion in the vision center of the brain (cortical blindness) and the nerves of the eyes may waste away (optic atrophy). The late symptoms of subacute sclerosing panencephalitis may include muscle rigidity, elevated body temperature (hyperthermia) and/or abnormalities of respiration, heartbeat, and blood pressure. These disturbances of normal bodily functions (homeostasis) indicate that the hypothalamus gland, which is located deep inside the brain, may be affected.The complications of subacute sclerosing panencephalitis, such as severe pneumonia or coma, usually become life-threatening within 1 to 3 years. However, there may be improvement in some affected individuals for extended periods of time.
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Symptoms of Subacute Sclerosing Panencephalitis. Subacute sclerosing panencephalitis is a rare neurological disease of childhood or young adulthood. The first signs are usually behavioral changes such as failing schoolwork, memory loss, and/or irritability. Involuntary muscle movements (myoclonic jerks) and generalized seizures follow. Subacute sclerosing panencephalitis is a progressive disease which results in personality changes, outbursts of temper, sleeplessness, disorientation, stupor, spasticity, loss of previously acquired intellectual skills, poor memory and judgment (dementia), and general neurological deterioration. Blindness may develop because of a lesion in the vision center of the brain (cortical blindness) and the nerves of the eyes may waste away (optic atrophy). The late symptoms of subacute sclerosing panencephalitis may include muscle rigidity, elevated body temperature (hyperthermia) and/or abnormalities of respiration, heartbeat, and blood pressure. These disturbances of normal bodily functions (homeostasis) indicate that the hypothalamus gland, which is located deep inside the brain, may be affected.The complications of subacute sclerosing panencephalitis, such as severe pneumonia or coma, usually become life-threatening within 1 to 3 years. However, there may be improvement in some affected individuals for extended periods of time.
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Causes of Subacute Sclerosing Panencephalitis
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Subacute sclerosing panencephalitis is thought to be caused by a slow measles virus (paramyxovirus). Slow viruses may stay dormant in humans for extended periods of time, then for reasons yet unknown may become reactivated. The role of heredity which may make a person susceptible to slow viruses is not well understood.The symptoms of SSPE, including inflammation of the brain (encephalitis) and the loss of the fatty covering on nerve fibers (demyelination), may develop due to reactivation of the virus many years after the initial illness. It may also be associated with an inappropriate immune response to the rubeola virus (measles). Typically, affected individuals have a history of measles infection 2 to 10 years before the onset of subacute sclerosing panencephalitis.A few cases of subacute sclerosing panencephalitis in the medical literature have been associated with animal contact. These affected individuals had contact with pets such as monkeys, dogs, or kittens that later died of the same illness.
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Causes of Subacute Sclerosing Panencephalitis. Subacute sclerosing panencephalitis is thought to be caused by a slow measles virus (paramyxovirus). Slow viruses may stay dormant in humans for extended periods of time, then for reasons yet unknown may become reactivated. The role of heredity which may make a person susceptible to slow viruses is not well understood.The symptoms of SSPE, including inflammation of the brain (encephalitis) and the loss of the fatty covering on nerve fibers (demyelination), may develop due to reactivation of the virus many years after the initial illness. It may also be associated with an inappropriate immune response to the rubeola virus (measles). Typically, affected individuals have a history of measles infection 2 to 10 years before the onset of subacute sclerosing panencephalitis.A few cases of subacute sclerosing panencephalitis in the medical literature have been associated with animal contact. These affected individuals had contact with pets such as monkeys, dogs, or kittens that later died of the same illness.
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Affects of Subacute Sclerosing Panencephalitis
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With widespread uss of the measles vaccine in the United States, the incidence of subacute sclerosing panencephalitis has been reduced dramatically, although about 10 cases per year are reported. However, in less developed parts of the world, this disorder is much more common. In India, for example, the incidence is estimated at about 20 cases per year per million of population. Subacute sclerosing panencephalitis seems to affect males more often than females and occurs far more often in children and adolescents than in adults.
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Affects of Subacute Sclerosing Panencephalitis. With widespread uss of the measles vaccine in the United States, the incidence of subacute sclerosing panencephalitis has been reduced dramatically, although about 10 cases per year are reported. However, in less developed parts of the world, this disorder is much more common. In India, for example, the incidence is estimated at about 20 cases per year per million of population. Subacute sclerosing panencephalitis seems to affect males more often than females and occurs far more often in children and adolescents than in adults.
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Related disorders of Subacute Sclerosing Panencephalitis
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Symptoms of the following disorders can be similar to those of subacute sclerosing panencephalitis. Comparisons may be useful for a differential diagnosis:Progressive rubella panencephalitis is a rare slowly progressive neurological disorder that closely resembles subacute sclerosing panencephalitis. It is caused by the rubella virus and develops because of congenital rubella syndrome or childhood rubella infection (German measles). Symptoms usually include behavioral changes, the loss of previously acquired intellectual skills, inability to coordinate movement (ataxia), involuntary muscle movements (spasticity), and/or seizures. There is no known treatment for this disorder. Fewer than 20 cases have been reported in the medical literature.Progressive multifocal leukoencephalopathy is a rare progressive neurological disorder which occurs in people with certain forms of cancer, Acquired immunodeficiency syndrome (AIDS), or those who are receiving immunosuppressant drugs. The disease develops during adulthood and symptoms may include paralysis of one side of the body (hemiplegia), loss of vision in one eye (hemianopsia), loss of verbal communication skills (aphasia), inability to coordinate movement (ataxia), stupor, and/or coma. Progressive multifocal leukoencephalopathy may be the result of reactivation of a slow virus (polyoma).Inclusion body encephalitis (subacute sclerosing leukoencephalitis) is a rare progressive neurological disorder that occurs mostly in children under the age of 12 years. The symptoms begin gradually and may include behavioral changes, loss of previously acquired intellectual skills, involuntary muscle contractions or spasms (myoclonus) of the trunk, arms, and/or legs, and the inability to communicate verbally. Later symptoms usually include loss of vision and hearing, muscle rigidity, and/or dementia.
