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The syndrome of brain atrophy in girls described by Andreas Rett in 1966 [Rett, Wien Klin Wochenschr, 1966;116:723-726] was brought to the attention of the English-speaking world by Hagberg et al. in 1983 [Hagberg et al., Ann Neurol, 1983;14:471-479]. Four clinical stages after the age of 6 months were described in classical cases of Rett syndrome (RS), namely early onset stagnation at 6 months to 1(1/2) years, the rapid destructive stage at 1-3 years, the pseudo-stationary stage from pre-school to school years, and the late motor deterioration stage at 15-30 or more years. The rapid destructive stage causes profound dementia with loss of speech and hand skills, stereotypic movements, ataxia, apraxia, irregular breathing with hyperventilation while awake, and frequently seizures. Most cases are isolated in their families, apart from identical twins. However, linkage studies in rare familial cases suggested a critical region at Xq28. In 1999 American investigators found several mutations in the X-linked gene MECP2 encoding Methyl-CpG-binding protein 2 in a proportion of Rett patients. The protein MeCP2 can bind methylated DNA and when mutated may interfere with transcriptional silencing of other genes and result in abnormal chromatin assembly. Many different mutations of the protein are being studied in humans and in mice. Neuropathological studies have shown decreased brain growth and decreased size of individual neurons, with thinned dendrites in some cortical layers, and abnormalities in substantia nigra, suggestive of deficient synaptogenic development, probably starting before birth. Electrophysiology demonstrates progressively abnormal electroencephalograms (EEG) in the first three stages of the syndrome, with some subsequent improvement and occurrence of pseudoseizures. Neurometabolic factors are discussed in detail, particularly reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. Autonomic dysfunction is described, particularly reduced vagal and overactive sympathetic activity. Neuro-imaging may be required for further investigation, as shown in the differential diagnosis.

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It has long been suspected that the Rett syndrome (RS) is associated with abnormality of monoaminergic systems, particularly in the brainstem and midbrain, with spread to basal ganglia and cerebral cortex. Early investigators found no significant abnormality in the level of metabolites of noradrenaline, dopamine or serotonin in the spinal fluid, but autopsy brain studies revealed reduced levels of these substances and their metabolites as well as cortical choline acetyltransferase (ChAT) and microtubule-associated proteins (MAP). Levels of Substance P in spinal fluid of RS girls have been reported to be low, while levels of glutamate are raised. Attempts to assess dopaminergic activity by positron emission tomography (PET) in RS have given variable results with different reagents, including [(18)F] 6-fluorodopa. Our group investigated nine RS patients after the age of 12 years and control girls of similar age. Volumetric scans of basal ganglia with Magnetic Resonance Imaging showed a significant reduction in the size of caudate heads and thalami in RS (but not in the size of lentiform nuclei). PET scans with [(11)C] raclopride and with [(18)F] 6-fluorodopa under intravenous propofol anesthesia showed the mean uptake of fluorodopa to be reduced by 13.1% in caudate and by 12.4% in putamen as compared to the controls, whereas dopamine D2 receptor binding, as indicated by raclopride binding, was significantly increased by 9.7% in caudate and by 9.6% in putamen.

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The Rett syndrome (RS) is a peculiar, sporadic, atrophic disorder, almost entirely confined to females. After the first six months of life there is developmental slowing with reduced communication and head growth for about one year. This is followed by a rapid destructive stage with severe dementia and loss of hand skills (with frequent hand wringing), apraxia and ataxia, autistic features and irregular breathing with hyperventilation. Seizures often supervene. Subsequently there is some stabilization in a pseudo-stationary stage during the preschool to school years, associated with more emotional contact but also abnormalities of the autonomic and skeletal systems. After the age of 15-20 years, a late motor deterioration occurs with dystonia and frequent spasticity but seizures become milder. RS has generally been considered an X-linked disorder in which affected females represent a new mutation, with male lethality. Linkage studies suggested a critical region at Xq28. In 1999, mutations in the gene MECP2 encoding X-linked methyl cytosine-binding protein 2 (MeCP2) were found in a proportion of Rett girls. This protein can bind methylated DNA. Analyses are leading to much further investigation of mutants and their effects on genes. Neuropathological and electrophysiological studies of RS are described. Description of neurometabolic factors includes reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. The results of neuroimaging are surveyed, including volumetric magnetic resonance imaging (MRI) and positron emission tomography (PET).

