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Acute disseminated encephalomyelitis
| 967 |
ADEM's symptoms resemble the symptoms of multiple sclerosis (MS), so the disease itself is sorted into the classification of the multiple sclerosis borderline diseases. However, ADEM has several features that distinguish it from MS. Unlike MS, ADEM occurs usually in children and is marked with rapid fever, although adolescents and adults can get the disease too. ADEM consists of a single flare-up whereas MS is marked with several flare-ups (or relapses), over a long period of time. Relapses following ADEM are reported in up to a quarter of patients, but the majority of these 'multiphasic' presentations following ADEM likely represent MS. ADEM is also distinguished by a loss of consciousness, coma and death, which is very rare in MS, except in severe cases.
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Acute disseminated encephalomyelitis
| 967 |
It affects about 8 per 1,000,000 people per year. Although it occurs in all ages, most reported cases are in children and adolescents, with the average age around 5 to 8 years old. The disease affects males and females almost equally. ADEM shows seasonal variation with higher incidence in winter and spring months which may coincide with higher viral infections during these months. The mortality rate may be as high as 5%; however, full recovery is seen in 50 to 75% of cases with increase in survival rates up to 70 to 90% with figures including minor residual disability as well. The average time to recover from ADEM flare-ups is one to six months.
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Acute disseminated encephalomyelitis
| 967 |
ADEM produces multiple inflammatory lesions in the brain and spinal cord, particularly in the white matter. Usually these are found in the subcortical and central white matter and cortical gray-white junction of both cerebral hemispheres, cerebellum, brainstem, and spinal cord, but periventricular white matter and gray matter of the cortex, thalami and basal ganglia may also be involved.
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Acute disseminated encephalomyelitis
| 967 |
When a person has more than one demyelinating episode of ADEM, the disease is then called recurrent disseminated encephalomyelitis or multiphasic disseminated encephalomyelitis (MDEM). Also, a fulminant course in adults has been described.
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Acute disseminated encephalomyelitis
| 967 |
Signs and symptoms
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ADEM has an abrupt onset and a monophasic course. Symptoms usually begin 1–3 weeks after infection. Major symptoms include fever, headache, nausea and vomiting, confusion, vision impairment, drowsiness, seizures and coma. Although initially the symptoms are usually mild, they worsen rapidly over the course of hours to days, with the average time to maximum severity being about four and a half days. Additional symptoms include hemiparesis, paraparesis, and cranial nerve palsies.
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Acute disseminated encephalomyelitis
| 967 |
Signs and symptoms
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Neurological symptoms were the main presentation of COVID-19, which did not correlate with the severity of respiratory symptoms. The high incidence of ADEM with hemorrhage is striking. Brain inflammation is likely caused by an immune response to the disease rather than neurotropism. CSF analysis was not indicative of an infectious process, neurological impairment was not present in the acute phase of the infection, and neuroimaging findings were not typical of classical toxic and metabolic disorders. The finding of bilateral periventricular relatively asymmetrical lesions allied with deep white matter involvement, that may also be present in cortical gray-white matter junction, thalami, basal ganglia, cerebellum, and brainstem suggests an acute demyelination process. Additionally, hemorrhagic white matter lesions, clusters of macrophages related to axonal injury and ADEM-like appearance were also found in subcortical white matter.
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Acute disseminated encephalomyelitis
| 967 |
Causes
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Since the discovery of the anti-MOG specificity against multiple sclerosis diagnosis it is considered that ADEM is one of the possible clinical causes of anti-MOG associated encephalomyelitis.
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Acute disseminated encephalomyelitis
| 967 |
Causes
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About how the anti-MOG antibodies appear in the patients serum there are several theories:
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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The term ADEM has been inconsistently used at different times. Currently, the commonly accepted international standard for the clinical case definition is the one published by the International Pediatric MS Study Group, revision 2007.
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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Given that the definition is clinical, it is currently unknown if all the cases of ADEM are positive for anti-MOG autoantibody; in any case, it appears to be strongly related to ADEM diagnosis.
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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While ADEM and MS both involve autoimmune demyelination, they differ in many clinical, genetic, imaging, and histopathological aspects. Some authors consider MS and its borderline forms to constitute a spectrum, differing only in chronicity, severity, and clinical course, while others consider them discretely different diseases.
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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Typically, ADEM appears in children following an antigenic challenge and remains monophasic. Nevertheless, ADEM does occur in adults, and can also be clinically multiphasic.
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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Problems for differential diagnosis increase due to the lack of agreement for a definition of multiple sclerosis. If MS were defined only by the separation in time and space of the demyelinating lesions as McDonald did, it would not be enough to make a difference, as some cases of ADEM satisfy these conditions. Therefore, some authors propose to establish the dividing line as the shape of the lesions around the veins, being therefore "perivenous vs. confluent demyelination".
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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The pathology of ADEM is very similar to that of MS with some differences. The pathological hallmark of ADEM is perivenous inflammation with limited "sleeves of demyelination". Nevertheless, MS-like plaques (confluent demyelination) can appear
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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Plaques in the white matter in MS are sharply delineated, while the glial scar in ADEM is smooth. Axons are better preserved in ADEM lesions. Inflammation in ADEM is widely disseminated and ill-defined, and finally, lesions are strictly perivenous, while in MS they are disposed around veins, but not so sharply.
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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Nevertheless, the co-occurrence of perivenous and confluent demyelination in some individuals suggests pathogenic overlap between acute disseminated encephalomyelitis and multiple sclerosis and misclassification even with biopsy or even postmortem ADEM in adults can progress to MS
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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When the person has more than one demyelinating episode of ADEM, the disease is then called recurrent disseminated encephalomyelitis or multiphasic disseminated encephalomyelitis (MDEM).
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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It has been found that anti-MOG auto-antibodies are related to this kind of ADEM
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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Another variant of ADEM in adults has been described, also related to anti-MOG auto-antibodies, has been named fulminant disseminated encephalomyelitis, and it has been reported to be clinically ADEM, but showing MS-like lesions on autopsy. It has been classified inside the anti-MOG associated inflammatory demyelinating diseases.