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Related disorders of Subacute Sclerosing Panencephalitis. Symptoms of the following disorders can be similar to those of subacute sclerosing panencephalitis. Comparisons may be useful for a differential diagnosis:Progressive rubella panencephalitis is a rare slowly progressive neurological disorder that closely resembles subacute sclerosing panencephalitis. It is caused by the rubella virus and develops because of congenital rubella syndrome or childhood rubella infection (German measles). Symptoms usually include behavioral changes, the loss of previously acquired intellectual skills, inability to coordinate movement (ataxia), involuntary muscle movements (spasticity), and/or seizures. There is no known treatment for this disorder. Fewer than 20 cases have been reported in the medical literature.Progressive multifocal leukoencephalopathy is a rare progressive neurological disorder which occurs in people with certain forms of cancer, Acquired immunodeficiency syndrome (AIDS), or those who are receiving immunosuppressant drugs. The disease develops during adulthood and symptoms may include paralysis of one side of the body (hemiplegia), loss of vision in one eye (hemianopsia), loss of verbal communication skills (aphasia), inability to coordinate movement (ataxia), stupor, and/or coma. Progressive multifocal leukoencephalopathy may be the result of reactivation of a slow virus (polyoma).Inclusion body encephalitis (subacute sclerosing leukoencephalitis) is a rare progressive neurological disorder that occurs mostly in children under the age of 12 years. The symptoms begin gradually and may include behavioral changes, loss of previously acquired intellectual skills, involuntary muscle contractions or spasms (myoclonus) of the trunk, arms, and/or legs, and the inability to communicate verbally. Later symptoms usually include loss of vision and hearing, muscle rigidity, and/or dementia.
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Diagnosis of Subacute Sclerosing Panencephalitis
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Diagnosis of Subacute Sclerosing Panencephalitis.
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Therapies of Subacute Sclerosing Panencephalitis
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The diagnosis of subacute sclerosing panencephalitis may be confirmed by clinical evaluation and blood testing that reveals abnormally high levels of the measles antibody. Examination of the electrical activity of the brain (EEG) usually shows a characteristic pattern. The fluid surrounding the brain and spinal cord (cerebrospinal fluid) typically has elevated levels of gammaglobulin and measles antibody.There is no specific treatment for subacute sclerosing panencephalitis. Anticonvulsants may help to control seizure activity. Other treatment is symptomatic and supportive.
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Therapies of Subacute Sclerosing Panencephalitis. The diagnosis of subacute sclerosing panencephalitis may be confirmed by clinical evaluation and blood testing that reveals abnormally high levels of the measles antibody. Examination of the electrical activity of the brain (EEG) usually shows a characteristic pattern. The fluid surrounding the brain and spinal cord (cerebrospinal fluid) typically has elevated levels of gammaglobulin and measles antibody.There is no specific treatment for subacute sclerosing panencephalitis. Anticonvulsants may help to control seizure activity. Other treatment is symptomatic and supportive.
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Overview of Succinic Semialdehyde Dehydrogenase Deficiency
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SummarySuccinic semialdehyde dehydrogenase (SSADH) deficiency is a rare inborn error of metabolism that is inherited in an autosomal recessive pattern. In individuals with the disorder, deficient activity of the SSADH enzyme disrupts the metabolism of gamma-aminobutyric acid (GABA). GABA is a natural chemical known as a “neurotransmitter” that serves to inhibit the electrical activities of nerve cells (inhibitory neurotransmitter). SSADH deficiency leads to abnormal accumulation of the compound succinic semialdehyde, which is reduced or converted to 4-hydroxybutyric acid, also known as GHB (gamma-hydroxybutyric acid). GHB is a natural compound that has a wide range of effects within the nervous system. The “hallmark” laboratory finding associated with SSADH deficiency is elevated levels of GHB in the urine (i.e., 4-hydroxybutyric or gamma-hydroxybutyric aciduria), the liquid portion of the blood (plasma), and the fluid that flows through the brain and spinal canal (cerebrospinal fluid [CSF]).SSADH deficiency leads to various neurological and neuromuscular symptoms and findings. These abnormalities may be extremely variable from person to person, including among affected members of the same families (kindreds). However, most individuals with SSADH deficiency are affected by mild to severe intellectual disability, delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation), and delays in language and speech development. In addition, in some people, initial findings may include diminished muscle tone (hypotonia), an impaired ability to coordinate voluntary movements (ataxia), and/or episodes of uncontrolled electrical activity in the brain (seizures). Some affected individuals may also have additional abnormalities, such as decreased reflex reactions (hyporeflexia); involuntary, rapid, rhythmic eye movements (nystagmus); increased muscular activity (hyperkinesis); and/or behavioral abnormalities.
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Overview of Succinic Semialdehyde Dehydrogenase Deficiency. SummarySuccinic semialdehyde dehydrogenase (SSADH) deficiency is a rare inborn error of metabolism that is inherited in an autosomal recessive pattern. In individuals with the disorder, deficient activity of the SSADH enzyme disrupts the metabolism of gamma-aminobutyric acid (GABA). GABA is a natural chemical known as a “neurotransmitter” that serves to inhibit the electrical activities of nerve cells (inhibitory neurotransmitter). SSADH deficiency leads to abnormal accumulation of the compound succinic semialdehyde, which is reduced or converted to 4-hydroxybutyric acid, also known as GHB (gamma-hydroxybutyric acid). GHB is a natural compound that has a wide range of effects within the nervous system. The “hallmark” laboratory finding associated with SSADH deficiency is elevated levels of GHB in the urine (i.e., 4-hydroxybutyric or gamma-hydroxybutyric aciduria), the liquid portion of the blood (plasma), and the fluid that flows through the brain and spinal canal (cerebrospinal fluid [CSF]).SSADH deficiency leads to various neurological and neuromuscular symptoms and findings. These abnormalities may be extremely variable from person to person, including among affected members of the same families (kindreds). However, most individuals with SSADH deficiency are affected by mild to severe intellectual disability, delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation), and delays in language and speech development. In addition, in some people, initial findings may include diminished muscle tone (hypotonia), an impaired ability to coordinate voluntary movements (ataxia), and/or episodes of uncontrolled electrical activity in the brain (seizures). Some affected individuals may also have additional abnormalities, such as decreased reflex reactions (hyporeflexia); involuntary, rapid, rhythmic eye movements (nystagmus); increased muscular activity (hyperkinesis); and/or behavioral abnormalities.