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The Canadian Association for Child Neurology (CACN) was founded in June 1971 to combine neurologists interested in children and paediatricians interested in the nervous system into an organization which would promote the development of this subspecialty. Initially, the members of the Association mostly wished to have a training programme under the combined supervision of University Departments of Paediatrics and Neurology. However, under the influence of the Royal College of Physicians & Surgeons of Canada, and its Committee on Neurology, the training of child neurologists was organized in a manner analogous to that of neurologists for adults, though with an initial one or two years of paediatrics instead of medicine. By 1975, four years within a recognized neurological training programme could lead to the Certification Examination in Neurology, as modified for paediatric neurology. In 1981, the CACN also joined the Canadian Congress of Neurological Sciences. It has played an increasing part in child care and also in a academic studies. However, evidence will be presented to show that the present number of paediatric neurologists in Canada is insufficient. The number of trainees also appears inadequate, and increased funding for training positions is needed. Close cooperation between paediatric neurologists, rehabilitation experts, developmental paediatricians and related subspecialists is required.

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The hypereosinophilic syndrome (HES) is a rare yet frequently fatal disorder of unknown etiology characterized by markedly elevated eosinophil counts and subsequent multiple organ failure due presumably to eosinophil-derived protein toxicity. We describe the laboratory and anatomic findings in a 15-year-old female with extraordinarily high circulating levels of eosinophil major basic protein (MBP) who sustained a precipitous cardiac death secondary to a massive myocardial infarction. Postmortem examination showed marked cardiomegaly with extensive recent left ventricular infarction. Occlusive thrombosis of small blood vessels was evident in the myocardium, spleen, lungs, and kidneys. Immunofluorescent staining showed massive MBP deposition in multiple organ parenchyma including the heart, renal glomeruli, adrenal cortex, bronchioles, and other visceral organs, suggesting a causal relationship. We hypothesize on the mechanisms of eosinophil toxicity in HES.

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Systemic sclerosis (scleroderma) is an uncommon disease of as-yet-unknown etiology. The hallmark of scleroderma is proliferation of collagen, particularly types I and III, with associated vascular changes. Visceral involvement, particularly pulmonary interstitial disease, can lead to significant morbidity and mortality.Specific therapy is unavailable to date, but there has been interest in the use of cyclosporine (CSA), because it inhibits interleukin-2 production and affects cytotoxic T cells. We present a case of a patient with a triad of suspected autoimmune diseases, systemic sclerosis and Crohn's. disease on CSA therapy for aplastic anemia. Despite hematologic response and cutaneous improvement on CSA therapy, this patient developed interstitial lung disease consistent with sclerodermatous lung.

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A previously healthy 22-month-old boy presented in status epilepticus with high fever. He was comatose, with upper respiratory-tract infection. The seizures responded to anticonvulsant therapy. The boy's temperature returned to normal within 24 hours and he recovered slowly from his encephalopathy. On the third hospital day, he exhibited the characteristic rash of reseola infantum. Acute infection with human herpes virus 6 (HHV-6) was established serologically by enzyme immunoassay. HHV-6 DNA was not detected by polymerase chain reaction in CSF or serum at the onset of illness, but was found three months later in the child's saliva. The pathogenesis of the patient's encephalopathy is discussed. It is concluded that HHV-6 infection should be considered in infants and young children with febrile status epilepticus.