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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Acute hemorrhagic leukoencephalitis (AHL, or AHLE), acute hemorrhagic encephalomyelitis (AHEM), acute necrotizing hemorrhagic leukoencephalitis (ANHLE), Weston-Hurst syndrome, or Hurst's disease, is a hyperacute and frequently fatal form of ADEM. AHL is relatively rare (less than 100 cases have been reported in the medical literature as of 2006), it is seen in about 2% of ADEM cases, and is characterized by necrotizing vasculitis of venules and hemorrhage, and edema. Death is common in the first week and overall mortality is about 70%, but increasing evidence points to favorable outcomes after aggressive treatment with corticosteroids, immunoglobulins, cyclophosphamide, and plasma exchange. About 70% of survivors show residual neurological deficits, but some survivors have shown surprisingly little deficit considering the extent of the white matter affected.
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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This disease has been occasionally associated with ulcerative colitis and Crohn's disease, malaria, sepsis associated with immune complex deposition, methanol poisoning, and other underlying conditions. Also anecdotal association with MS has been reported
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Acute disseminated encephalomyelitis
| 967 |
Diagnosis
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Laboratory studies that support diagnosis of AHL are: peripheral leukocytosis, cerebrospinal fluid (CSF) pleocytosis associated with normal glucose and increased protein. On magnetic resonance imaging (MRI), lesions of AHL typically show extensive T2-weighted and fluid-attenuated inversion recovery (FLAIR) white matter hyperintensities with areas of hemorrhages, significant edema, and mass effect.
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Acute disseminated encephalomyelitis
| 967 |
Treatment
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No controlled clinical trials have been conducted on ADEM treatment, but aggressive treatment aimed at rapidly reducing inflammation of the CNS is standard. The widely accepted first-line treatment is high doses of intravenous corticosteroids, such as methylprednisolone or dexamethasone, followed by 3–6 weeks of gradually lower oral doses of prednisolone. Patients treated with methylprednisolone have shown better outcomes than those treated with dexamethasone. Oral tapers of less than three weeks duration show a higher chance of relapsing, and tend to show poorer outcomes. Other anti-inflammatory and immunosuppressive therapies have been reported to show beneficial effect, such as plasmapheresis, high doses of intravenous immunoglobulin (IVIg), mitoxantrone and cyclophosphamide. These are considered alternative therapies, used when corticosteroids cannot be used or fail to show an effect.
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Acute disseminated encephalomyelitis
| 967 |
Treatment
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There is some evidence to suggest that patients may respond to a combination of methylprednisolone and immunoglobulins if they fail to respond to either separately In a study of 16 children with ADEM, 10 recovered completely after high-dose methylprednisolone, one severe case that failed to respond to steroids recovered completely after IV Ig; the five most severe cases – with ADAM and severe peripheral neuropathy – were treated with combined high-dose methylprednisolone and immunoglobulin, two remained paraplegic, one had motor and cognitive handicaps, and two recovered. A recent review of IVIg treatment of ADEM (of which the previous study formed the bulk of the cases) found that 70% of children showed complete recovery after treatment with IVIg, or IVIg plus corticosteroids. A study of IVIg treatment in adults with ADEM showed that IVIg seems more effective in treating sensory and motor disturbances, while steroids seem more effective in treating impairments of cognition, consciousness and rigor. This same study found one subject, a 71-year-old man who had not responded to steroids, that responded to an IVIg treatment 58 days after disease onset.
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Acute disseminated encephalomyelitis
| 967 |
Prognosis
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Full recovery is seen in 50 to 70% of cases, ranging to 70 to 90% recovery with some minor residual disability (typically assessed using measures such as mRS or EDSS), average time to recover is one to six months. The mortality rate may be as high as 5–10%. Poorer outcomes are associated with unresponsiveness to steroid therapy, unusually severe neurological symptoms, or sudden onset. Children tend to have more favorable outcomes than adults, and cases presenting without fevers tend to have poorer outcomes. The latter effect may be due to either protective effects of fever, or that diagnosis and treatment is sought more rapidly when fever is present.
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Acute disseminated encephalomyelitis
| 967 |
Prognosis
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ADEM can progress to MS. It will be considered MS if some lesions appear in different times and brain areas
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Acute disseminated encephalomyelitis
| 967 |
Prognosis
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Residual motor deficits are estimated to remain in about 8 to 30% of cases, the range in severity from mild clumsiness to ataxia and hemiparesis.
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Acute disseminated encephalomyelitis
| 967 |
Prognosis
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Patients with demyelinating illnesses, such as MS, have shown cognitive deficits even when there is minimal physical disability. Research suggests that similar effects are seen after ADEM, but that the deficits are less severe than those seen in MS. A study of six children with ADEM (mean age at presentation 7.7 years) were tested for a range of neurocognitive tests after an average of 3.5 years of recovery. All six children performed in the normal range on most tests, including verbal IQ and performance IQ, but performed at least one standard deviation below age norms in at least one cognitive domain, such as complex attention (one child), short-term memory (one child) and internalizing behaviour/affect (two children). Group means for each cognitive domain were all within one standard deviation of age norms, demonstrating that, as a group, they were normal. These deficits were less severe than those seen in similar aged children with a diagnosis of MS.
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Acute disseminated encephalomyelitis
| 967 |
Prognosis
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Another study compared nineteen children with a history of ADEM, of which 10 were five years of age or younger at the time (average age 3.8 years old, tested an average of 3.9 years later) and nine were older (mean age 7.7y at time of ADEM, tested an average of 2.2 years later) to nineteen matched controls. Scores on IQ tests and educational achievement were lower for the young onset ADEM group (average IQ 90) compared to the late onset (average IQ 100) and control groups (average IQ 106), while the late onset ADEM children scored lower on verbal processing speed. Again, all groups means were within one standard deviation of the controls, meaning that while effects were statistically reliable, the children were as a whole, still within the normal range. There were also more behavioural problems in the early onset group, although there is some suggestion that this may be due, at least in part, to the stress of hospitalization at a young age.
