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Stroke in william syndrome
266. ARTHROGRYPOSIS MULTIPLEX CONGENITA DUE TO CONGENITAL MYASTHENIC SYNDROME Jiri Vajsar, Avril Sloane, Daune L. MacGregor, Laurence E. Becker, Venita Jay, and Gabriel M. Ronen, Toronto and Hamilton, Canada
268. DO DEVELOPMENTAL ABNORMALITIES IN DOWN SYNDROME CONTRIBUTE TO EARLY-ONSET DEMENTIA? J. Patrick Kesslak, Brian Cummings, and Ira Lott, Irvine, Califoruia
Two children, 6 and 5.5 years, presented in the neonatal period with hypotonia, multiple joint contractures, ptosis, extraocular weakness, bulbar symptoms, and respiratory distress. Symptoms were characterized by fluctuations and episodic exacerbations of weakness necessitating respiratory support. Development in both children has been delayed and independent walking has not been achieved, although 1 child underwent bilateral Achilles tendons lengthening procedures. Biochemical and metabolic investigations, EMG, and nerve conductions, including slow rate repetitive nerve stimulation, were normal. Acetylcholine receptor antibodies in serum were absent. Single-fiber EMG and axonal stimulation revealed prolonged mean jitter in the tibialis anterior and extensor digitorum muscles, with more than 2 abnormal individual jitter values in each muscle. Muscle biopsy demonstrated normal pattern and morphology of muscle fibers, and present histochemical staining for cholinesterase. However, electron microscopy revealed abnormalities in motor endplates. There was atrophy, flattening of the primary synaptic clefts, and paucity of side branches. Both children improved clinically on pyridostigmine therapy. The findings most likely represent one of the postsynaptic abnormalities (i.e., acetylcholine receptor deficiency, or paucity of synaptic folds). Arthrogryposis due to congenital myasthenic syndrome, as diagnosed in our children, has been reported in one previous patient. The diagnosis can be established by the characteristic clinical history, neurologic examination, electrophysiologic and pathologic findings. Clinical improvement can be achieved with anticholinesterase therapy.
Anatomic and biochemical characteristics of the brain in Down syndrome (DS) may promote the early development of dementia. It is critical to document these changes from childhood to adulthood. A key feature of the mature DS brain is the prevalence of amyloid plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD). Deposition of amyloid has been observed as early as 12 years of age, but was not detected in patients 2 and 5 years of age. At the earliest stages of senile plaque development, intact, morphologically normal, neurofilament positive neurons are present in amyloid deposits. In the early stages of plaque formation, 13-amyloid is not thioflavine positive and there is little astrocytic response. As the DS brain ages and plaques become thioflavine positive, neurons may be lost and reactive astrocytosis is typically present. These postmortem results correspond to antemortem quantitative MRI findings that suggest an accelerated neural loss compared to age-matched controls. In addition to a relatively smaller frontal cortex and hippocampus, and a larger parahippocampal gyrus, DS MRIs had a sharper rate of increased ventricular area and decreased area of temporal lobe structures compared to age-matched volunteers. Examination of factors that contribute to the early onset of pathologic conditions in DS may contribute to an understanding of early maturational changes associated with the disorder as well as AD.
267. BRAIN ABSCESS IN CHILDREN AT CHULALONGKORN HOSPITAL Suwannee Phancharoen, Bangkok, Thailand This study retrospectively reviewed 45 pediatric patients with brain abscesses admitted to Chulalongkorn Hospital between January, 1984 to December, 1993. There is a male to female ratio of 1.5:1. A peak in the age distribution was seen at 4 to 10 years of age. The majority of patients had prolonged headaches, fever, and clinical symptoms and signs of increased intracranial pressure. Abnormal neurologic signs were detected in 80% of patients. Congenital cyanotic heart disease was the most common predisposing factor. The most common organisms isolated from brain abscesses included anaerobic Streptococci, Staphylococcus aureus, and Gram-negative bacilli depending on the predisposing factors. Frontal and parietal lobes were the 2 most common sites of abscesses. Investigation by CT yielded 100% accuracy. Treatment included simple aspiration and/or primary excision together with intravenous antibiotics. Mortality rate in this study was 8.8%, which declined significantly compared with the past decade (1974-1983), in which the rate was 30% P < .05 (chi square). Brain herniation was the most common cause of death. Although neither the site nor the source of infection was a consistent prognostic factor, the patient's level of consciousness at admission was considered significant.
