小坂 仁

We analyzed follow-up magnetic resonance images (MRI) in eight children with clinical postinfectious encephalitis (PIE), and discussed their pathogeneses. Three categories of MRI findings were apparent: (1) multifocal lesions in the white matter with/without basal ganglia involvement consistent with acute disseminated encephalomyelitis (ADEM) (three patients) (2) single or multifocal lesions localized only in the gray matter (two patients) and (3) localized lesions in the brain stem, basal ganglia or cerebellum. Some lesions in the patients in Categories 1 and 2 migrated or were resolved quickly, sometimes within 10 days. Gadolinium caused linear or spotty enhancement in the patients in Category 2. These findings suggest that Categories 1 and 2 are a self-limiting allergic angiopathy without demyelination. In contrast, the lesions in the patients in Category 3 were fixed, and not resolved within 6 months (three patients). The pathogenesis of Category 3 is not known. All except one patient had no prednisolone (PSL) therapy, however all lesions were resolved completely or markedly reduced in size, which indicates PSL therapy is not always necessary in patients with PIE.

The coefficient of variation of R-R intervals (CVRR) was studied in 18 children having severe brain damage with a mean ± standard deviation (S.D.) age of 8.4 ± 5.9 years, who were divided into ten patients complicated with respiratory insufficiency (RI: group) and eight patients with severe athetotic cerebral palsy (SA group). CVRR was obtained in the resting supine position, and was compared with that in 22 neurologically normal controls. CVRR in the RI group (mean ± S.D., 2.19 ± 1.28%) was significantly lower than that in controls (5.56 ± 1.53%), while CVRR in the SA group (11.30 ± 3.91%) was significantly higher than that in controls (both P &lt 0.01, ANOVA). In particular, the four patients with brain death showed extremely low CVRR of 1.00-1.29%. Since CVRR was 4.09% in the patient aged 4 years with birth injury of the upper cervical spinal cord causing absence of spontaneous respiration, the extremely low CVRR in patients with brain death may be directly related to brainstem dysfunction. The cause of the high CVRR in the SA group was not determined. Thus, CVRR may be useful for quantitative evaluation of severe neurological disorder.

We studied the effect of digitalis on nerve conduction dysfunction in Pelizaeus-Merzbacher disease (PMD). The patients were three Japanese boys with PMD, aged 7-10 years. Digitalis was administered orally in a daily dose of 0.06 mg/kg for 2 consecutive months, and the obtained serum concentrations ranged from 0.33 to 0.55 ng/ml. The digitalis therapy induced slight improvement of severe dysarthria and cognitive dysfunction in the two older patients. Electrophysiological examinations revealed the following results: In brainstem auditory evoked potentials (BAEPs), while waves II (or III) to V were absent before treatment, on treatment all waves of BAEPs except a wave IV were restored in all patients. While visual evoked potentials (VEPs) in response to transient flash stimulation showed markedly prolonged latencies before treatment, digitalis produced a mild, although not statistically significant, shortening of the latency of N160. There were also no significant changes in inter-peak amplitudes of VEPs. Transcranial cortical magnetic stimulation continued to fail to elicit motor evoked potentials of the first dorsal interosseous muscles in all patients. Thus, although the serum concentrations were insufficient to elicit favorable therapeutic effects, digitalis therapy provided slight relief of clinical symptoms with evidence of improvement of conduction dysfunction. It is suggested that patients with PMD may respond to symptomatic treatment modulating nerve conduction.

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive inherited disorder with dysmyelination restricted to the central nervous system. Thus far, molecular analyses have revealed various gene defects in proteolipid protein (PIP) in patients with PMD, and mutations in the coding region of the PIP gene are observed in 10-30% of PMD patients. We analyzed the PLP gene in 11 patients with PMD, 9 with classical form and 2 (twin males) with atypical form who clinically meet the criteria of X-linked spastic paraplesia. Four new point mutations -C-'Tat nt. -34 T→A at nt. 623 (V208N) C-T at nt. 629 (P210L) and G-C at nt. 721 (A241P)- were observed in patients with classical form. The patient with a transition at nt. -34 is the first PMD case with a mutation in the 5'LfTR of the PLP gene. Ala241 is the neighboring residue of Ala242 which is substituted by Val in the jimpymad mouse, and the patient with A241P exhibits a severe dysmyelinating pattern and clinical manifestations. Concerning the atypical patients, we identified the G→A transition at nt. 431 resulting W144X. These atypical patients could be classified into X-linked spastic paraplesia type 2 which links to Xq 21 and is allelic to PMD (Saugier-Veber et al., 1994).