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Symptoms of Succinic Semialdehyde Dehydrogenase Deficiency
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In individuals with SSADH deficiency, the range, severity, and presentation of certain symptoms and findings may be variable, including among affected family members. In addition, such neurological and neuromuscular symptoms are often considered “nonspecific”, meaning that they may be associated with any number of underlying disorders, potentially leading to difficulties with diagnosis. (For further information, please see the “Standard Therapies: Diagnosis” section of this report below.) However, during childhood, most affected individuals appear to have some degree of delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (i.e., “developmental milestones”). Initial or “presenting” symptoms vary from person to person. However, initial symptoms often include delays in achieving certain motor milestones (e.g., crawling, sitting unaided, walking without assistance); reduced muscle tone (hypotonia); and/or intellectual or language delays. In some people, additional presenting symptoms are an impaired ability to coordinate voluntary movements (ataxia); episodes of uncontrolled electrical activity in the brain (seizures); and/or certain abnormalities during early infancy including failure to cry or respond to certain visual stimuli. Although symptoms usually begin during infancy or childhood, the disorder sometimes is not diagnosed until adulthood. The language and speech abnormalities associated with SSADH deficiency may be extremely variable. For example, in severe cases, individuals may be nonverbal or speech may be infrequent and consist of only a few words or simple phrases but some people have normal speech and language development. As mentioned above, ataxia or incoordination is sometimes an initial finding associated with SSADH deficiency. The ataxia is typically non-progressive, may be confined to muscles of the trunk and the arms or legs (limbs), and tends to resolve with age. Some individuals with SSADH deficiency may also develop additional neurological and neuromuscular symptoms. Such abnormalities may include decreased or absent reflex reactions (hyporeflexia or areflexia); abnormally increased muscular activity (hyperkinesis); and/or, less commonly, a movement disorder known as choreoathetosis. This condition is characterized by involuntary, rapid, jerky movements (chorea) occurring in association with relatively slow, sinuous, writhing motions (athetosis). Some affected individuals may also develop behavioral abnormalities, such as unusual irritability, easy agitation or frustration, increasingly aggressive behavior, obsessive compulsive disorder (OCD) or “autistic-like” behaviors. The latter may include impaired communication and social interaction, extreme withdrawal, and/or a tendency to engage in certain ritualistic behaviors or repeated body movements (e.g., frequent rocking). Additional abnormalities have been reported in association with SSADH deficiency. For example, some individuals may be affected by unusual drowsiness (somnolence); psychotic behaviors, such as the perception of certain sounds, sights, or other sensations in the absence of external stimuli (hallucinations); and/or certain eye (locular) abnormalities. Ocular findings may include involuntary, rapid, rhythmic eye movements (nystagmus); and impaired ability to consciously coordinate movements of the eyes (oculomotor apraxia); and/or poor vision. Some affected individuals have been reported to have abnormalities of the skull and facial (craniofacial) area, including unusual smallness or largeness of the head (microcephaly or macrocephaly). As mentioned above, non-progressive ataxia associated with SSADH deficiency may tend to significantly improve with age. In addition, evidence suggests that there may be additional variations with age seen in associated symptoms. For example, whereas some younger individuals may tend to be affected by drowsiness (somnolence), older individuals may be more likely to develop abnormally increased activity (hyperactivity) or aggressive behaviors.
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Symptoms of Succinic Semialdehyde Dehydrogenase Deficiency. In individuals with SSADH deficiency, the range, severity, and presentation of certain symptoms and findings may be variable, including among affected family members. In addition, such neurological and neuromuscular symptoms are often considered “nonspecific”, meaning that they may be associated with any number of underlying disorders, potentially leading to difficulties with diagnosis. (For further information, please see the “Standard Therapies: Diagnosis” section of this report below.) However, during childhood, most affected individuals appear to have some degree of delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (i.e., “developmental milestones”). Initial or “presenting” symptoms vary from person to person. However, initial symptoms often include delays in achieving certain motor milestones (e.g., crawling, sitting unaided, walking without assistance); reduced muscle tone (hypotonia); and/or intellectual or language delays. In some people, additional presenting symptoms are an impaired ability to coordinate voluntary movements (ataxia); episodes of uncontrolled electrical activity in the brain (seizures); and/or certain abnormalities during early infancy including failure to cry or respond to certain visual stimuli. Although symptoms usually begin during infancy or childhood, the disorder sometimes is not diagnosed until adulthood. The language and speech abnormalities associated with SSADH deficiency may be extremely variable. For example, in severe cases, individuals may be nonverbal or speech may be infrequent and consist of only a few words or simple phrases but some people have normal speech and language development. As mentioned above, ataxia or incoordination is sometimes an initial finding associated with SSADH deficiency. The ataxia is typically non-progressive, may be confined to muscles of the trunk and the arms or legs (limbs), and tends to resolve with age. Some individuals with SSADH deficiency may also develop additional neurological and neuromuscular symptoms. Such abnormalities may include decreased or absent reflex reactions (hyporeflexia or areflexia); abnormally increased muscular activity (hyperkinesis); and/or, less commonly, a movement disorder known as choreoathetosis. This condition is characterized by involuntary, rapid, jerky movements (chorea) occurring in association with relatively slow, sinuous, writhing motions (athetosis). Some affected individuals may also develop behavioral abnormalities, such as unusual irritability, easy agitation or frustration, increasingly aggressive behavior, obsessive compulsive disorder (OCD) or “autistic-like” behaviors. The latter may include impaired communication and social interaction, extreme withdrawal, and/or a tendency to engage in certain ritualistic behaviors or repeated body movements (e.g., frequent rocking). Additional abnormalities have been reported in association with SSADH deficiency. For example, some individuals may be affected by unusual drowsiness (somnolence); psychotic behaviors, such as the perception of certain sounds, sights, or other sensations in the absence of external stimuli (hallucinations); and/or certain eye (locular) abnormalities. Ocular findings may include involuntary, rapid, rhythmic eye movements (nystagmus); and impaired ability to consciously coordinate movements of the eyes (oculomotor apraxia); and/or poor vision. Some affected individuals have been reported to have abnormalities of the skull and facial (craniofacial) area, including unusual smallness or largeness of the head (microcephaly or macrocephaly). As mentioned above, non-progressive ataxia associated with SSADH deficiency may tend to significantly improve with age. In addition, evidence suggests that there may be additional variations with age seen in associated symptoms. For example, whereas some younger individuals may tend to be affected by drowsiness (somnolence), older individuals may be more likely to develop abnormally increased activity (hyperactivity) or aggressive behaviors.