269. STROKE IN WILLIAM SYNDROME Jan B. Wollack, Marie Kaifer, and Marian Lamonte, Baltimore, Maryland William syndrome (WS) is a genetic disorder featuring infantile hypercalcemia, elfin-like features, "cocktail party" personality, and cardiovascular abnormalities including congenital heart disease, supravalvular aortic stenosis, supravalvular pulmonic stenosis, ventricular septal defects, patent ductus arteriosus, and hypertension. Despite the frequency and severity of the reported cardiovascular features of WS, the literature does not contain any reports of cerebral infarction. We describe a 19-year-old adolescent with WS who presented with acute stroke. She was the product of a normal pregnancy and delivery who had feeding difficulties as an infant, and hypercalcemia was documented at age 2 years. At age 14 her serum cholesterol was 200-230 and she was placed on a modified diet. At age 16, her blood pressure was 170/105, and an echocardiogram revealed left atrial and ventricular dilatation, mitral valve prolapse, and mitral regurgitation. She was begun on an ACE inhibitor. At age 19, she awakened with weakness which progressed during the day to right hemiparesis, hemianesthesia, and dysarthria. Initial CT showed a 1 cm 2 hypodensity lateral to the left internal capsule and adjacent to the left putamen. No evidence of a coagulopathy was found. Three days later, her examination disclosed right arm plegia. Cranial MRI revealed a 3 x 1.5 cm area consistent with infarct in the left internal capsule and putamen. Transesophageal echocardiography failed to show an embolic source. Cerebral and renal angiograms were performed. Left carotid injection resuited in severe vasospasm requiring treatment with intra-arterial
PEDIATRIC NEUROLOGY Vol. 11 No. 2 155
nitroglycerin. Right carotid injection revealed a normal pattern of intracranial circulation. On both sides, the vasculature appeared somewhat attenuated and tortuous for her age. In addition, during the renal portion of the angiogram, cannulation of the renal artery resulted in local vasospasm. The patient's deficits stabilized in the hospital, and she was begun on ticlopidine and a calcium channel blocker. Our experience with this patient suggests that patients with WS should be carefully evaluated for the presence of stroke risk factors, and that caution should be exercised in employing angiography.
270. ULLRICH DISEASE Kimio Sasaki, Satoshi Tsugawa, Nobutada Tachi, Sadao Sugiyama, Kimio Minagawa, and Ryoji Minami, Sapporo, Otaru, and Yakumo, Japan
Ullrich disease is a rare disorder characterized by congenital muscle weakness, hypotonia, contractures of proximal joints, hyperextensibility of distal joints, and spur-like protrusions of calcaneus. We report 3 patients (Patient 1: 4-year-old girl; Patient 2: 14-year-old boy; Patient 3: 2-year-old girl) with Ullrich disease. The major clinical features were muscle weakness, hyperextensibility of distal joints, contractures of proximal joints, spur-like protrusion of calcaneus, hyperhydrosis, and normal intelligence. Muscle biopsy revealed variation of muscle fibers and increase of interstitial fibrous tissue. Histochemical stains showed type 1 fiber predominance (Patient 1) and a mild increase of type 2C fibers (Patient 1). Skin biopsy disclosed thin collagen fiber bundles and a mild increase of elastic fibers in the dermis (Patient 1). Autopsy, which was done in Patient 2, revealed marked atrophy of muscle fibers with fibrosis and adipose tissue replacement in diaphragm, rectus abdominis, and iliopsoas muscles. We suggest that Ullrich disease be classified into a congenital muscle-connective tissue disorder.