We experienced five children having T1-shortening lesions in basal ganglia or thalami on magnetic resonance imaging (MRI), which were supposed to be caused by manganese (Mn) overdosis. Instead of the presence of above mentioned lesions, no neurological manifestations corresponding to them had developed in all patients. This observation suggests that a MRI is useful for detecting the side effects caused by overdosis of Mn in patients having parenteral nutrition.

Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder caused by abnormalities in the proteolipid protein (PLP) gene, which is essential for oligodendrocyte differentiation and CNS myelin formation. Although linkage analysis has shown the homogeneity at the PLP locus in patients with PMD, exonic mutations in the PLP gene have been identified in only 10%-25% of all cases, which suggests the presence of other genetic aberrations, including gene duplication. In this study, we examined five families with PMD not carrying exonic mutations in PLP gene, using comparative multiplex PCR (CM-PCR) as a semiquantitative assay of gene dosage. PLP gene duplications were identified in four families by CM-PCR and confirmed in three families by densitometric RFLP analysis. Because a homologous myelin protein gene, PMP22, is duplicated in the majority of patients with Charcot-Marie-Tooth 1A, PLP gene overdosage may be a important genetic abnormality in PMD and affect myelin formation.

We experienced a 15-year-old female, whose healthy parents were second cousins, who was suspected of having a dysmyelinating disease involving only the central nervous system (CNS). She was noticed to have congenital pendular nystagmus, and spastic gait disturbance developed at the age of 10 years. Mild athetosis of the upper limbs and ataxia were recognized at age 13 years, and dysarthria presented at age 15. MRI and electrophysiological findings showed the characteristics of Pelizaeus-Merzbacher disease (PMD), although the extensive nerve conduction slowing of the CNS was less severe than that in male patients with PMD. No promoter or exonic mutations of proteolipid protein (PLP) gene were detected. Although this patient might be heterozygous for a mutation of the extraexonic PLP gene sequences or of other unknown X-linked PLP associated genes, we speculate that this case had a dysmyelinating disease with an autosomal recessive trait characterized by the same phenotype as that of PMD.

Lymphoblastoid cells are useful materials for the diagnosis and basic studies of many human genetic disorder. To elucidate the etiology of Leigh syndrome, biochemical analyses and mitochondrial DNA analyses were performed on cultured lymphoblastoid cells from 20 patients with the clinical characteristics of this disorder. In 9 of 20 cases, we were able to define the following defects. Eight patients had biochemical defects, including 3 with pyruvate dehydrogenase complex (PDHC), 3 with cytochrome c oxidase (complex IV), and 2 with NADH cytochrome c reductase (complex I) deficiencies. Two of 3 patients with PDHC deficiency were diagnosed with thiamine-responsive PDHC deficiency. One patient had a point mutation (T→G) of mitochondrial DNA at nucleotide position 8993. These results indicate that the underlying defects in Leigh syndrome are heterogenous and cultured lymphoblastoid cells are very useful materials for diagnosis of the etiology of Leigh syndrome.

We report a rare polymorphism in the human proteolipid protein (PLP) gene. A synonymous mutation, 168 A→G, was detected in exon 2 of the PLP gene. Mutations in this gene have been reported in some cases of Pelizaeus-Merzbacher disease. © 1995 Springer-Verlag.

Two cases of a 13-year-old girl and a 14-year-old boy with postinfectious focal encephalitis due to influenza are reported. The clinical and magnetic resonance imaging (MRI) findings included: (1) partial motor seizures as the initial central nervous system manifestation, appearing more than 20 days after the influenzal infection, (2) no change in the level of consciousness although a boy demonstrated apraxia, and (3) high signal intensity lesions noticed with T2-weighted MRI located mainly in the cortex. The girl's lesion appeared to resolve within 10 days on MRI, while that of the boy (demonstrated in the thalamus on a third MRI) resolved within 1 week. However, a new lesion appeared in the cortex approximately 1 month later, that was visualized on a fourth MRI. Small gadolinium-enhanced lesions also were noticed during earlier stages in both patients. The pathogenesis of these MRI lesions is unknown, but the coexistence of small enhancing lesions, rapidly resolving lesions, and the elevated thrombin anti-thrombin III complexes, may indicate the presence of an angiopathy. Serial MRI examinations in patients with postinfectious encephalitis may lead to a better understanding of the pathogenesis of this disorder. © 1995.