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Acute disseminated encephalomyelitis
| 967 |
Research
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The relationship between ADEM and anti-MOG associated encephalomyelitis is currently under research. A new entity called MOGDEM has been proposed.
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Acute disseminated encephalomyelitis
| 967 |
Research
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About animal models, the main animal model for MS, experimental autoimmune encephalomyelitis (EAE) is also an animal model for ADEM. Being an acute monophasic illness, EAE is far more similar to ADEM than MS.
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Ataxia
| 969 |
Ataxia (from Greek α- [a negative prefix] + -τάξις [order] = "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements, that indicates dysfunction of parts of the nervous system that coordinate movement, such as the cerebellum.
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Ataxia
| 969 |
These nervous system dysfunctions occur in several different patterns, with different results and different possible causes. Ataxia can be limited to one side of the body, which is referred to as hemiataxia. Friedreich's ataxia has gait abnormality as the most commonly presented symptom. Dystaxia is a mild degree of ataxia.
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Ataxia
| 969 |
Types
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The term cerebellar ataxia is used to indicate ataxia due to dysfunction of the cerebellum. The cerebellum is responsible for integrating a significant amount of neural information that is used to coordinate smoothly ongoing movements and to participate in motor planning. Although ataxia is not present with all cerebellar lesions, many conditions affecting the cerebellum do produce ataxia. People with cerebellar ataxia may have trouble regulating the force, range, direction, velocity, and rhythm of muscle contractions. This results in a characteristic type of irregular, uncoordinated movement that can manifest itself in many possible ways, such as asthenia, asynergy, delayed reaction time, and dyschronometria. Individuals with cerebellar ataxia could also display instability of gait, difficulty with eye movements, dysarthria, dysphagia, hypotonia, dysmetria, and dysdiadochokinesia. These deficits can vary depending on which cerebellar structures have been damaged, and whether the lesion is bi- or unilateral.
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Ataxia
| 969 |
Types
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People with cerebellar ataxia may initially present with poor balance, which could be demonstrated as an inability to stand on one leg or perform tandem gait. As the condition progresses, walking is characterized by a widened base and high stepping, as well as staggering and lurching from side to side. Turning is also problematic and could result in falls. As cerebellar ataxia becomes severe, great assistance and effort are needed to stand and walk. Dysarthria, an impairment with articulation, may also be present and is characterized by "scanning" speech that consists of slower rate, irregular rhythm, and variable volume. Also, slurring of speech, tremor of the voice, and ataxic respiration may occur. Cerebellar ataxia could result with incoordination of movement, particularly in the extremities. Overshooting (or hypermetria) occurs with finger-to-nose testing and heel to shin testing; thus, dysmetria is evident. Impairments with alternating movements (dysdiadochokinesia), as well as dysrhythmia, may also be displayed. Tremor of the head and trunk (titubation) may be seen in individuals with cerebellar ataxia.
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Ataxia
| 969 |
Types
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Dysmetria is thought to be caused by a deficit in the control of interaction torques in multijoint motion. Interaction torques are created at an associated joint when the primary joint is moved. For example, if a movement required reaching to touch a target in front of the body, flexion at the shoulder would create a torque at the elbow, while extension of the elbow would create a torque at the wrist. These torques increase as the speed of movement increases and must be compensated and adjusted for to create coordinated movement. This may, therefore, explain decreased coordination at higher movement velocities and accelerations.
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Ataxia
| 969 |
Types
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The term sensory ataxia is used to indicate ataxia due to loss of proprioception, the loss of sensitivity to the positions of joint and body parts. This is generally caused by dysfunction of the dorsal columns of the spinal cord, because they carry proprioceptive information up to the brain. In some cases, the cause of sensory ataxia may instead be dysfunction of the various parts of the brain that receive positional information, including the cerebellum, thalamus, and parietal lobes.
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Ataxia
| 969 |
Types
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Sensory ataxia presents itself with an unsteady "stomping" gait with heavy heel strikes, as well as a postural instability that is usually worsened when the lack of proprioceptive input cannot be compensated for by visual input, such as in poorly lit environments.
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Ataxia
| 969 |
Types
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Physicians can find evidence of sensory ataxia during physical examination by having patients stand with their feet together and eyes shut. In affected patients, this will cause the instability to worsen markedly, producing wide oscillations and possibly a fall; this is called a positive Romberg's test. Worsening of the finger-pointing test with the eyes closed is another feature of sensory ataxia. Also, when patients are standing with arms and hands extended toward the physician, if the eyes are closed, the patients' fingers tend to "fall down" and then be restored to the horizontal extended position by sudden muscular contractions (the "ataxic hand").
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Ataxia
| 969 |
Types
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The term vestibular ataxia is used to indicate ataxia due to dysfunction of the vestibular system, which in acute and unilateral cases is associated with prominent vertigo, nausea, and vomiting. In slow-onset, chronic bilateral cases of vestibular dysfunction, these characteristic manifestations may be absent, and dysequilibrium may be the sole presentation.
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Ataxia
| 969 |
Causes
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The three types of ataxia have overlapping causes, so can either coexist or occur in isolation. Cerebellar ataxia can have many causes despite normal neuroimaging.
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Ataxia
| 969 |
Causes
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Any type of focal lesion of the central nervous system (such as stroke, brain tumor, multiple sclerosis, inflammatory [such as sarcoidosis], and "chronic lymphocytyc inflammation with pontine perivascular enhancement responsive to steroids syndrome" [CLIPPERS]) will cause the type of ataxia corresponding to the site of the lesion: cerebellar if in the cerebellum; sensory if in the dorsal spinal cord...to include cord compression by thickened ligamentum flavum or stenosis of the boney spinal canal...(and rarely in the thalamus or parietal lobe); or vestibular if in the vestibular system (including the vestibular areas of the cerebral cortex).