271. I N F A N T I L E N E U R O A X O N A L D Y S T R O P H Y WITH URINARY O L I G O S A C C H A R I D E EXCRETION NOT DUE TO D E F E C T I V E o t - N - A C E T Y L G A L A C TOSAMINIDASE ACTIVITY Michael Shevell, Bernard Rosenblatt, Leon Wolfe, and Stirling Carpenter, Montreal, Canada Infantile neuroaxonal dystrophy (Seitelberger disease) is an autosomal-recessive neurodegenerative disorder characterized pathologically by axonal enlargements (spheroids) in the terminal nerve endings which ultrastructurally consist of dense tubulovesicular networks with interspersed clefts. Presumably the disorder is the result of defective retrograde axonal transport. In 1 reported sibship, urinary oligosaccharide excretion was noted which was demonstrated to be the result of lysosomal oL-Nacetylgalactosaminidase deficiency (Schindler disease). In the remainder of patients a biochemical basis for Seitelberger disease remains elusive. We report a male child with severe psychomotor regression beginning shortly after his first birthday with marked global hypotonia, hyperreflexia, bilateral plantar responses, and visual impairment. Extensive neurometabolic investigations were negative except for a peripheral nerve/muscle/ skin biopsy diagnostic for neuroaxonal dystrophy and abnormal urinary oligosaccharide (neutral and sialated) excretion on sev-
156 PEDIATRIC NEUROLOGY Vol. 11 No. 2
eral occasions. Measurement of ot-N-acetylgalactosaminidase was normal. The findings of this patient confirm that infantile neuroaxonal dystrophy is biochemically heterogeneous and that an abnormality in lysosomal or other enzymes may result in the characteristic clinical profile and pathologic changes. Efforts are under way to characterize precisely oligosaccharide excretion, which may further our understanding of the role played by glycoprotein or proteoglycan metabolism in axonal transport.
272, IS EARLY DEVELOPMENT NORMAL IN RETT SYNDROME? S. Naidu, S. Hyman, E. Harris, G. Negrin, S. Hosain, M.B. Yablonski, and H.W. Moser, Baltimore, Maryland and Portland, Oregon The commonly held notion is that Rett syndrome (RS) is a neurodegenerative disorder predominantly affecting females, in whom early development is normal from 8-18 months. Information to evaluate early developmental history was obtained by a questionnaire from parents of 43 RS patients and compared to that of 33 female siblings and 97 healthy controls. Girls with RS had a statistically significant increase of early developmental abnormalities that were not attributable to pre- or perinatal complications, or low birth weights. These frequencies were confirmed by the review of birth and pediatric records in 62 patients. In addition serial head circumference measurements (at least 6 girls under 2 yrs of age) of 30 RS girls obtained from medical records showed deceleration of head growth as early as 2-4 months, followed by weight at 4 months and height at 6 months, indicating an early impact of the disease on brain and systemic growth. Although RS is considered a neurodegenerative disease, our cross-sectional evaluation of 112 patients and serial evaluation of 20 girls (4-20 yrs) after a 2-6-year interval revealed no age-related cognitive decline and even acquisition of simple new skills. Conclusion: (1) Subtle early developmental decline may be under-recognized in RS. (2) Preservation of normal head circumference at birth may be due to a postnatal insult; protective maternal or placental influences; prenatal onset where the impact of the disease becomes evident only when rapid synapse formation is required postnatally. (3) Lack of progressive cognitive decline provides hope that identification of a marker and early pathogenesis-based therapeutic interventions could have a longterm impact as in PKU. This study was supported by NIH grants RR00052 and HD24448.