An 12-old-year girl with Tolosa-Hunt syndrome(THS) complicated with pseudotumor cerebri is presented. She suffered from alternating, recurrent and painful ophthalmoplegia at the age of 8, and bilateral papilledema which did not affect visual acuity was also recognized. THS subsided readily on steroid therapy, and the remission lasted more than 3 years after discontinuing steroid. However, papilledema did not change despite remission of THS, and resulted in optic atrophy with a mildly enlarged scotoma and 10% decrease in visual acuity 6 months after the onset. MRI disclosed slightly contrasted masses in the bilateral enlarged cavernous sinuses and narrowing of the left carotid siphon. Another small mass with partial gadolinium enhancement was revealed adjacent to the left narrowing of the carotid siphon in the optochiasmatic cistern however, there was no lesion causing intracranial hypertension. The intracavernous MRI findings were considered characteristics of THS, and papilledema seemed to be due to pseudotumor cerebri by exclusion. Since subsequent MRI confirmed no progression of the above findings, the intracavernous and intracisternal masses were suspected to be non-specific inflammatory granulomas associated with THS. © 1995 Elsevier Science B.V. All rights reserved.

Brain lesions exhibited on MRI and CT scan in 2 patients with mitochondrial encephalomyelopathy representing Leigh syndrome were improved by administration of dichloroacetate (DCA). One patient had pyruvic acid dehydrogenase complex (PDHC) deficiency, the other had complex I deficiency. The efficacy of DCA was transient in the patient with the PDHC deficiency, lasting for about 2.5 months. The patient died at the age of 6, about 2 years after the initiation of DCA treatment. DCA administration was started in the patient with complex I deficiency when he was 15 months old and it is still effective at his present age of 24 months. His motor ability is developing, and he could walk without support at the age of 19 months. DCA administration should be tried in patients with mitochondrial diseases. © 1995.

We report a third mutation of the proteolipid protein gene in male Japanese patients withX-linked spastic paraplegia. Although the proteolipid protein gene encodes two myelin proteins, proteolipid protein and DM 20, our W144X mutation resides in the latter part of exon 3 (exon 3B), which is spliced out in DM 20. This mutation may reserve the function of DM 20. Findings in our patients support that this form of spastic paraplesiais allelic to Pelizaeus-Merzbacher disease and that the mild clinical phenotype of this disorder may be related to a mutation within exon 3B of thePLP gene. © 1995 by Academic Press, Inc.

We report a 12 year old girl with double cortex syndrome. She was moderately retarded and had bilateral tonic seizures of upper extremities and atonic seizures of lower extremities with consciousness disturbances. An interictal EEG showed two foci of spikes, left frontpolar and left posteriortemporal. She was hospitalized due to fluctuating disturbance of consciousness from a nearly normal to an almost unresponsive state. An electro encephalogram recorded during the unresponsive state disclosed a diffuse but posteriorly predominant 4-5 Hz hypersynchronous waves that began as a 10-11 Hz focal rhythmic waves at left parieto-occipital or frontal area 2-3 Hz spike and wave complex, following right frontal dominant 12-13 Hz wave, sometimes accompanied this high voltage wave. This pattern continued for a few minutes slid the consciousness returned to a nearly normal state as these waves disappeared. This complex partial status was composed of complex partial seizure for some minutes long and interictal state, in which the consciousness did not return to normal. These states were periodically repeated in a few minutes and were effectively controlled by intravenous diazepam. Although double cortex syndrome is a rare migratory disorder, it has often been reported together with intractable epilepsy. As far as we know, this is the first case of double cortex syndrome accompanied by complex partial status epilepticus.

A 13-year-old girl with nephrotic syndrome (NS) developed acute leucoencephalopathy during combination therapy with cyclosporin A (CyA) and prednisolone (PSL). The patient had a generalized motor seizure followed by coma at 19 days after CyA administration. Magnetic resonance scanning performed on the 1st hospital day revealed white matter lesions in the subcortices of the parietal and occipital lobes, brain stem and cerebellum. These lesions had completely resolved on the 10th hospital day. This episode might be caused by CyA because the clinical course and laboratory data revealed neither inflammation nor other causative factors. To our knowledge, this is the first report of acute leucoencephalopathy during combination therapy with CyA and PSL in a patient with NS. © 1994 IPNA.

We report clinical and neuropathological studies of 2 patients with glutaric aciduria type 1. A 10-month-old male with involuntary movements expired suddenly at home. The second, a 15-year-old female, died after three episodes of acute encephalopathy including a Reye syndrome-like episode and an episode of severe hypoglycemia. Hypocarnitinemia was also present. Selective involvement of type II muscle fibers was observed during the Reye syndrome-like episode. Magnetic resonance imaging of the 2 patients showed marked widening of the sylvian fissure, atrophy of the basal ganglia, and white matter lesions. Neuropathology of the 10-month-old patient showed: (1) temporal and frontal lobe hypoplasia, (2) degeneration of the putamen and the pallidum, (3) mild status spongiosus in the cerebral white matters, (4) heterotopic neurons in the cerebellum, and (5) hypoplasia of the cerebral white matter. This patient appeared to manifest a migration and/or maturation abnormality of the brain as well as previously observed basal ganglia and white matter degeneration. © 1994.