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Ataxia
| 969 |
Causes
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Exogenous substances that cause ataxia mainly do so because they have a depressant effect on central nervous system function. The most common example is ethanol (alcohol), which is capable of causing reversible cerebellar and vestibular ataxia. Chronic intake of ethanol causes atrophy of the cerebellum by oxidative and endoplasmic reticulum stresses induced by thiamine deficiency.
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Ataxia
| 969 |
Causes
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Other examples include various prescription drugs (e.g. most antiepileptic drugs have cerebellar ataxia as a possible adverse effect), Lithium level over 1.5mEq/L, synthetic cannabinoid HU-211 ingestion and various other medical and recreational drugs (e.g. ketamine, PCP or dextromethorphan, all of which are NMDA receptor antagonists that produce a dissociative state at high doses). A further class of pharmaceuticals which can cause short term ataxia, especially in high doses, are benzodiazepines. Exposure to high levels of methylmercury, through consumption of fish with high mercury concentrations, is also a known cause of ataxia and other neurological disorders.
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Ataxia
| 969 |
Causes
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Ataxia can be induced as a result of severe acute radiation poisoning with an absorbed dose of more than 30 grays.
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Ataxia
| 969 |
Causes
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Vitamin B12 deficiency may cause, among several neurological abnormalities, overlapping cerebellar and sensory ataxia. Neuropsychological symptoms may include sense loss, difficulty in proprioception, poor balance, loss of sensation in the feet, changes in reflexes, dementia, and psychosis, can be reversible with treatment. Complications may include a neurological complex known as subacute combined degeneration of spinal cord, and other neurological disorders.
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Ataxia
| 969 |
Causes
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Symptoms of neurological dysfunction may be the presenting feature in some patients with hypothyroidism. These include reversible cerebellar ataxia, dementia, peripheral neuropathy, psychosis and coma. Most of the neurological complications improve completely after thyroid hormone replacement therapy.
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Ataxia
| 969 |
Causes
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Peripheral neuropathies may cause generalised or localised sensory ataxia (e.g. a limb only) depending on the extent of the neuropathic involvement. Spinal disorders of various types may cause sensory ataxia from the lesioned level below, when they involve the dorsal columns.
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Ataxia
| 969 |
Causes
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Non-hereditary causes of cerebellar degeneration include chronic alcohol use disorder, head injury, paraneoplastic and non-paraneoplastic autoimmune ataxia, high altitude cerebral oedema, coeliac disease, normal pressure hydrocephalus and infectious or post-infectious cerebellitis.
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Ataxia
| 969 |
Causes
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Ataxia may depend on hereditary disorders consisting of degeneration of the cerebellum or of the spine; most cases feature both to some extent, and therefore present with overlapping cerebellar and sensory ataxia, even though one is often more evident than the other. Hereditary disorders causing ataxia include autosomal dominant ones such as spinocerebellar ataxia, episodic ataxia, and dentatorubropallidoluysian atrophy, as well as autosomal recessive disorders such as Friedreich's ataxia (sensory and cerebellar, with the former predominating) and Niemann Pick disease, ataxia-telangiectasia (sensory and cerebellar, with the latter predominating),autosomal recessive spinocerebellar ataxia-14 and abetalipoproteinaemia. An example of X-linked ataxic condition is the rare fragile X-associated tremor/ataxia syndrome or FXTAS.
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Ataxia
| 969 |
Causes
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Arnold–Chiari malformation is a malformation of the brain. It consists of a downward displacement of the cerebellar tonsils and the medulla through the foramen magnum, sometimes causing hydrocephalus as a result of obstruction of cerebrospinal fluid outflow.
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Ataxia
| 969 |
Causes
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Succinic semialdehyde dehydrogenase deficiency is an autosomal-recessive gene disorder where mutations in the ALDH5A1 gene results in the accumulation of gamma-Hydroxybutyric acid (GHB) in the body. GHB accumulates in the nervous system and can cause ataxia as well as other neurological dysfunction.
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Ataxia
| 969 |
Causes
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Wilson's disease is an autosomal-recessive gene disorder whereby an alteration of the ATP7B gene results in an inability to properly excrete copper from the body. Copper accumulates in the nervous system and liver and can cause ataxia as well as other neurological and organ impairments.
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Ataxia
| 969 |
Causes
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Gluten ataxia is an autoimmune disease triggered by the ingestion of gluten. Early diagnosis and treatment with a gluten-free diet can improve ataxia and prevent its progression. The effectiveness of the treatment depends on the elapsed time from the onset of the ataxia until diagnosis, because the death of neurons in the cerebellum as a result of gluten exposure is irreversible. It accounts for 40% of ataxias of unknown origin and 15% of all ataxias. Less than 10% of people with gluten ataxia present any gastrointestinal symptom and only about 40% have intestinal damage. This entity is classified into primary auto-immune cerebellar ataxias (PACA).
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Ataxia
| 969 |
Causes
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Malfunction of the sodium-potassium pump may be a factor in some ataxias. The Na-K pump has been shown to control and set the intrinsic activity mode of cerebellar Purkinje neurons. This suggests that the pump might not simply be a homeostatic, "housekeeping" molecule for ionic gradients; but could be a computational element in the cerebellum and the brain. Indeed, an ouabain block of Na-K pumps in the cerebellum of a live mouse results in it displaying ataxia and dystonia. Ataxia is observed for lower ouabain concentrations, dystonia is observed at higher ouabain concentrations.
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Ataxia
| 969 |
Causes
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Antibodies against the enzyme glutamic acid decarboxylase (GAD: enzyme changing glutamate into GABA) cause cerebellar deficits. The antibodies impair motor learning and cause behavioral deficits. GAD antibodies related ataxia is part of the group called immune-mediated cerebellar ataxias. The antibodies induce a synaptopathy. The cerebellum is particularly vulnerable to autoimmune disorders. Cerebellar circuitry has capacities to compensate and restore function thanks to cerebellar reserve, gathering multiple forms of plasticity. LTDpathies gather immune disorders targeting long-term depression (LTD), a form of plasticity.
