Experimental cortical dysplasia following ibotenate administration in hamsters: pathogenesis of microgyria and associated gray matter heterotopia

The study presented here investigated the pathogenetic relationship among different types of neuronal migration disorders occurring simultaneously in the brain using an experimental model induced by ibotenate in hamsters. In the cerebral cortex, abnormal neuronal arrangement was induced 1 day after ibotenate injection. This brain lesion resulted in microgyria in the rostral portion, focal subcortical heterotopia in the mid-portion, and focal subependymal heterotopia in the caudal portion in the same specimen. Vimentin-immunoreactive radial glial fibers were lacking in the area of disorganized neuronal arrangement, but were detected around the microgyria and the intermediate zone surrounding focal subcortical heterotopia. The focal subependymal heterotopia did not include radial glial elements. Glial fibrillary acidic protein (GFAP)-positive glial reaction was weak in these cortical lesions. We suggest that the occurrence of each type of migration disorder depends on the depth of the cortical lesion, that is, the production of microgyria, focal subcortical heterotopia and focal subependymal heterotopia are closely related to the lesions including the cortical plate, subplate and ventricular zone, respectively.     

Molecular pathology of human cerebral malformations

ABSTRACT  Molecular pathogenesis of human cerebral malformations is briefly reviewed from a neuro-pathologic viewpoint, with emphasis on holoprosencephaly and neuronal migration disorders. Immunopathologic approaches are useful in elucidating the essential pathomechanism of these anomalies. In alobar holoprosencephaly, for instance, immunostaining for glial fibrillary acidic protein clarifies the pathologic significance of the leptomeningeal glioneuronal heterotopia along the ventral prosencephalic surface. In type 1 lissencephaly and subcortical laminar heterotopia, immunohistochemistry for the causative gene products revealed the temporal and spatial pattern of their localization in the normally developing cerebrum, as well as their reduction in these disorders.     

儿童灰质异位症的研究进展

灰质异位症为神经元移行障碍的一种,可分为室管膜下型、皮层下型、板层型及混合型四种临床类型;发生于神经元移行期的各种理化及生物因素、遗传因素均可导致该症的产生.最新研究表明,基因异常在灰质异位症,尤其是室管膜下型灰质异位症及板层型灰质异位症的发生中,占有重要作用,且其表现有一定特异性.灰质异位症儿童期发病主要表现为发育落后、癫（痫）及运动障碍,其诊断主要依靠影像学检查,尤其是磁共振检查.磁共振新技术,如磁共振波谱分析、功能磁共振等可协助诊断该病.     

Cerebral developmental disorders

PURPOSE OF REVIEW: The development of the cerebral cortex progresses through defined stages including neural proliferation, neuroblast migration and neuronal differentiation. Disruptions in each of these developmental stages can lead to characteristic cerebral cortical malformations. This review provides an overview of the known genetic causes of human cerebral developmental disorders and discusses the potential molecular mechanisms that contribute to these malformations. RECENT FINDINGS: Mutations in genes that are involved in neural proliferation give rise to microcephaly (small brain). Mutations in genes that direct the onset of neuroblast migration give rise to periventricular heterotopia (clusters of neurons along the ventricles of the brain). Mutations in genes that are required for neuroblast migration cause type I lissencephaly (smooth brain) and subcortical band heterotopia (smooth brain with a band of neurons beneath the cortex). Mutations in genes that direct migratory neurons to arrest in the cortex lead to type II lissencephaly (smooth brain with clusters of neurons along the surface of the brain). SUMMARY: The identification of causative genes involved in the formation of the cerebral cortex now allows for a rational approach with which to interpret the underlying mechanistic basis for many of these disorders.     