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Causes of Succinic Semialdehyde Dehydrogenase Deficiency
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SSADH deficiency is a rare inborn error of metabolism that is inherited in an autosomal recessive pattern. “Metabolism” refers to all the chemical processes in the body, including the breakdown of complex substances into simpler ones (catabolism), usually with the release of energy, and processes in which complex substances are built up from simpler ones (anabolism), usually resulting in energy consumption. Inborn errors of metabolism result from abnormal functioning of a specific protein or enzyme that accelerates particular chemical activities in the body. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. The gene responsible for most cases of SSADH deficiency is ALDH5A1 that codes for the SSADH enzyme. Evidence suggests that most affected families have had different changes (mutations) of the SSADH gene that leads to impaired functioning of the SSADH enzyme. Impaired functioning of the SSADH enzyme results in disrupted metabolism of GABA (gamma-aminobutyric acid), an amino acid neurotransmitter. Amino acids are the chemical building blocks that form proteins in the body. Neurotransmitters modify or result in the transmission of nerve impulses from one nerve cell (neuron) to another, enabling neurons to communicate. More specifically, these natural chemicals either serve to trigger or inhibit the electrical activities of “targeted” neurons (i.e., excitatory or inhibitory neurons). GABA is the main inhibitory neurotransmitter in the brain. SSADH deficiency leads to abnormal accumulation of the compound succinic semialdehyde, which is converted to 4-hydroxybutyric acid (4-HBA) or “GHB” (gamma-hydroxybutyric acid). Thus, individuals with SSADH deficiency have unusually elevated levels of GHB in urine, plasma, and cerebrospinal fluid. As mentioned above, GHB is a natural compound that has a wide range of affects within the nervous system (i.e., neurophysiologic effects). Although there is evidence that it acts as a neurotransmitter, its specific functions in the brain remain unknown. In the 1960s, GHB was developed by the pharmaceutical industry as an agent similar to GABA (analog). It was initially used as an anesthetic for children due to its sedative properties; however, such use resulted in adverse side effects. More recently, evidence suggests that GHB plays an important role in energy regulation and as a “protector” against tissue damage (e.g., during lack of adequate oxygen supply to tissues [hypoxia]). Its current clinical application is in the treatment of cataplexy, part of a sleep disorder known as narcolepsy, though it has also been used for alcohol-withdrawal syndrome and difficult labor and delivery during childbirth. Certain effects potentially associated with the therapeutic use of GHB (i.e., pharmacologic effects) are similar to those seen in individuals with SSADH deficiency. These include diminished muscle tone (hypotonia), drowsiness (somnolence), and seizures or seizure-like activity. In addition, reports suggest that in some affected individuals, there may be age-related decreases of GHB concentrations in bodily fluids, potentially leading to the symptom variations seen in some cases. For example, younger individuals with relatively high GHB concentrations in bodily fluids may tend to be affected by drowsiness. In contrast, in older individuals with lower GHB concentrations, symptoms may tend to include abnormally increased activity or aggressive behaviors. Based upon such findings, some investigators suggest that GHB may act on inhibitory nerve cell (neuron) receptors at high concentrations and excitatory receptors at low concentrations. (Receptors are specific sites on the surface of a neuron that bind with neurotransmitters.) Furthermore, SSADH deficiency results in a decrease in GABA receptors in early life, also likely contributing to the shift towards more excitation. Further research is required to learn more about GHB’s mode of action and to determine whether the neurological symptoms associated with SSADH deficiency result from increased accumulations of GHB, disturbances of GABA levels, a combination of both, or other abnormalities.