273. OUTCOME OF CHILDREN WITH OPSOCLONUSMYOCLONUS REGARDLESS OF ETIOLOGY Michael S. Hammer, Marianne B. Larsen, and Cynthia Stack, Chicago, Illinois Reviewing the medical records for all admissions from 1983 to 1993 uncovered 11 patients with opsoclonus and myoclonus (OM) with or without histories of neuroblastoma (NB). Eight of these children were found to have an occult NB. The other 3 children to date have had a negative workup. Three of the 11 children have normal development, 1 with an associated NB. The remaining 8 children have delayed development with motor incoordination and speech delay. Three of 8 have experienced behavioral problems. One of 8 children has borderline intelli-
268. DO DEVELOPMENTAL ABNORMALITIES IN DOWN SYNDROME CONTRIBUTE TO EARLY-ONSET DEMENTIA? J. Patrick Kesslak, Brian Cummings, and Ira Lott, Irvine, Califoruia
Two children, 6 and 5.5 years, presented in the neonatal period with hypotonia, multiple joint contractures, ptosis, extraocular weakness, bulbar symptoms, and respiratory distress. Symptoms were characterized by fluctuations and episodic exacerbations of weakness necessitating respiratory support. Development in both children has been delayed and independent walking has not been achieved, although 1 child underwent bilateral Achilles tendons lengthening procedures. Biochemical and metabolic investigations, EMG, and nerve conductions, including slow rate repetitive nerve stimulation, were normal. Acetylcholine receptor antibodies in serum were absent. Single-fiber EMG and axonal stimulation revealed prolonged mean jitter in the tibialis anterior and extensor digitorum muscles, with more than 2 abnormal individual jitter values in each muscle. Muscle biopsy demonstrated normal pattern and morphology of muscle fibers, and present histochemical staining for cholinesterase. However, electron microscopy revealed abnormalities in motor endplates. There was atrophy, flattening of the primary synaptic clefts, and paucity of side branches. Both children improved clinically on pyridostigmine therapy. The findings most likely represent one of the postsynaptic abnormalities (i.e., acetylcholine receptor deficiency, or paucity of synaptic folds). Arthrogryposis due to congenital myasthenic syndrome, as diagnosed in our children, has been reported in one previous patient. The diagnosis can be established by the characteristic clinical history, neurologic examination, electrophysiologic and pathologic findings. Clinical improvement can be achieved with anticholinesterase therapy.
Anatomic and biochemical characteristics of the brain in Down syndrome (DS) may promote the early development of dementia. It is critical to document these changes from childhood to adulthood. A key feature of the mature DS brain is the prevalence of amyloid plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD). Deposition of amyloid has been observed as early as 12 years of age, but was not detected in patients 2 and 5 years of age. At the earliest stages of senile plaque development, intact, morphologically normal, neurofilament positive neurons are present in amyloid deposits. In the early stages of plaque formation, 13-amyloid is not thioflavine positive and there is little astrocytic response. As the DS brain ages and plaques become thioflavine positive, neurons may be lost and reactive astrocytosis is typically present. These postmortem results correspond to antemortem quantitative MRI findings that suggest an accelerated neural loss compared to age-matched controls. In addition to a relatively smaller frontal cortex and hippocampus, and a larger parahippocampal gyrus, DS MRIs had a sharper rate of increased ventricular area and decreased area of temporal lobe structures compared to age-matched volunteers. Examination of factors that contribute to the early onset of pathologic conditions in DS may contribute to an understanding of early maturational changes associated with the disorder as well as AD.
267. BRAIN ABSCESS IN CHILDREN AT CHULALONGKORN HOSPITAL Suwannee Phancharoen, Bangkok, Thailand This study retrospectively reviewed 45 pediatric patients with brain abscesses admitted to Chulalongkorn Hospital between January, 1984 to December, 1993. There is a male to female ratio of 1.5:1. A peak in the age distribution was seen at 4 to 10 years of age. The majority of patients had prolonged headaches, fever, and clinical symptoms and signs of increased intracranial pressure. Abnormal neurologic signs were detected in 80% of patients. Congenital cyanotic heart disease was the most common predisposing factor. The most common organisms isolated from brain abscesses included anaerobic Streptococci, Staphylococcus aureus, and Gram-negative bacilli depending on the predisposing factors. Frontal and parietal lobes were the 2 most common sites of abscesses. Investigation by CT yielded 100% accuracy. Treatment included simple aspiration and/or primary excision together with intravenous antibiotics. Mortality rate in this study was 8.8%, which declined significantly compared with the past decade (1974-1983), in which the rate was 30% P < .05 (chi square). Brain herniation was the most common cause of death. Although neither the site nor the source of infection was a consistent prognostic factor, the patient's level of consciousness at admission was considered significant.