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Of 23 children with hereditary spastic paraplegia (HSP), spasticity was the only neurological abnormality in eight patients (pure form). Additional neurological abnormalities in the 15 with complicated HSP included cognitive impairment, pseudo-bulbar palsy, cerebellar dysfunction and polyneuropathy. 19 children presented with abnormal gait, recognised at a mean age of three years in the pure form and five years in the complicated form. These forms were distinguished at a mean age of 11 years. Early non-motor developmental delay or rapidly ascending paraparesis, with spread of spasticity to the arms and with involvement of bulbar structures, predicted development of the complicated form. The pure form was inherited in an autosomal dominant manner in five patients. The autosomal recessive form was commonly associated with additional neurological abnormalities and a more rapid rate of progression.

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An infant girl had the clinical and immunologic findings of congenital rubella syndrome but also had arthrogryposis multiplex and calcific epiphyseal stippling. Spastic quadriparesis developed, and both physical and behavioral development were slow. Increased spasticity of the legs at 5 1/2 years was related not to progressive rubella encephalomyelopathy but to spinal cord compression by abnormal cartilaginous tissue. The presence of a peroxisomal disorder was demonstrated by a greatly increased level of phytanic acid and slightly increased levels of hexacosanoate in serum and by reduced activity of peroxisomal dihydroxyacetone phosphate acyltransferase and a slightly increased ratio of cytosolic to peroxisomal catalase activity in cultured fibroblasts. A reduction in the number and size of peroxisomes was demonstrated in cultured fibroblasts, and a needle biopsy specimen of the liver also showed the peroxisomes to have a smaller diameter than usual. We recommend that any child with epiphyseal stippling be assessed for peroxisomal disease and that the potential for spinal cord compression by dysplastic bone or cartilage be recognized. The association of peroxisomal dysfunction with congenital rubella has not been described previously. The interaction between rubella virus infection and peroxisomal function may need further investigation.

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A case of myasthenia gravis with histopathologic confirmation of spindle cell thymoma and pure red blood cell aplasia is reported. This is the twelfth case in the literature in which a simultaneous occurrence of all three disorders, with documented thymic pathology, is noted. Immunologic observations in this patient include an elevated acetylcholine receptor antibody and antinuclear antibody titer, agglutination of mouse red blood cells when combined with the patient's serum, and lack of inhibition of binding of radioactive erythropoietin to mouse red cell receptors when combined with the patient's serum. Although both myasthenia with thymoma and pure red blood cell aplasia may have a common immunologic denominator, our findings in this case indicate that inhibition of erythropoiesis is unrelated to erythropoietin receptor blockade. An alternative hypothesis is offered based on defective T-cell function.

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We measured concentrations of 3-methoxy-4-hydroxy-phenylglycol, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid--the metabolites of noradrenaline, dopamine, and serotonin used as central neurotransmitters--in the cerebrospinal fluid (CSF) specimens of five girls with Rett syndrome. These patients met the clinical criteria for both inclusion and exclusion of the diagnosis of Rett syndrome. In contrast to previous reports, cerebral monoamine metabolites were present in normal concentrations in CSF. In addition, concentrations of gamma-aminobutyric acid and of a large number of other amino acids and related compounds were normal in the CSF of patients with the syndrome. We doubt that an underlying biochemical cause for this disorder has yet been discovered.

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We studied a family with dominantly inherited dystonia and intracranial calcification. Thirty-seven members were examined; 13 were affected by dystonia that was segmental in most patients, affecting especially the voice, face, neck, and limbs. Intracranial calcification involved the putamen, pallidum, cerebral white matter and cortex, and cerebellar nuclei. Several patients had both dystonia and calcification, but others had either dystonia or calcification alone.

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Two infants presented with fever and signs of brainstem dysfunction, including impaired consciousness, miosis, absence of oculocephalic responses, respiratory depression and a very peculiar tremor of the tongue and floor of the mouth. They were found to have methadone poisoning caused by accidental contamination of prescribed antibiotics in the same pharmacy, which was a dispensing centre for a methadone maintenance program. They recovered with supportive treatment only.