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Causes of Succinic Semialdehyde Dehydrogenase Deficiency. SSADH deficiency is a rare inborn error of metabolism that is inherited in an autosomal recessive pattern. “Metabolism” refers to all the chemical processes in the body, including the breakdown of complex substances into simpler ones (catabolism), usually with the release of energy, and processes in which complex substances are built up from simpler ones (anabolism), usually resulting in energy consumption. Inborn errors of metabolism result from abnormal functioning of a specific protein or enzyme that accelerates particular chemical activities in the body. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. The gene responsible for most cases of SSADH deficiency is ALDH5A1 that codes for the SSADH enzyme. Evidence suggests that most affected families have had different changes (mutations) of the SSADH gene that leads to impaired functioning of the SSADH enzyme. Impaired functioning of the SSADH enzyme results in disrupted metabolism of GABA (gamma-aminobutyric acid), an amino acid neurotransmitter. Amino acids are the chemical building blocks that form proteins in the body. Neurotransmitters modify or result in the transmission of nerve impulses from one nerve cell (neuron) to another, enabling neurons to communicate. More specifically, these natural chemicals either serve to trigger or inhibit the electrical activities of “targeted” neurons (i.e., excitatory or inhibitory neurons). GABA is the main inhibitory neurotransmitter in the brain. SSADH deficiency leads to abnormal accumulation of the compound succinic semialdehyde, which is converted to 4-hydroxybutyric acid (4-HBA) or “GHB” (gamma-hydroxybutyric acid). Thus, individuals with SSADH deficiency have unusually elevated levels of GHB in urine, plasma, and cerebrospinal fluid. As mentioned above, GHB is a natural compound that has a wide range of affects within the nervous system (i.e., neurophysiologic effects). Although there is evidence that it acts as a neurotransmitter, its specific functions in the brain remain unknown. In the 1960s, GHB was developed by the pharmaceutical industry as an agent similar to GABA (analog). It was initially used as an anesthetic for children due to its sedative properties; however, such use resulted in adverse side effects. More recently, evidence suggests that GHB plays an important role in energy regulation and as a “protector” against tissue damage (e.g., during lack of adequate oxygen supply to tissues [hypoxia]). Its current clinical application is in the treatment of cataplexy, part of a sleep disorder known as narcolepsy, though it has also been used for alcohol-withdrawal syndrome and difficult labor and delivery during childbirth. Certain effects potentially associated with the therapeutic use of GHB (i.e., pharmacologic effects) are similar to those seen in individuals with SSADH deficiency. These include diminished muscle tone (hypotonia), drowsiness (somnolence), and seizures or seizure-like activity. In addition, reports suggest that in some affected individuals, there may be age-related decreases of GHB concentrations in bodily fluids, potentially leading to the symptom variations seen in some cases. For example, younger individuals with relatively high GHB concentrations in bodily fluids may tend to be affected by drowsiness. In contrast, in older individuals with lower GHB concentrations, symptoms may tend to include abnormally increased activity or aggressive behaviors. Based upon such findings, some investigators suggest that GHB may act on inhibitory nerve cell (neuron) receptors at high concentrations and excitatory receptors at low concentrations. (Receptors are specific sites on the surface of a neuron that bind with neurotransmitters.) Furthermore, SSADH deficiency results in a decrease in GABA receptors in early life, also likely contributing to the shift towards more excitation. Further research is required to learn more about GHB’s mode of action and to determine whether the neurological symptoms associated with SSADH deficiency result from increased accumulations of GHB, disturbances of GABA levels, a combination of both, or other abnormalities.
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Affects of Succinic Semialdehyde Dehydrogenase Deficiency
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SSADH deficiency appears to affect males and females relatively equally. Since the disorder was originally described in 1981 (C. Jakobs), over 400 cases of SSADH deficiency have been identified. According to one review published in 1997 reporting 23 affected individuals (from 20 families), the age at diagnosis ranged from three months to 25 years. Most affected individuals were of Turkish, American Caucasian, Indian, and Northern European descent. Additional nationalities were also noted, including Korean, Palestinian, Syrian, Pakistani, Saudi, Chinese, and Inuit descent. A recent review of adult cases included one with long-standing intellectual disability diagnosed with SSADH deficiency at 63 years old when he had a progressive decline of function and increased seizures. Due to the variability and nonspecific nature of associated symptoms, experts suggest that the disorder may be significantly underdiagnosed. As a result, it is difficult to determine the true frequency of SSADH deficiency in the general population.
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Affects of Succinic Semialdehyde Dehydrogenase Deficiency. SSADH deficiency appears to affect males and females relatively equally. Since the disorder was originally described in 1981 (C. Jakobs), over 400 cases of SSADH deficiency have been identified. According to one review published in 1997 reporting 23 affected individuals (from 20 families), the age at diagnosis ranged from three months to 25 years. Most affected individuals were of Turkish, American Caucasian, Indian, and Northern European descent. Additional nationalities were also noted, including Korean, Palestinian, Syrian, Pakistani, Saudi, Chinese, and Inuit descent. A recent review of adult cases included one with long-standing intellectual disability diagnosed with SSADH deficiency at 63 years old when he had a progressive decline of function and increased seizures. Due to the variability and nonspecific nature of associated symptoms, experts suggest that the disorder may be significantly underdiagnosed. As a result, it is difficult to determine the true frequency of SSADH deficiency in the general population.