269. STROKE IN WILLIAM SYNDROME Jan B. Wollack, Marie Kaifer, and Marian Lamonte, Baltimore, Maryland William syndrome (WS) is a genetic disorder featuring infantile hypercalcemia, elfin-like features, "cocktail party" personality, and cardiovascular abnormalities including congenital heart disease, supravalvular aortic stenosis, supravalvular pulmonic stenosis, ventricular septal defects, patent ductus arteriosus, and hypertension. Despite the frequency and severity of the reported cardiovascular features of WS, the literature does not contain any reports of cerebral infarction. We describe a 19-year-old adolescent with WS who presented with acute stroke. She was the product of a normal pregnancy and delivery who had feeding difficulties as an infant, and hypercalcemia was documented at age 2 years. At age 14 her serum cholesterol was 200-230 and she was placed on a modified diet. At age 16, her blood pressure was 170/105, and an echocardiogram revealed left atrial and ventricular dilatation, mitral valve prolapse, and mitral regurgitation. She was begun on an ACE inhibitor. At age 19, she awakened with weakness which progressed during the day to right hemiparesis, hemianesthesia, and dysarthria. Initial CT showed a 1 cm 2 hypodensity lateral to the left internal capsule and adjacent to the left putamen. No evidence of a coagulopathy was found. Three days later, her examination disclosed right arm plegia. Cranial MRI revealed a 3 x 1.5 cm area consistent with infarct in the left internal capsule and putamen. Transesophageal echocardiography failed to show an embolic source. Cerebral and renal angiograms were performed. Left carotid injection resuited in severe vasospasm requiring treatment with intra-arterial
PEDIATRIC NEUROLOGY Vol. 11 No. 2 155
nitroglycerin. Right carotid injection revealed a normal pattern of intracranial circulation. On both sides, the vasculature appeared somewhat attenuated and tortuous for her age. In addition, during the renal portion of the angiogram, cannulation of the renal artery resulted in local vasospasm. The patient's deficits stabilized in the hospital, and she was begun on ticlopidine and a calcium channel blocker. Our experience with this patient suggests that patients with WS should be carefully evaluated for the presence of stroke risk factors, and that caution should be exercised in employing angiography.
270. ULLRICH DISEASE Kimio Sasaki, Satoshi Tsugawa, Nobutada Tachi, Sadao Sugiyama, Kimio Minagawa, and Ryoji Minami, Sapporo, Otaru, and Yakumo, Japan
Ullrich disease is a rare disorder characterized by congenital muscle weakness, hypotonia, contractures of proximal joints, hyperextensibility of distal joints, and spur-like protrusions of calcaneus. We report 3 patients (Patient 1: 4-year-old girl; Patient 2: 14-year-old boy; Patient 3: 2-year-old girl) with Ullrich disease. The major clinical features were muscle weakness, hyperextensibility of distal joints, contractures of proximal joints, spur-like protrusion of calcaneus, hyperhydrosis, and normal intelligence. Muscle biopsy revealed variation of muscle fibers and increase of interstitial fibrous tissue. Histochemical stains showed type 1 fiber predominance (Patient 1) and a mild increase of type 2C fibers (Patient 1). Skin biopsy disclosed thin collagen fiber bundles and a mild increase of elastic fibers in the dermis (Patient 1). Autopsy, which was done in Patient 2, revealed marked atrophy of muscle fibers with fibrosis and adipose tissue replacement in diaphragm, rectus abdominis, and iliopsoas muscles. We suggest that Ullrich disease be classified into a congenital muscle-connective tissue disorder.