We report a 21-year-old man with agammaglobulinemia and chronic progressive encephalopathy. The patient was diagnosed as having X-linked agammaglobulinemia at 6 months of age, and gamma globulin supplementation was initiated. He exhibited normal development until he was 11 years old, when he showed a decline in school performance and a personality change. Computed tomography images at that time disclosed diffuse cerebral atrophy. Several generalized tonic-clonic convulsions, myoclonus and spasticity appeared at the age of 13 years. He lost his ability to walk and speak at the age of 17 years old. He is currently 21 years old and displays severe mental deterioration and spastic tetraplegia. Magnetic resonance imaging showed progressive diffuse cerebral atrophy with no change in intensity. The cerebellum and the brain stem were relatively well maintained. Viral isolations were negative and serum antibody titers for rubella, measles, and human immune deficiency virus were not elevated. Our patient's symptoms resemble those previously reported as chronic progressive encephalopathy without viral isolation. This condition may be a complication of agammaglobulinemia. It is possible that the encephalopathy of our patient has the same etiology as that described in the other reports. Further attempts to identify the etiology of the encephalopathy using molecular techniques are necessary.

A 7-year-old boy had symmetrical transient high signal lesions in the external capsules on T2-weighted image during the recovery phase of herpes simplex virus (HSV) encephalitis. Although this finding has never been reported in HSV or other viral encephalitis, a postinfectious allergic mechanism is suspected in this patient. With the development of magnetic resonance imaging and other neuroimaging studies, a more detailed analysis of central nervous system is now possible.

Two MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) patients with diabetes mellitus (DM), and their family members are described clinically and genetically. The probands have the following features in common normal early development, short stature, deterioration of intellectual ability, convulsions, cardiac conduction defect, sensorineural hearing loss, cortical blindness, and hemiparesis. Biochemical tests showed high levels of lactate and pyruvate in the blood and cerebrospinal fluid. Muscle biopsy showed ragged-red fibers. Molecular genetic analysis of both patients revealed that they had an A-to-G substitution at nucleotide position 3243 of the mitochondrial DNA in a heteroplasmic fashion. From these clinical and molecular genetic data they were diagnosed as having MELAS. In addition, fasting blood glucose levels were also high and they were diagnosed as having insulin-dependent DM. Some of the maternal family members in both cases also had insulin-dependent DM and several clinical symptoms of MELAS. DM and clinical features of MELAS were transmitted exclusively in the maternal line. In these cases, DM and MELAS might be a clinical manifestation of the same metabolic defect. © 1993.

A 10-month-old male with glutaric aciduria type-1 (GA-1) is reported. This patient showed frequent partial motor seizures, irritability, and involuntary movements, including oral dyskinesia at the age of 3 months. On admission, magnetic resonance (MR) scanning revealed a chronic subdural hematoma and widening of the bilateral insular cisterns. Urine organic acid analysis showed marked excretion of glutaric acid, 3-hydroxy glutaric acid and glutaconic acid, suggesting GA-1. Removal of the subdural hematoma was effective for the irritability but not for the extrapyramidal signs. This is the first report of a subdural hematoma as an initial symptom in a patient with GA-1. However, the complication of subdural fluid collection in GA-1 is not rare. To our knowledge, of 29 patients with GA-1 who underwent computed tomographic or MR scans, 5 had subdural fluid collection. Disproportional hypoplasia of the temporal lobes may be a suggestive etiology of subdural fluid collection/chronic subdural hematoma. © 1993.

Serial imaging studies in a 16-year-old female affected by Fahr's disease accompanied with persistent vitreous artery were performed. She suffered from chronic subdural hematoma, which was removed at the age of 5 months. Brain CT scan performed at the age of 4 revealed calcified lesions at the corticomedullary junctions in the frontal lobes of cerebrum. Yearly repeated CT scans revealed an increasing number of the calcified lesions, which were observed at the cortico-medullary junction of cerebrum, globus pallidus, thalami and dentate nuclei of the cerebellum. Calcifications have not increased in the last 4 years. Laboratory examinations of serum and urine failed to prove any abnormalities. She also had bilateral persistent vitreous arteries. The combination of these rare two diseases may have occurred coincidentaly, but there is a possibility that the capillary dysfunction played a role in the pathogenesis of two diseases. © 1992, The Japanese Society of Child Neurology. All rights reserved.