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Although aseptic meningitis, lethargy and irritability occur frequently in Kawasaki disease and infantile polyarteritis nodosa, other neurological manifestations are rare. The authors report one case of Kawasaki disease and one of infantile polyarteritis nodosa, both associated with acute hemiplegia. Both patients had received courses of oral corticosteroids for their underlying disease prior to the onset of the hemiplegia. Pathological studies, as well as the four previously reported cases, are reviewed.

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PIP: The categories of low birth weigth infants, social vs. racial factors, factors increasing the risk of low birth weight, prevention of low birth weight, social factors in the development of low birth weight children, the influence of social factors vs. other variables, and implications for management are reviewed. In 1948 the World Health Assembly designated children who were born weighing 2500 g or less as "immature" and further stated that a liveborn infant with a period of gestation of less than 37 weeks or specified as "premature" may be considered as the equivalent of an immature event. In 1961 it was recommended that babies weighing 2500 g or less should no longer be referred to as being "premature" and that the concept of "prematurity" in the definition should give way to that of "low birth weight." Intrauterine growth curves for liveborn males and females were devised from data on birth weight and gestational age. Infants born prior to 37 completed weeks of gestation whose weight lies between the 10th and 90th percentiles on such curves may be called preterm with a weight appropriate for gestational age (AGA), whereas infants born after any length of gestation whose birth weight is at or below the 10th percentile may be named hypotrophic or small for gestational age (SGA). On a worldwide scale it has been estimated that about 22 million low birth weight babies, representing roughly 1/6 of all births, are born alive each day. Only about 1 million of them (mostly preterm) are born in developed countries; of the 21 million born in developing areas, roughly 16 million are SGA full-term and not preterm babies. Socioeconomic status appears as 1 of the most important dterminants of the ultimate level of brain function in children of low birth weight, and this is true with respect to neurologic, psychologic, and educational outcome. Social class also has an indirect effect through birth weight, frequency of perinatal brain injury, and other biological variables as well as maternal habits, the quality of nutrition and health care for mother and child, and other "culture factors." The following seem important facets of the management of low birth weight children: optimal obstetric and perinatal care; "bonding" by parents visiting the intensive care nursery and handling the infant; anticipatory guidance; regular pediatric follow-up for at-risk infants; infant stimulation; early correction of refractive errors, strabismus, other visual defects, hearing defects and orthopedic deformities; and developmental assessments and school readiness tests.^ieng

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An Amerindian girl with Friedreich's ataxia presented at the age of 14 years with intermittent bifrontal headaches and abdominal aching, often associated with nausea and recurrent vomiting and an evanescent pink, blotchy rash on the upper trunk. In these attacks she also had hypertension up to 210/160 mm Hg. Renal function studies, including intravenous pyelogram and angiography, were normal. Plasma renin activity (2.5 ng/ml/hr) was also normal. Total body CT scan was negative for phaeochromocytoma, and repeated estimations of 24-hour excretion of urinary VMA were normal or borderline high. Levels of total catecholamines in 24-hour urine were normal twice, but two random specimens during the paroxysmal episodes contained abnormally high levels of norepinephrine and dopamine. Plasma catecholamine concentrations were increased but not as high as with phaeochromocytoma. Blood pressure monitoring demonstrated marked fluctuations with position and temperature. A clonidine suppression test showed a substantial fall of plasma catecholamine levels, consistent with dysautonomia and not with phaeochromocytoma. It is concluded that the patient has dysautonomia of central origin, probably as a manifestation of Friedreich's ataxia. These findings are discussed in relation to the recent demonstration of increased levels of plasma catecholamines in that disease.

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The diagnosis of childhood migraine cannot be confirmed in any objective way. The danger of missing brain tumours or cerebral vascular malformations in these patients was examined in two groups. 73 children who were diagnosed as childhood migraine were followed for 5.4 years. No brain tumour or vascular malformation was found, but two children diagnosed as "abdominal migraine" had a different important disease. The charts of 83 children with brain tumours and seven children with vascular malformations were examined. Only three children could be confused with migraine, and only one actually was.

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