New trends in neuronal migration disorders

Neuronal migration disorders are an heterogeneous group of disorders of nervous system development and they are considered to be one of the most significant causes of neurological and developmental disabilities and epileptic seizures in childhood. In the last ten years, molecular biologic and genetic investigations have widely increased our knowledge about the regulation of neuronal migration during development.One of the most frequent disorders is lissencephaly. It is characterized by a paucity of normal gyri and sulci resulting in a “smooth brain”. There are two pathologic subtypes: classical and cobblestone. Classical lissencephaly is caused by an arrest of neuronal migration whereas cobblestone lissencephaly caused by overmigration.Heterotopia is another important neuronal migration disorder. It is characterized by a cluster of disorganized neurons in abnormal locations and it is divided into three main groups: periventricular nodular heterotopia, subcortical heterotopia and marginal glioneural heterotopia.Polymicrogyria develops at the final stages of neuronal migration, in the earliest phases of cortical organization; bilateral frontoparietal form is characterized by bilateral, symmetric polymicrogyria in the frontoparietal regions. Bilateral perisylvian polymicrogyria causes a clinical syndrome which manifests itself in the form of mild mental retardation, epilepsy and pseudobulbar palsy.Schizencephaly is another important neuronal migration disorder whose clinical characteristics are extremely variable.This review reports the main clinical and pathophysiological aspects of these disorders paying particular attention to the recent advances in molecular genetics.     

Neuronal migration disorders: clinical, neuroradiologic and genetics aspects

Disorders of neuronal migration are a heterogeneous group of disorders of nervous system development. One of the most frequent disorders is lissencephaly, characterized by a paucity of normal gyri and sulci resulting in a ‘smooth brain’. There are two pathologic subtypes: classical and cobblestone. Six different genes could be responsible for this entity (LIS1, DCX, TUBA1A, VLDLR, ARX, RELN), although co‐delection of YWHAE gene with LIS1 could result in Miller–Dieker Syndrome. Heterotopia is defined as a cluster of normal neurons in abnormal locations, and divided into three main groups: periventricular nodular heterotopia, subcortical heterotopia and marginal glioneural heterotopia. Genetically, heterotopia is related to Filamin A (FLNA) or ADP‐ribosylation factor guanine exchange factor 2 (ARFGEF2) genes mutations. Polymicrogyria is described as an augmentation of small circonvolutions separated by shallow enlarged sulci; bilateral frontoparietal form is characterized by bilateral, symmetric polymicrogyria in the frontoparietal regions. Bilateral perisylvian polymicrogyria results in a clinical syndrome manifested by mild mental retardation, epilepsy and pseudobulbar palsy. Gene mutations linked to this disorder are SRPX2, PAX6, TBR2, KIAA1279, RAB3GAP1 and COL18A1. Schizencephaly, consisting in a cleft of cerebral hemisphere connecting extra‐axial subaracnoid spaces and ventricles, is another important disorder of neuronal migration whose clinical characteristics are extremely variable. EMX2 gene could be implicated in its genesis. Focal cortical dysplasia is characterized by three different types of altered cortical laminations, and represents one of most severe cause of epilepsy in children. TSC1 gene could play a role in its etiology. Conclusion: This review reports the main clinical, genetical and neuroradiological aspects of these disorders. It is hoped that accumulating data of the development mechanisms underlying the expanded network formation in the brain will lead to the development of therapeutic options for neuronal migration disorders.     

Neural migration disorders studied by cerebral ultrasound and colour Doppler flow imaging.

Cerebral ultrasound and colour Doppler flow imaging (CDFI) were used to diagnose a wide spectrum of anomalies of cell migration (17 patients): presumed lissencephaly (n = 12); schizencephaly of both fused (n = 2) and open lips (n = 2); hemimegalencephaly (n = 1); and subependymal type grey matter heterotopia (n = 12). The patients with grey matter heterotopia had irregular ventricular margins (n = 10), periventricular hyperechogenic bands (n = 12), and/or periventricular hyperechogenic nodules (n = 7). Some patients had more than one type of migration disorder as well as other central nervous system malformations. Cerebral ultrasound diagnoses were confirmed by magnetic resonance imaging (MRI) or necropsy. It is concluded that colour Doppler flow imaging is a worthwhile addition to the assessment of brain surface anomalies.     