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Ataxia
| 969 |
Treatment
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The treatment of ataxia and its effectiveness depend on the underlying cause. Treatment may limit or reduce the effects of ataxia, but it is unlikely to eliminate them entirely. Recovery tends to be better in individuals with a single focal injury (such as stroke or a benign tumour), compared to those who have a neurological degenerative condition. A review of the management of degenerative ataxia was published in 2009. A small number of rare conditions presenting with prominent cerebellar ataxia are amenable to specific treatment and recognition of these disorders is critical. Diseases include vitamin E deficiency, abetalipoproteinemia, cerebrotendinous xanthomatosis, Niemann–Pick type C disease, Refsum's disease, glucose transporter type 1 deficiency, episodic ataxia type 2, gluten ataxia, glutamic acid decarboxylase ataxia. Novel therapies target the RNA defects associated with cerebellar disorders, using in particular anti-sense oligonucleotides.
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Ataxia
| 969 |
Treatment
|
The movement disorders associated with ataxia can be managed by pharmacological treatments and through physical therapy and occupational therapy to reduce disability. Some drug treatments that have been used to control ataxia include: 5-hydroxytryptophan (5-HTP), idebenone, amantadine, physostigmine, L-carnitine or derivatives, trimethoprim/sulfamethoxazole, vigabatrin, phosphatidylcholine, acetazolamide, 4-aminopyridine, buspirone, and a combination of coenzyme Q10 and vitamin E.
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Ataxia
| 969 |
Treatment
|
Physical therapy requires a focus on adapting activity and facilitating motor learning for retraining specific functional motor patterns. A recent systematic review suggested that physical therapy is effective, but there is only moderate evidence to support this conclusion. The most commonly used physical therapy interventions for cerebellar ataxia are vestibular habituation, Frenkel exercises, proprioceptive neuromuscular facilitation (PNF), and balance training; however, therapy is often highly individualized and gait and coordination training are large components of therapy.
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Ataxia
| 969 |
Treatment
|
Current research suggests that, if a person is able to walk with or without a mobility aid, physical therapy should include an exercise program addressing five components: static balance, dynamic balance, trunk-limb coordination, stairs, and contracture prevention. Once the physical therapist determines that the individual is able to safely perform parts of the program independently, it is important that the individual be prescribed and regularly engage in a supplementary home exercise program that incorporates these components to further improve long term outcomes. These outcomes include balance tasks, gait, and individual activities of daily living. While the improvements are attributed primarily to changes in the brain and not just the hip or ankle joints, it is still unknown whether the improvements are due to adaptations in the cerebellum or compensation by other areas of the brain.
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Ataxia
| 969 |
Treatment
|
Decomposition, simplification, or slowing of multijoint movement may also be an effective strategy that therapists may use to improve function in patients with ataxia. Training likely needs to be intense and focused—as indicated by one study performed with stroke patients experiencing limb ataxia who underwent intensive upper limb retraining. Their therapy consisted of constraint-induced movement therapy which resulted in improvements of their arm function. Treatment should likely include strategies to manage difficulties with everyday activities such as walking. Gait aids (such as a cane or walker) can be provided to decrease the risk of falls associated with impairment of balance or poor coordination. Severe ataxia may eventually lead to the need for a wheelchair. To obtain better results, possible coexisting motor deficits need to be addressed in addition to those induced by ataxia. For example, muscle weakness and decreased endurance could lead to increasing fatigue and poorer movement patterns.
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Ataxia
| 969 |
Treatment
|
There are several assessment tools available to therapists and health care professionals working with patients with ataxia. The International Cooperative Ataxia Rating Scale (ICARS) is one of the most widely used and has been proven to have very high reliability and validity. Other tools that assess motor function, balance and coordination are also highly valuable to help the therapist track the progress of their patient, as well as to quantify the patient's functionality. These tests include, but are not limited to:
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Ataxia
| 969 |
Other uses
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The term "ataxia" is sometimes used in a broader sense to indicate lack of coordination in some physiological process. Examples include optic ataxia (lack of coordination between visual inputs and hand movements, resulting in inability to reach and grab objects) and ataxic respiration (lack of coordination in respiratory movements, usually due to dysfunction of the respiratory centres in the medulla oblongata).
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Ataxia
| 969 |
Other uses
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Optic ataxia may be caused by lesions to the posterior parietal cortex, which is responsible for combining and expressing positional information and relating it to movement. Outputs of the posterior parietal cortex include the spinal cord, brain stem motor pathways, pre-motor and pre-frontal cortex, basal ganglia and the cerebellum. Some neurons in the posterior parietal cortex are modulated by intention. Optic ataxia is usually part of Balint's syndrome, but can be seen in isolation with injuries to the superior parietal lobule, as it represents a disconnection between visual-association cortex and the frontal premotor and motor cortex.
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Ada Lovelace
| 974 |
Augusta Ada King, Countess of Lovelace (née Byron; 10 December 1815 – 27 November 1852) was an English mathematician and writer, chiefly known for her work on Charles Babbage's proposed mechanical general-purpose computer, the Analytical Engine. She was the first to recognise that the machine had applications beyond pure calculation.
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Ada Lovelace
| 974 |
Ada Byron was the only legitimate child of poet Lord Byron and reformer Lady Byron. All Lovelace's half-siblings, Lord Byron's other children, were born out of wedlock to other women. Byron separated from his wife a month after Ada was born and left England forever. He died in Greece when Ada was eight. Her mother was anxious about her upbringing and promoted Ada's interest in mathematics and logic in an effort to prevent her from developing her father's perceived insanity. Despite this, Ada remained interested in him, naming her two sons Byron and Gordon. Upon her death, she was buried next to him at her request. Although often ill in her childhood, Ada pursued her studies assiduously. She married William King in 1835. King was made Earl of Lovelace in 1838, Ada thereby becoming Countess of Lovelace.
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Ada Lovelace
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Her educational and social exploits brought her into contact with scientists such as Andrew Crosse, Charles Babbage, Sir David Brewster, Charles Wheatstone, Michael Faraday, and the author Charles Dickens, contacts which she used to further her education. Ada described her approach as "poetical science" and herself as an "Analyst (& Metaphysician)".