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Related disorders of Succinic Semialdehyde Dehydrogenase Deficiency
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Symptoms of the following conditions may be similar to those of SSADH deficiency. Comparisons may be useful for a differential diagnosis: There are additional metabolic disorders that have been identified in which certain enzyme deficiencies result in disrupted metabolism of a neurotransmitter or neurotransmitters. These disorders include GTP cyclohydrolase I deficiency (dopa-responsive dystonia), aromatic L-amino acid decarboxylase deficiency, and tyrosine hydroxylase deficiency. Although associated neurological and neuromuscular symptoms may vary, these disorders may have certain features that are similar to those associated with SSADH deficiency. Such abnormalities may include abnormally low muscle tone (hypotonia), delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation), irritability, and/or other symptoms and findings. Depending upon the specific metabolic defect(s) and other factors, the age at symptom onset may vary from early infancy to childhood. Various genetic disorders including single gene disorders and chromosomal deletion syndromes may appear quite similar, especially when they lack other associated systemic or dysmorphic features. Evidence suggests that there may be other currently unidentified metabolic disorders resulting in disrupted metabolism of neurotransmitters. There are additional disorders of infancy or childhood that may be characterized by abnormally diminished muscle tone (hypotonia), psychomotor delays, speech and language delays, intellectual disability, seizures, and/or other symptoms and findings similar to those potentially associated with SSADH deficiency. (For further information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Succinic Semialdehyde Dehydrogenase Deficiency. Symptoms of the following conditions may be similar to those of SSADH deficiency. Comparisons may be useful for a differential diagnosis: There are additional metabolic disorders that have been identified in which certain enzyme deficiencies result in disrupted metabolism of a neurotransmitter or neurotransmitters. These disorders include GTP cyclohydrolase I deficiency (dopa-responsive dystonia), aromatic L-amino acid decarboxylase deficiency, and tyrosine hydroxylase deficiency. Although associated neurological and neuromuscular symptoms may vary, these disorders may have certain features that are similar to those associated with SSADH deficiency. Such abnormalities may include abnormally low muscle tone (hypotonia), delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation), irritability, and/or other symptoms and findings. Depending upon the specific metabolic defect(s) and other factors, the age at symptom onset may vary from early infancy to childhood. Various genetic disorders including single gene disorders and chromosomal deletion syndromes may appear quite similar, especially when they lack other associated systemic or dysmorphic features. Evidence suggests that there may be other currently unidentified metabolic disorders resulting in disrupted metabolism of neurotransmitters. There are additional disorders of infancy or childhood that may be characterized by abnormally diminished muscle tone (hypotonia), psychomotor delays, speech and language delays, intellectual disability, seizures, and/or other symptoms and findings similar to those potentially associated with SSADH deficiency. (For further information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Diagnosis of Succinic Semialdehyde Dehydrogenase Deficiency
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The diagnosis of SSADH deficiency is usually made after birth (postnatally) during infancy or childhood (or, in some cases, adulthood), based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests. Due to the nonspecific nature and variability of associated symptoms, experts suggest that SSADH deficiency should be considered in any individuals with two or more features of intellectual, language, and motor delay and abnormally diminished muscle tone (hypotonia) of unknown cause (idiopathic). Specialized testing to confirm a diagnosis of SSADH deficiency typically includes studies (i.e., quantitative organic acid analysis in an appropriate specialist laboratory) that may detect increased concentrations of 4-hydroxybutyric acid (4-HBA) in urine (i.e., 4-hydroxybutyric aciduria) and testing to confirm deficient activity of the SSADH enzyme in white blood cells (leukocytes) isolated from whole blood. (Note: As mentioned above, increased concentrations of 4-HBA may also be detected in plasma and cerebrospinal fluid. In addition, deficient SSADH activity has also been demonstrated in certain cells other than leukocytes.) Molecular genetic testing to identify bi-allelic mutations (abnormal changes found on both copies of a gene) or deletions in the ALDH5A1 gene is increasingly used to make or confirm a diagnosis of SSADH deficiency. Physicians who are interested in obtaining information on testing for SSADH deficiency may wish to contact: K. M. Gibson, PhD, FACMG
Allen I. White Professor and Chair
Experimental and Systems Pharmacology (ESP)
WSU College of Pharmacy
PBS Building Room 347
412 E. Spokane Falls Blvd
Spokane WA 99202-2131
509 358 7954
[email protected] In some instances, other specialized tests may also be conducted to help detect or characterize certain abnormalities that may be associated with the disorder. Such testing may include computerized tomography (CT) scanning, magnetic resonance imaging (MRI), or electroencephalography (EEG). During CT scanning, a computer and x-rays may be used to create a film showing cross-sectional images of the brain. In MRI, a magnetic field and radio waves may create detailed cross-sectional images of the brain. An EEG is conducted to record the brain’s electrical impulses, potentially detecting brain wave patterns that are characteristic of certain types of seizures. In some cases, a diagnosis of SSADH deficiency may be suggested before birth (prenatally) by specialized tests. These include studies that may detect increased concentrations of 4-ydroxybutyric acid (GHB) in fluid surrounding the developing fetus (amniotic fluid) and deficient activity of the SSADH enzyme in certain fetal cells obtained via amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the fetus is removed and analyzed, whereas CVS involves the removal of tissue samples from a portion of the placenta.
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Diagnosis of Succinic Semialdehyde Dehydrogenase Deficiency. The diagnosis of SSADH deficiency is usually made after birth (postnatally) during infancy or childhood (or, in some cases, adulthood), based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests. Due to the nonspecific nature and variability of associated symptoms, experts suggest that SSADH deficiency should be considered in any individuals with two or more features of intellectual, language, and motor delay and abnormally diminished muscle tone (hypotonia) of unknown cause (idiopathic). Specialized testing to confirm a diagnosis of SSADH deficiency typically includes studies (i.e., quantitative organic acid analysis in an appropriate specialist laboratory) that may detect increased concentrations of 4-hydroxybutyric acid (4-HBA) in urine (i.e., 4-hydroxybutyric aciduria) and testing to confirm deficient activity of the SSADH enzyme in white blood cells (leukocytes) isolated from whole blood. (Note: As mentioned above, increased concentrations of 4-HBA may also be detected in plasma and cerebrospinal fluid. In addition, deficient SSADH activity has also been demonstrated in certain cells other than leukocytes.) Molecular genetic testing to identify bi-allelic mutations (abnormal changes found on both copies of a gene) or deletions in the ALDH5A1 gene is increasingly used to make or confirm a diagnosis of SSADH deficiency. Physicians who are interested in obtaining information on testing for SSADH deficiency may wish to contact: K. M. Gibson, PhD, FACMG
Allen I. White Professor and Chair
Experimental and Systems Pharmacology (ESP)
WSU College of Pharmacy
PBS Building Room 347
412 E. Spokane Falls Blvd
Spokane WA 99202-2131
509 358 7954
[email protected] In some instances, other specialized tests may also be conducted to help detect or characterize certain abnormalities that may be associated with the disorder. Such testing may include computerized tomography (CT) scanning, magnetic resonance imaging (MRI), or electroencephalography (EEG). During CT scanning, a computer and x-rays may be used to create a film showing cross-sectional images of the brain. In MRI, a magnetic field and radio waves may create detailed cross-sectional images of the brain. An EEG is conducted to record the brain’s electrical impulses, potentially detecting brain wave patterns that are characteristic of certain types of seizures. In some cases, a diagnosis of SSADH deficiency may be suggested before birth (prenatally) by specialized tests. These include studies that may detect increased concentrations of 4-ydroxybutyric acid (GHB) in fluid surrounding the developing fetus (amniotic fluid) and deficient activity of the SSADH enzyme in certain fetal cells obtained via amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the fetus is removed and analyzed, whereas CVS involves the removal of tissue samples from a portion of the placenta.