Congenital Anomalies of Central Nervous System and Neuronal Plasticity*

Abstract Pathological studies on autopsied brains of mentally and physically handicapped children disclose not infrequently various abnormalities at the histological and cytological levels, such as the abnormal cytoarchitecture, heterotopic neuronal nests, abnormal orientation of neurons and tortuous dendrites. These abnormalities have generally been considered to result from the disorders of neuron production and/or mechanical obstruction of neuronal migration including abnormal radial fibers. Our experimental studies on the microcephalic mouse, which was induced either by prenatal or by postnatal administration of cytosine arabinoside, indicated that the following factors play important roles for above mentioned histological and cytological changes: (1) Disturbance of the neuron production following the destruction of the matrix layer. (2) Regional and incomplete regeneration of the matrix layer and delayed neuron production in the regenerated matrix layer. (3) Unbalanced and plastic synaptogenesis between the remaining neurons which have been produced prior to the destruction of the matrix layer, migrating young neurons produced in the regenerated matrix layer and the afferent fiber terminals which originate from subcortical neurons.     

Potential neuronal repair in cerebral white matter injury in the human neonate

Periventricular leukomalacia (PVL) in the premature infant represents the major substrate underlying cognitive deficits and cerebral palsy and is characterized as focal periventricular necrosis and diffuse gliosis in the immature cerebral white matter. We have recently shown a significant decrease in the density of neurons in PVL relative to controls throughout the white matter, including the subventricular, periventricular, and subcortical regions. These neurons are likely to be remnants of the subplate and/or GABAergic neurons in late migration to the cerebral cortex, both of which are important for proper cortical circuitry in development and throughout adulthood. Here, we tested the hypothesis that intrinsic repair occurs in PVL to attempt to compensate for the deficits in white matter neurons. By using doublecortin (DCX) immunopositivity as a marker of postmitotic migrating neurons, we found significantly increased densities (p < 0.05) of DCX-immunopositive cells in PVL cases (n = 9) compared with controls (n = 7) in the subventricular zone (their presumed site of origin), necrotic foci, and subcortical white matter in the perinatal time-window, i.e. 35-42 postconceptional weeks. These data provide the first evidence suggestive of an attempt at neuronal repair or regeneration in human neonatal white matter injury.     

Leptomeningeal metastases in pediatrics: magnetic resonance image manifestations and correlation with cerebral spinal fluid cytology

Background: Detection of leptomeningeal metastases is fundamental to a complete evaluation of central nervous system (CNS) or non‐CNS tumor with suspected involvement of the neuroaxis. Our purpose was to assess the appearances of different magnetic resonance (MR) sequences in the diagnosis of leptomeningeal metastases and correlate those positive findings with the cerebral spinal fluid (CSF) cytology results. Methods: The authors reviewed the medical records and MR image manifestations of leptomeningeal metastases from 18 children who had positive MR findings and retrospectively correlated them with CSF cytologic results. There was a uniform MR protocol and the patients were examined with the same sequences. Results: The abnormalities included pial‐arachnoid disease (n= 16), disease coating the nerves (n= 12), hydrocephalus (n= 3) and subependymal metastases (n= 2). Enhanced T1 images were better than unenhanced fluid attenuated inversion recovery (FLAIR) and T2 to delineate cranial and spinal leptomeningeal metastases. In our sample, seven out of 18 cases were cytologically negative on a single lumbar puncture. Conclusions: Contrast‐enhanced MR imaging can be invaluable, detecting the false‐negative lumbar punctures. FLAIR and diffusion images can be helpful in diagnosing leptomeningeal metastases of non‐enhancing primary tumors. Prognosis was more related to the primary tumor type than to the leptomeningeal enhancement MR pattern.     