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Ada Lovelace
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When she was eighteen, her mathematical talents led her to a long working relationship and friendship with fellow British mathematician Charles Babbage, who is known as "the father of computers". She was in particular interested in Babbage's work on the Analytical Engine. Lovelace first met him in June 1833, through their mutual friend, and her private tutor, Mary Somerville.
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Ada Lovelace
| 974 |
Between 1842 and 1843, Ada translated an article by the military engineer Luigi Menabrea (later Prime Minister of Italy) about the Analytical Engine, supplementing it with an elaborate set of seven notes, simply called "Notes".
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Ada Lovelace
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Lovelace's notes are important in the early history of computers, especially since the seventh one contained what many consider to be the first computer program—that is, an algorithm designed to be carried out by a machine. Other historians reject this perspective and point out that Babbage's personal notes from the years 1836/1837 contain the first programs for the engine. She also developed a vision of the capability of computers to go beyond mere calculating or number-crunching, while many others, including Babbage himself, focused only on those capabilities. Her mindset of "poetical science" led her to ask questions about the Analytical Engine (as shown in her notes) examining how individuals and society relate to technology as a collaborative tool.
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Ada Lovelace
| 974 |
Biography
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Lord Byron expected his child to be a "glorious boy" and was disappointed when Lady Byron gave birth to a girl. The child was named after Byron's half-sister, Augusta Leigh, and was called "Ada" by Byron himself. On 16 January 1816, at Lord Byron's command, Lady Byron left for her parents' home at Kirkby Mallory, taking their five-week-old daughter with her. Although English law at the time granted full custody of children to the father in cases of separation, Lord Byron made no attempt to claim his parental rights, but did request that his sister keep him informed of Ada's welfare.
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Ada Lovelace
| 974 |
Biography
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On 21 April, Lord Byron signed the deed of separation, although very reluctantly, and left England for good a few days later. Aside from an acrimonious separation, Lady Byron continued throughout her life to make allegations about her husband's immoral behaviour. This set of events made Lovelace infamous in Victorian society. Ada did not have a relationship with her father. He died in 1824 when she was eight years old. Her mother was the only significant parental figure in her life. Lovelace was not shown the family portrait of her father until her 20th birthday.
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Ada Lovelace
| 974 |
Biography
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Lovelace did not have a close relationship with her mother. She was often left in the care of her maternal grandmother Judith, Hon. Lady Milbanke, who doted on her. However, because of societal attitudes of the time—which favoured the husband in any separation, with the welfare of any child acting as mitigation—Lady Byron had to present herself as a loving mother to the rest of society. This included writing anxious letters to Lady Milbanke about her daughter's welfare, with a cover note saying to retain the letters in case she had to use them to show maternal concern. In one letter to Lady Milbanke, she referred to her daughter as "it": "I talk to it for your satisfaction, not my own, and shall be very glad when you have it under your own." Lady Byron had her teenage daughter watched by close friends for any sign of moral deviation. Lovelace dubbed these observers the "Furies" and later complained they exaggerated and invented stories about her.
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Ada Lovelace
| 974 |
Biography
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Lovelace was often ill, beginning in early childhood. At the age of eight, she experienced headaches that obscured her vision. In June 1829, she was paralyzed after a bout of measles. She was subjected to continuous bed rest for nearly a year, something which may have extended her period of disability. By 1831, she was able to walk with crutches. Despite the illnesses, she developed her mathematical and technological skills.
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Ada Lovelace
| 974 |
Biography
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When Ada was twelve years old, this future "Lady Fairy", as Charles Babbage affectionately called her, decided she wanted to fly. Ada Byron went about the project methodically, thoughtfully, with imagination and passion. Her first step, in February 1828, was to construct wings. She investigated different material and sizes. She considered various materials for the wings: paper, oilsilk, wires, and feathers. She examined the anatomy of birds to determine the right proportion between the wings and the body. She decided to write a book, Flyology, illustrating, with plates, some of her findings. She decided what equipment she would need; for example, a compass, to "cut across the country by the most direct road", so that she could surmount mountains, rivers, and valleys. Her final step was to integrate steam with the "art of flying".
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Ada Lovelace
| 974 |
Biography
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Ada Byron had an affair with a tutor in early 1833. She tried to elope with him after she was caught, but the tutor's relatives recognised her and contacted her mother. Lady Byron and her friends covered the incident up to prevent a public scandal. Lovelace never met her younger half-sister, Allegra, the daughter of Lord Byron and Claire Clairmont. Allegra died in 1822 at the age of five. Lovelace did have some contact with Elizabeth Medora Leigh, the daughter of Byron's half-sister Augusta Leigh, who purposely avoided Lovelace as much as possible when introduced at court.
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Ada Lovelace
| 974 |
Biography
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Lovelace became close friends with her tutor Mary Somerville, who introduced her to Charles Babbage in 1833. She had a strong respect and affection for Somerville, and they corresponded for many years. Other acquaintances included the scientists Andrew Crosse, Sir David Brewster, Charles Wheatstone, Michael Faraday and the author Charles Dickens. She was presented at Court at the age of seventeen "and became a popular belle of the season" in part because of her "brilliant mind". By 1834 Ada was a regular at Court and started attending various events. She danced often and was able to charm many people, and was described by most people as being dainty, although John Hobhouse, Byron's friend, described her as "a large, coarse-skinned young woman but with something of my friend's features, particularly the mouth". This description followed their meeting on 24 February 1834 in which Ada made it clear to Hobhouse that she did not like him, probably due to her mother's influence, which led her to dislike all of her father's friends. This first impression was not to last, and they later became friends.
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Ada Lovelace
| 974 |
Biography
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On 8 July 1835, she married William, 8th Baron King, becoming Lady King. They had three homes: Ockham Park, Surrey; a Scottish estate on Loch Torridon in Ross-shire; and a house in London. They spent their honeymoon at Worthy Manor in Ashley Combe near Porlock Weir, Somerset. The Manor had been built as a hunting lodge in 1799 and was improved by King in preparation for their honeymoon. It later became their summer retreat and was further improved during this time. From 1845, the family's main house was Horsley Towers, built in the Tudorbethan fashion by the architect of the Houses of Parliament, Charles Barry, and later greatly enlarged to Lovelace's own designs.