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Therapies of Succinic Semialdehyde Dehydrogenase Deficiency
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Treatment
The treatment of SSADH deficiency is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; physicians who specialize in the diagnosis and treatment of neurological disorders in children (pediatric neurologists); and/or other health care professionals. In some affected individuals, treatment may include the use of certain medications to help prevent, reduce, or control seizures (anticonvulsants, e.g., carbamazepine, levetiracetam, etc.) or to alleviate other symptoms potentially associated with the disorder. (For further information, please see the “Investigational Therapies” section of this report below). A variety of anti-seizure medications are utilized. While valproic acid may reduce residual SSADH enzyme activity, it may sometimes be considered in cases with refractory seizures. Early intervention may be important in ensuring that children with SSADH deficiency reach their potential. Special services that may be beneficial include physical therapy, special remedial education, speech therapy, occupational therapy and other medical, social, and/or vocational services. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. Patients, families and physicians interested in obtaining clinical and/or therapeutic information on SSADH deficiency may wish to contact: Phillip L. Pearl, MD
Chief of Epilepsy and Clinical Neurophysiology
Boston Children’s Hospital
Harvard Medical School
[email protected]
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Therapies of Succinic Semialdehyde Dehydrogenase Deficiency. Treatment
The treatment of SSADH deficiency is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; physicians who specialize in the diagnosis and treatment of neurological disorders in children (pediatric neurologists); and/or other health care professionals. In some affected individuals, treatment may include the use of certain medications to help prevent, reduce, or control seizures (anticonvulsants, e.g., carbamazepine, levetiracetam, etc.) or to alleviate other symptoms potentially associated with the disorder. (For further information, please see the “Investigational Therapies” section of this report below). A variety of anti-seizure medications are utilized. While valproic acid may reduce residual SSADH enzyme activity, it may sometimes be considered in cases with refractory seizures. Early intervention may be important in ensuring that children with SSADH deficiency reach their potential. Special services that may be beneficial include physical therapy, special remedial education, speech therapy, occupational therapy and other medical, social, and/or vocational services. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. Patients, families and physicians interested in obtaining clinical and/or therapeutic information on SSADH deficiency may wish to contact: Phillip L. Pearl, MD
Chief of Epilepsy and Clinical Neurophysiology
Boston Children’s Hospital
Harvard Medical School
[email protected]
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Overview of Sudden Infant Death Syndrome
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Sudden infant death syndrome (SIDS) is the sudden death of an infant under the age of 1 year that remains unexplained after careful review of the history, death scene investigation, and thorough autopsy. In 2008, the most recent published data from the National Vital Statistics System indicated that SIDS was listed as the third leading cause of death in infants in the United States. Causes of SIDS are considered to be multifactorial. The triple risk hypothesis describes the presence of three risk factors that, when overlapping, predispose a baby to SIDS. These include an environmental trigger/stress, a critical developmental period, and an underlying vulnerability. Physician-scientists and scientists are studying neuropathological tissue and genetic material from SIDS victims to ascertain factors that might be responsible for heightening an infant’s vulnerability to SIDS. Others are performing physiologic studies on infants known to have an increased risk for SIDS. Basic scientists are studying animal models that might provide insight into mechanisms responsible for SIDS. Current clinical management targets improving education for families and caregivers regarding known modifiable environmental stressors (risk factors) (see below).
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Overview of Sudden Infant Death Syndrome. Sudden infant death syndrome (SIDS) is the sudden death of an infant under the age of 1 year that remains unexplained after careful review of the history, death scene investigation, and thorough autopsy. In 2008, the most recent published data from the National Vital Statistics System indicated that SIDS was listed as the third leading cause of death in infants in the United States. Causes of SIDS are considered to be multifactorial. The triple risk hypothesis describes the presence of three risk factors that, when overlapping, predispose a baby to SIDS. These include an environmental trigger/stress, a critical developmental period, and an underlying vulnerability. Physician-scientists and scientists are studying neuropathological tissue and genetic material from SIDS victims to ascertain factors that might be responsible for heightening an infant’s vulnerability to SIDS. Others are performing physiologic studies on infants known to have an increased risk for SIDS. Basic scientists are studying animal models that might provide insight into mechanisms responsible for SIDS. Current clinical management targets improving education for families and caregivers regarding known modifiable environmental stressors (risk factors) (see below).
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Symptoms of Sudden Infant Death Syndrome
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There are typically no symptoms prior to a SIDS death. Though SIDS occurs during sleep, the deaths may occur during day or night time sleep. Existing literature does not indicate any evidence for suffering by the infant in the moments preceding the sudden death.
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Symptoms of Sudden Infant Death Syndrome. There are typically no symptoms prior to a SIDS death. Though SIDS occurs during sleep, the deaths may occur during day or night time sleep. Existing literature does not indicate any evidence for suffering by the infant in the moments preceding the sudden death.