Cell-to-cell Interactions during Development of the Neocortex,with Special Reference to Neuronal Migration*

Abstract Neuronal migration plays a key role in forming a characteristic laminar cytoarchitecture of the neocortex. In this review, the localization of cell-surface molecules in developing murine neocortex including that of the reeler mutant were described in association with their functional significance. L1 antigen appeared solely on neurons which were placed in the intermediate zone, the cortical plate and the marginal zone. In the cortical plate the surface of neuronal cell body was positively stained until embryonic day 17. Later on, the cell body became negative whereas cell processes in the intermediate and the marginal zones remained positive. Migrating neurons in the intermediate zone were L1 positive. N-CAM, on the contrary, were detectable on both matrix cells and neurons. The L2/HNK-1 epitope was present on endfeet of matrix cells, in addition to on the neuronal surface. In vitro perturbation assays using embryonic neocortical explants showed that the antibody for L1 could modify the rate of neuronal migration to some degree. These results suggest the functional roles of the L1 molecule in neuronal migration. However, L1 was present in the reeler mouse that is supposed to have a genetic defect in neuronal migration resulting in a disorganized cytoarchitecture. The scanning electron microscope (SEM) fractographic studies revealed a defective formation of the bundles of matrix cell processes in the developing reeler neocortex. Our observations indicate deranged cellular interactions among matrix cells in the reeler, although no molecular abnormalities have so far been demonstrable. The significance of cell-to-cell interactions in neocortical histogenesis was discussed.     

Neural Crest and Central Nervous System Malformation*

ABSTRACT The normal development of some neural crest derivatives and the spinal cord, and the neuropathology of the neurocutaneous syndrome were studied. In developing human embryos and fetuses, HNK-1 was expresed in the intermediate zone of the neural tube and somites in 3–4 week embryos and weakly remained in the white matter until 20 weeks’gestation, and remained positive in peripheral nerves from embryo to adult. High signal intensity was observed in the basal ganglia, brainstem and cerebellum on T2-weighted MRI. Neuropathological examination revealed proliferation of astroglial fibers in the leptomeninges and the perivascular area in the cerebellum and basal ganglia. In tuberous sclerosis, immunohistochemistry revealed GFAP-positive structure in the dermis of adenoma sebaceum. Giant astrocytes in tubers and tumors were positive for GFAP and NSE. Thus, the tumor cells have the characteristics of both astrocytes and neurons. HNK-1 immunoreactivity reappeared in tissue surrounding giant astrocytoma. The nuropathology of hemimegalencephaly comprised abnormal gyration, LGH, disturbed lamination, large neurons and increased neuronal heterotopia in the subcortical and deep white matter. Fenitin-positive oligodendroglia were increased on affected side. The dysplasia may have arisen from neural crest cells.     

Prenatal exposure to toluene results in abnormal neurogenesis and migration in rat somatosensory cortex

Toluene inhalant abuse during pregnancy may result in growth-retarded microcephalic newborns who subsequently demonstrate developmental impairment. By using a rat model of toluene-abuse embryopathy, we studied the effects of prenatal toluene exposure on the generation and migration of cortical neurons. Dams were exposed by gavage to either corn oil or toluene diluted in corn oil on d 6-21 of gestation. The time of origin of cortical neurons was determined in the mature pups of dams injected with the thymidine analogue 5'-bromodeoxyuridine on 1 d during the period from d 13-21 of gestation. 5'-Bromodeoxyuridine-labeled neurons were identified by immunohistochemistry in a 400-microm-wide column of somatosensory cortex. The brains of the toluene-exposed pups had a significant reduction in the number of neurons within each cortical layer (p < 0.001). Depending on the cortical layer, the generation of neurons in the toluene-exposed pups was delayed by 1 or 2 d. In addition, the brains of the toluene-exposed pups also showed evidence of abnormal neuronal migration. However, there were no differences in either brain weight or body weight between the control and toluene-exposed pups. These observations suggest that although prenatal toluene exposure results in abnormal neuronal proliferation and migration, brain weight in the toluene-exposed pups may be preserved by enhanced development of glia or the neuropil.     

Congenital colonic hypoganglionosis in murine trisomy 16--an animal model for Down's syndrome.