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Ada Lovelace
| 974 |
Biography
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They had three children: Byron (born 1836); Anne Isabella (called Annabella, born 1837); and Ralph Gordon (born 1839). Immediately after the birth of Annabella, Lady King experienced "a tedious and suffering illness, which took months to cure". Ada was a descendant of the extinct Barons Lovelace and in 1838, her husband was made Earl of Lovelace and Viscount Ockham, meaning Ada became the Countess of Lovelace. In 1843–44, Ada's mother assigned William Benjamin Carpenter to teach Ada's children and to act as a "moral" instructor for Ada. He quickly fell for her and encouraged her to express any frustrated affections, claiming that his marriage meant he would never act in an "unbecoming" manner. When it became clear that Carpenter was trying to start an affair, Ada cut it off.
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Ada Lovelace
| 974 |
Biography
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In 1841, Lovelace and Medora Leigh (the daughter of Lord Byron's half-sister Augusta Leigh) were told by Ada's mother that Ada's father was also Medora's father. On 27 February 1841, Ada wrote to her mother: "I am not in the least astonished. In fact, you merely confirm what I have for years and years felt scarcely a doubt about, but should have considered it most improper in me to hint to you that I in any way suspected." She did not blame the incestuous relationship on Byron, but instead blamed Augusta Leigh: "I fear she is more inherently wicked than he ever was." In the 1840s, Ada flirted with scandals: firstly, from a relaxed approach to extra-marital relationships with men, leading to rumours of affairs; and secondly, from her love of gambling. She apparently lost more than £3,000 on the horses during the later 1840s. The gambling led to her forming a syndicate with male friends, and an ambitious attempt in 1851 to create a mathematical model for successful large bets. This went disastrously wrong, leaving her thousands of pounds in debt to the syndicate, forcing her to admit it all to her husband. She had a shadowy relationship with Andrew Crosse's son John from 1844 onwards. John Crosse destroyed most of their correspondence after her death as part of a legal agreement. She bequeathed him the only heirlooms her father had personally left to her. During her final illness, she would panic at the idea of the younger Crosse being kept from visiting her.
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Ada Lovelace
| 974 |
Biography
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From 1832, when she was seventeen, her mathematical abilities began to emerge, and her interest in mathematics dominated the majority of her adult life. Her mother's obsession with rooting out any of the insanity of which she accused Byron was one of the reasons that Ada was taught mathematics from an early age. She was privately educated in mathematics and science by William Frend, William King, and Mary Somerville, the noted 19th-century researcher and scientific author. In the 1840s, the mathematician Augustus De Morgan extended her "much help in her mathematical studies" including study of advanced calculus topics including the "numbers of Bernoulli" (that formed her celebrated algorithm for Babbage's Analytical Engine). In a letter to Lady Byron, De Morgan suggested that Ada's skill in mathematics might lead her to become "an original mathematical investigator, perhaps of first-rate eminence".
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Ada Lovelace
| 974 |
Biography
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Lovelace often questioned basic assumptions through integrating poetry and science. Whilst studying differential calculus, she wrote to De Morgan:
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Ada Lovelace
| 974 |
Biography
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I may remark that the curious transformations many formulae can undergo, the unsuspected and to a beginner apparently impossible identity of forms exceedingly dissimilar at first sight, is I think one of the chief difficulties in the early part of mathematical studies. I am often reminded of certain sprites and fairies one reads of, who are at one's elbows in one shape now, and the next minute in a form most dissimilar.
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Ada Lovelace
| 974 |
Biography
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Lovelace believed that intuition and imagination were critical to effectively applying mathematical and scientific concepts. She valued metaphysics as much as mathematics, viewing both as tools for exploring "the unseen worlds around us".
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Ada Lovelace
| 974 |
Biography
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Lovelace died at the age of 36 on 27 November 1852, from uterine cancer. The illness lasted several months, in which time Annabella took command over whom Ada saw, and excluded all of her friends and confidants. Under her mother's influence, Ada had a religious transformation and was coaxed into repenting of her previous conduct and making Annabella her executor. She lost contact with her husband after confessing something to him on 30 August which caused him to abandon her bedside. It is not known what she told him. She was buried, at her request, next to her father at the Church of St. Mary Magdalene in Hucknall, Nottinghamshire. A memorial plaque, written in Latin, to her and her father is in the chapel attached to Horsley Towers.
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Ada Lovelace
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Throughout her life, Lovelace was strongly interested in scientific developments and fads of the day, including phrenology and mesmerism. After her work with Babbage, Lovelace continued to work on other projects. In 1844, she commented to a friend Woronzow Greig about her desire to create a mathematical model for how the brain gives rise to thoughts and nerves to feelings ("a calculus of the nervous system"). She never achieved this, however. In part, her interest in the brain came from a long-running pre-occupation, inherited from her mother, about her "potential" madness. As part of her research into this project, she visited the electrical engineer Andrew Crosse in 1844 to learn how to carry out electrical experiments. In the same year, she wrote a review of a paper by Baron Karl von Reichenbach, Researches on Magnetism, but this was not published and does not appear to have progressed past the first draft. In 1851, the year before her cancer struck, she wrote to her mother mentioning "certain productions" she was working on regarding the relation of maths and music.
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Ada Lovelace
| 974 |
Work
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Lovelace first met Charles Babbage in June 1833, through their mutual friend Mary Somerville. Later that month, Babbage invited Lovelace to see the prototype for his difference engine. She became fascinated with the machine and used her relationship with Somerville to visit Babbage as often as she could. Babbage was impressed by Lovelace's intellect and analytic skills. He called her "The Enchantress of Number". In 1843, he wrote to her:
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Ada Lovelace
| 974 |
Work
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Forget this world and all its troubles and if possible its multitudinous Charlatans—every thing in short but the Enchantress of Number.