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Causes of Sudden Infant Death Syndrome
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By definition, the cause of SIDS is unknown. Therefore, the existing research addresses modifiable environmental risk factors, neuropathological and genetic factors that may predispose to SIDS, potential physiologic markers in at-risk infants, and animal modeling. The American Academy of Pediatrics summarizes modifiable environmental factors with current recommendations for reducing the risk of SIDS. The focus is on modification of sleep position, sleep environment, and nicotine exposure. Infants should be placed to sleep in the supine position (on her or his back). The “Back to Sleep” NICHD campaign in 1994 encouraged parents to place their infant to sleep on their back or side, then the AAP campaign in 1996 recommendation that “back is best” (no side sleeping) led to a significant decrease in SIDS. The risks of supine sleep are positional plagiocephaly (malformation of the skull related to position) which can be decreased by giving the infant “tummy time” while awake, avoiding prolonged periods of time in car seats or bouncy chairs, and encouraging upright “cuddle time.” Modifications of sleep environment include placing the infant to sleep on a firm surface without soft bedding, blankets or toys, placing the infant to sleep in the same room as the parent without bed-sharing, and in a bedroom with temperature that is comfortable for a lightly clothed adult. If an additional blanket is to be used, it should be placed on the infant so that the sheet reaches only to the infant’s chest and is tucked in around the crib mattress to prevent it from covering the baby’s face. The rationale is that these actions may reduce the chance of suffocation and overheating for the infant. Offering a pacifier at the onset of sleep is associated with decreased SIDS risk, but pacifier use should be delayed until after 1 month of age if the baby is breastfeeding and should not be reintroduced into the baby’s mouth after (s)he falls asleep. Smoking or second hand exposure for the pregnant woman, new mother, and baby should be avoided to reduce SIDS risk and for many other health reasons. Though the cause for SIDS is unknown, there has been much investigation into the pathophysiology (functional changes due to disease) and neuropathology (study of brain disease and diseases of the nervous system) of SIDS with many thoughts regarding the underlying problems that may make an infant vulnerable. Considering this, the etiology of SIDS is thought to include, but is not limited to, serotonergic system dysfunction, autonomic nervous system dysfunction, and impaired arousal mechanisms. All of these are inter-related in the baby’s developing nervous system. Serotonin is a neurotransmitter (brain chemical involved in neuron-cell signaling) that has influence over a broad range of functions such as the sleep-wake cycle, thermoregulation, cardiovascular control, and modulation of motor activity. Neuropathological studies have found a decrease in serotonergic receptor binding in the medulla (area of the brain important for homeostatic function) of SIDS victims. Further, the serotonergic system has been found to be abnormal in 50% of SIDS cases. These findings have led to candidate gene studies, primarily based on clues from the neuropathological findings in SIDS victims and the limited clinical information documented before the sudden death; thus far, findings in the serotonergic system and genes expressed in the early embryology of the autonomic nervous system have not identified variations strongly associated with SIDS risk. Testing of additional genes, in larger cohorts, is currently under way.
|
Causes of Sudden Infant Death Syndrome. By definition, the cause of SIDS is unknown. Therefore, the existing research addresses modifiable environmental risk factors, neuropathological and genetic factors that may predispose to SIDS, potential physiologic markers in at-risk infants, and animal modeling. The American Academy of Pediatrics summarizes modifiable environmental factors with current recommendations for reducing the risk of SIDS. The focus is on modification of sleep position, sleep environment, and nicotine exposure. Infants should be placed to sleep in the supine position (on her or his back). The “Back to Sleep” NICHD campaign in 1994 encouraged parents to place their infant to sleep on their back or side, then the AAP campaign in 1996 recommendation that “back is best” (no side sleeping) led to a significant decrease in SIDS. The risks of supine sleep are positional plagiocephaly (malformation of the skull related to position) which can be decreased by giving the infant “tummy time” while awake, avoiding prolonged periods of time in car seats or bouncy chairs, and encouraging upright “cuddle time.” Modifications of sleep environment include placing the infant to sleep on a firm surface without soft bedding, blankets or toys, placing the infant to sleep in the same room as the parent without bed-sharing, and in a bedroom with temperature that is comfortable for a lightly clothed adult. If an additional blanket is to be used, it should be placed on the infant so that the sheet reaches only to the infant’s chest and is tucked in around the crib mattress to prevent it from covering the baby’s face. The rationale is that these actions may reduce the chance of suffocation and overheating for the infant. Offering a pacifier at the onset of sleep is associated with decreased SIDS risk, but pacifier use should be delayed until after 1 month of age if the baby is breastfeeding and should not be reintroduced into the baby’s mouth after (s)he falls asleep. Smoking or second hand exposure for the pregnant woman, new mother, and baby should be avoided to reduce SIDS risk and for many other health reasons. Though the cause for SIDS is unknown, there has been much investigation into the pathophysiology (functional changes due to disease) and neuropathology (study of brain disease and diseases of the nervous system) of SIDS with many thoughts regarding the underlying problems that may make an infant vulnerable. Considering this, the etiology of SIDS is thought to include, but is not limited to, serotonergic system dysfunction, autonomic nervous system dysfunction, and impaired arousal mechanisms. All of these are inter-related in the baby’s developing nervous system. Serotonin is a neurotransmitter (brain chemical involved in neuron-cell signaling) that has influence over a broad range of functions such as the sleep-wake cycle, thermoregulation, cardiovascular control, and modulation of motor activity. Neuropathological studies have found a decrease in serotonergic receptor binding in the medulla (area of the brain important for homeostatic function) of SIDS victims. Further, the serotonergic system has been found to be abnormal in 50% of SIDS cases. These findings have led to candidate gene studies, primarily based on clues from the neuropathological findings in SIDS victims and the limited clinical information documented before the sudden death; thus far, findings in the serotonergic system and genes expressed in the early embryology of the autonomic nervous system have not identified variations strongly associated with SIDS risk. Testing of additional genes, in larger cohorts, is currently under way.
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