Human trisomy 21 (Down's syndrome) affects the development of multiple organ systems frequently including gastrointestinal anomalies such as Hirschsprung's disease. To elucidate the underlying morphogenetical mechanisms a murine model (trisomy 16 mouse) for Down's syndrome has been established. However, previous studies on trisomy 16 (TS 16) mice have been confined to non-enteric developmental disorders. Therefore, the aim of the present study was to assess the enteric nervous system and the morphology of the terminal colon in TS 16 mice during late intrauterine development. Immunohistochemical examination (protein gene product 9.5) revealed a reduction of myenteric ganglionic size and density as well as the presence of ectopic ganglia, thus resembling typical features of colonic hypoganglionosis and myenteric heterotopia. Enzyme histochemistry for NADPH-diaphorase showed a remarkable decrease of NADPH-positive neurons in TS 16 mice, whose sparse distribution was confined to a minor portion of the oligoneuronal myenteric ganglia. Electron microscopical studies of TS 16 mice confirmed the myenteric hypoganglionosis and, additionally, demonstrated the absence of submucosal neurons. Whereas neurons of controls were characterized by arborizing neuronal processes, neurons of TS 16 mice were reduced in size and exhibited only few and shortened cytoplasmic protrusions. Additionally, prominent bundles of parallel nerve fibers passed through the intermuscular zone and lacked the arborization pattern of normal neuropil. They were not observed in controls and resembled features of extrinsic nerves. Approximately one third of TS 16 mice developed a colonic dilatation proximally to an obstructed segment characterized by a pronounced hypoganglionosis. Although TS 16 mice did not develop complete aganglionosis, the abundance of nerve fiber bundles and the colonic dilatation were consistent with the morphological characteristics of Hirschsprung's disease. The findings suggest that even a hypoganglionosis characterized by ultrastructurally altered and NADPH-diaphorase-deficient neurons may be capable of provoking a functional intestinal obstruction. Similar abnormalities of the enteric nervous system as observed in TS 16 mice may also be present in such trisomy 21 patients who suffer from chronic intestinal motility disorders which are not caused by complete aganglionosis.     

Effect of perinatal alcohol exposure on ibotenic acid-induced excitotoxic cortical lesions in newborn hamsters

Alcohol is one of the most common noxious substance to which fetuses are exposed. The aim of the study was to determine the effects of in utero alcohol exposure on excitotoxin-induced neuronal migration disorders. Female hamsters received alcohol (7%) for 3-5 mo or for the last 9-12 d of gestation. Alcohol diet was continued for 5 d during lactation in both groups. Drinking behavior was monitored. Peak plasma alcohol levels were 104+/-12 mg/dL and 225+/-6 mg/dL after 30 min for hamsters receiving an intragastric dose of 3 mL or 5 mL alcohol, respectively. At birth, pups received intrapallial injections ibotenic acid (1 ng, 100 ng, or 10 microg). Histology and N-methyl-D-aspartic acid (NMDA) receptor labeling by 3H-MK-801 in the pups cortices were studied. Short-term-alcohol-exposed pups had normal body and brain weights at birth, but their body growth was retarded postnatally. Ibotenic acid induced similar neuronal migration impairments in control and alcohol-exposed pups (nodular heterotopia in the white matter and/or deep cortical layers, subpial ectopia, and micro- or polymicrogyria). The size of lesions induced by 100 ng ibotenic acid was increased in alcohol-exposed pups; the 10 microg dose was lethal. The density of 3H-MK-801 binding sites was similar in the three groups, indicating that exacerbated ibotenic acid excitotoxicity in alcohol-exposed pups did not result from increased NMDA receptor density. This study shows that alcohol exposure at levels that do not induce neuron migration disorders is sufficient to enhance the effects of the hypoxia-ischemia mimicking effects of ibotenic acid.     

Inborn Errors of Peroxisome Biogenesis and Brain Malformation: Clinical and Biochemical Studies*

Zellweger's cerebro-hepato-renal syndrome is characterized by the absence of peroxisomes, severe neurologic manifestations, and neuropathological findings such as polymicrogyria and neuronal heterotopia which are based on disturbances of neuronal migration. We investigated the pathogenesis of peroxisome-deficient disorders in attempts to clarify the molecular basis of these brain dysgenesis. Complementation analysis revealed that at least 9 genes contribute to the formation of peroxisomes. One of these gene products, peroxisome assembly factor-1 (PAF-1), was isolated, using a functional cloning method and a mutant Chinese hamster ovary cell line with defective peroxisomes. PAF-1 restored the peroxisomes and biochemical abnormalities in fibroblasts from patients with Zellweger syndrome and who belonged to complementation group F. Defects in PAF-1 would result in dysfunction of peroxisomal membrane or in the transport machinery of peroxisomal proteins, and metabolic disturbances such as accumulation of very long chain fatty acids and defects in plasmalogen may occur.     