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Ada Lovelace
| 974 |
Work
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During a nine-month period in 1842–43, Lovelace translated the Italian mathematician Luigi Menabrea's article on Babbage's newest proposed machine, the Analytical Engine. With the article, she appended a set of notes. Explaining the Analytical Engine's function was a difficult task; many other scientists did not grasp the concept and the British establishment had shown little interest in it. Lovelace's notes even had to explain how the Analytical Engine differed from the original Difference Engine. Her work was well received at the time; the scientist Michael Faraday described himself as a supporter of her writing.
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Ada Lovelace
| 974 |
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The notes are around three times longer than the article itself and include (in Note G), in complete detail, a method for calculating a sequence of Bernoulli numbers using the Analytical Engine, which might have run correctly had it ever been built (only Babbage's Difference Engine has been built, completed in London in 2002). Based on this work, Lovelace is now considered by many to be the first computer programmer and her method has been called the world's first computer program. Others dispute this because some of Charles Babbage's earlier writings could be considered computer programs.
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Ada Lovelace
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Note G also contains Lovelace's dismissal of artificial intelligence. She wrote that "The Analytical Engine has no pretensions whatever to originate anything. It can do whatever we know how to order it to perform. It can follow analysis; but it has no power of anticipating any analytical relations or truths." This objection has been the subject of much debate and rebuttal, for example by Alan Turing in his paper "Computing Machinery and Intelligence". Most modern computer scientists argue that this view is outdated and that computer software can develop in ways that cannot necessarily be anticipated by programmers.
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Ada Lovelace
| 974 |
Work
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Lovelace and Babbage had a minor falling out when the papers were published, when he tried to leave his own statement (criticising the government's treatment of his Engine) as an unsigned preface, which could have been mistakenly interpreted as a joint declaration. When Taylor's Scientific Memoirs ruled that the statement should be signed, Babbage wrote to Lovelace asking her to withdraw the paper. This was the first that she knew he was leaving it unsigned, and she wrote back refusing to withdraw the paper. The historian Benjamin Woolley theorised that "His actions suggested he had so enthusiastically sought Ada's involvement, and so happily indulged her ... because of her 'celebrated name'." Their friendship recovered, and they continued to correspond. On 12 August 1851, when she was dying of cancer, Lovelace wrote to him asking him to be her executor, though this letter did not give him the necessary legal authority. Part of the terrace at Worthy Manor was known as Philosopher's Walk; it was there that Lovelace and Babbage were reputed to have walked while discussing mathematical principles.
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Ada Lovelace
| 974 |
Work
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In 1840, Babbage was invited to give a seminar at the University of Turin about his Analytical Engine. Luigi Menabrea, a young Italian engineer and the future Prime Minister of Italy, transcribed Babbage's lecture into French, and this transcript was subsequently published in the Bibliothèque universelle de Genève in October 1842. Babbage's friend Charles Wheatstone commissioned Ada Lovelace to translate Menabrea's paper into English. She then augmented the paper with notes, which were added to the translation. Ada Lovelace spent the better part of a year doing this, assisted with input from Babbage. These notes, which are more extensive than Menabrea's paper, were then published in the September 1843 edition of Taylor's Scientific Memoirs under the initialism AAL.
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Ada Lovelace
| 974 |
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Ada Lovelace's notes were labelled alphabetically from A to G. In Note G, she describes an algorithm for the Analytical Engine to compute Bernoulli numbers. It is considered to be the first published algorithm ever specifically tailored for implementation on a computer, and Ada Lovelace has often been cited as the first computer programmer for this reason. The engine was never completed and so her program was never tested.
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Ada Lovelace
| 974 |
Work
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In 1953, more than a century after her death, Ada Lovelace's notes on Babbage's Analytical Engine were republished as an appendix to B. V. Bowden's Faster than Thought: A Symposium on Digital Computing Machines. The engine has now been recognised as an early model for a computer and her notes as a description of a computer and software.
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Ada Lovelace
| 974 |
Work
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In her notes, Ada Lovelace emphasised the difference between the Analytical Engine and previous calculating machines, particularly its ability to be programmed to solve problems of any complexity. She realised the potential of the device extended far beyond mere number crunching. In her notes, she wrote:
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Ada Lovelace
| 974 |
Work
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[The Analytical Engine] might act upon other things besides number, were objects found whose mutual fundamental relations could be expressed by those of the abstract science of operations, and which should be also susceptible of adaptations to the action of the operating notation and mechanism of the engine...Supposing, for instance, that the fundamental relations of pitched sounds in the science of harmony and of musical composition were susceptible of such expression and adaptations, the engine might compose elaborate and scientific pieces of music of any degree of complexity or extent.
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Ada Lovelace
| 974 |
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This analysis was an important development from previous ideas about the capabilities of computing devices and anticipated the implications of modern computing one hundred years before they were realised. Walter Isaacson ascribes Ada's insight regarding the application of computing to any process based on logical symbols to an observation about textiles: "When she saw some mechanical looms that used punchcards to direct the weaving of beautiful patterns, it reminded her of how Babbage's engine used punched cards to make calculations." This insight is seen as significant by writers such as Betty Toole and Benjamin Woolley, as well as the programmer John Graham-Cumming, whose project Plan 28 has the aim of constructing the first complete Analytical Engine.
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Ada Lovelace
| 974 |
Work
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According to the historian of computing and Babbage specialist Doron Swade:
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Ada Lovelace
| 974 |
Work
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Ada saw something that Babbage in some sense failed to see. In Babbage's world his engines were bound by number...What Lovelace saw...was that number could represent entities other than quantity. So once you had a machine for manipulating numbers, if those numbers represented other things, letters, musical notes, then the machine could manipulate symbols of which number was one instance, according to rules. It is this fundamental transition from a machine which is a number cruncher to a machine for manipulating symbols according to rules that is the fundamental transition from calculation to computation—to general-purpose computation—and looking back from the present high ground of modern computing, if we are looking and sifting history for that transition, then that transition was made explicitly by Ada in that 1843 paper.
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