271. I N F A N T I L E N E U R O A X O N A L D Y S T R O P H Y WITH URINARY O L I G O S A C C H A R I D E EXCRETION NOT DUE TO D E F E C T I V E o t - N - A C E T Y L G A L A C TOSAMINIDASE ACTIVITY Michael Shevell, Bernard Rosenblatt, Leon Wolfe, and Stirling Carpenter, Montreal, Canada Infantile neuroaxonal dystrophy (Seitelberger disease) is an autosomal-recessive neurodegenerative disorder characterized pathologically by axonal enlargements (spheroids) in the terminal nerve endings which ultrastructurally consist of dense tubulovesicular networks with interspersed clefts. Presumably the disorder is the result of defective retrograde axonal transport. In 1 reported sibship, urinary oligosaccharide excretion was noted which was demonstrated to be the result of lysosomal oL-Nacetylgalactosaminidase deficiency (Schindler disease). In the remainder of patients a biochemical basis for Seitelberger disease remains elusive. We report a male child with severe psychomotor regression beginning shortly after his first birthday with marked global hypotonia, hyperreflexia, bilateral plantar responses, and visual impairment. Extensive neurometabolic investigations were negative except for a peripheral nerve/muscle/ skin biopsy diagnostic for neuroaxonal dystrophy and abnormal urinary oligosaccharide (neutral and sialated) excretion on sev-
156 PEDIATRIC NEUROLOGY Vol. 11 No. 2
eral occasions. Measurement of ot-N-acetylgalactosaminidase was normal. The findings of this patient confirm that infantile neuroaxonal dystrophy is biochemically heterogeneous and that an abnormality in lysosomal or other enzymes may result in the characteristic clinical profile and pathologic changes. Efforts are under way to characterize precisely oligosaccharide excretion, which may further our understanding of the role played by glycoprotein or proteoglycan metabolism in axonal transport.
272, IS EARLY DEVELOPMENT NORMAL IN RETT SYNDROME? S. Naidu, S. Hyman, E. Harris, G. Negrin, S. Hosain, M.B. Yablonski, and H.W. Moser, Baltimore, Maryland and Portland, Oregon The commonly held notion is that Rett syndrome (RS) is a neurodegenerative disorder predominantly affecting females, in whom early development is normal from 8-18 months. Information to evaluate early developmental history was obtained by a questionnaire from parents of 43 RS patients and compared to that of 33 female siblings and 97 healthy controls. Girls with RS had a statistically significant increase of early developmental abnormalities that were not attributable to pre- or perinatal complications, or low birth weights. These frequencies were confirmed by the review of birth and pediatric records in 62 patients. In addition serial head circumference measurements (at least 6 girls under 2 yrs of age) of 30 RS girls obtained from medical records showed deceleration of head growth as early as 2-4 months, followed by weight at 4 months and height at 6 months, indicating an early impact of the disease on brain and systemic growth. Although RS is considered a neurodegenerative disease, our cross-sectional evaluation of 112 patients and serial evaluation of 20 girls (4-20 yrs) after a 2-6-year interval revealed no age-related cognitive decline and even acquisition of simple new skills. Conclusion: (1) Subtle early developmental decline may be under-recognized in RS. (2) Preservation of normal head circumference at birth may be due to a postnatal insult; protective maternal or placental influences; prenatal onset where the impact of the disease becomes evident only when rapid synapse formation is required postnatally. (3) Lack of progressive cognitive decline provides hope that identification of a marker and early pathogenesis-based therapeutic interventions could have a longterm impact as in PKU. This study was supported by NIH grants RR00052 and HD24448.
273. OUTCOME OF CHILDREN WITH OPSOCLONUSMYOCLONUS REGARDLESS OF ETIOLOGY Michael S. Hammer, Marianne B. Larsen, and Cynthia Stack, Chicago, Illinois Reviewing the medical records for all admissions from 1983 to 1993 uncovered 11 patients with opsoclonus and myoclonus (OM) with or without histories of neuroblastoma (NB). Eight of these children were found to have an occult NB. The other 3 children to date have had a negative workup. Three of the 11 children have normal development, 1 with an associated NB. The remaining 8 children have delayed development with motor incoordination and speech delay. Three of 8 have experienced behavioral problems. One of 8 children has borderline intelli-