Patients with moyamoya disease presenting with movement disorder

Moyamoya disease is a rare cerebrovascular disease characterized by idiopathic bilateral stenosis or occlusion of bilateral internal carotid arteries and the development of characteristic leptomeningeal collateral vessels at the base of the brain. Typical presentations include transient ischemic attacks or stroke, and hemorrhage. Presentation with movement disorders is extremely rare, especially in the pediatric population. The authors describe the cases of 4 children with moyamoya disease who presented with movement disorders. Among 446 patients (118 pediatric) with moyamoya disease surgically treated by the senior author, 4 pediatric patients had presented with movement disorders. The clinical records, imaging studies, surgical details, and postoperative clinical and imaging data were retrospectively reviewed. The initial presenting symptom was movement disorder in all 4 patients: chorea in 2, hemiballismus in 1, and involuntary limb shaking in 1. All the patients had watershed infarcts involving the frontal subcortical region on MR imaging. Additionally, 1 patient had a ganglionic infarct. Single-photon emission computed tomography studies showed frontoparietal cortical and subcortical hypoperfusion in all patients. Three patients had bilateral disease, whereas 1 had unilateral disease. All the patients underwent superficial temporal artery-middle cerebral artery bypass. Postoperatively, all 4 patients had complete improvement in their symptoms. The SPECT scans revealed normal perfusion in 3 patients and a small residual perfusion deficit in 1. Movement disorders are a rare presenting feature of moyamoya disease. Hypoperfusion of the frontal cortical and subcortical region was seen in all patients, and the symptomatology was attributed to ischemic dysfunction and imbalance in the cortical-subcortical-ganglionic-thalamic-cortical circuitry. Combined revascularization with superficial temporal artery-middle cerebral artery bypass and encephaloduroarteriosynangiosis leads to excellent results.     

Cajal-Retzius and subplate neurons: their role in cortical development.

Cajal-Retzius (C-R) neurons and their processes form a synaptic network in the marginal zone of the early telencephalon prior to the arrival of the first wave of radial migration of neuroblasts from the subventricular zone. Their origin is not yet proved but may be either the medial ganglionic eminence or the mesencephalic neuromere. These bipolar or multipolar neurons populate the molecular layers of both the fetus and the adult, though sparse in the adult. Their thick axon emits collaterals that make synaptic contact with pyramidal neurons initially in layer 6 and later within all layers. C-R neurons produce GABA, possibly ACh, several calcium-binding proteins (e.g. calmodulin; parvalbumin; possibly calretinin), several neuropeptides and are rich in ribosomes. Subplate neurons, beneath the cortical plate, emit pioneer axons in the incipient formation of the internal capsule and also commissural fibres of the early hippocampus. C-R cells express products of the genes reelin, LIS1 and DS-CAM, that mediate radial neuroblast migration and lamination of the cortical plate and are important in the pathogenesis of lissencephaly. In addition to forming the first intrinsic synaptic circuits of the cortical plate and its first afferent and efferent connections with subcortical structures, they may play additional roles in the formation of ocular dominance columns, in regulating neuronogenesis and in cortical repair. They do not later disappear by apoptosis as we previously thought, but their functional role in the mature brain is unknown.     

Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: Case study and literature review

BackgroundThe BIG2 protein, coded by ARFGEF2 indirectly assists neuronal proliferation and migration during cortical development. Mutations in ARFGEF2 have been reported as a rare cause of periventricular heterotopia.MethodsThe presence of periventricular heterotopia, acquired microcephaly and suspected recessive inheritance led to mutation analysis of ARFGEF2 in two affected siblings and their healthy consanguineous parents, after mutations in FLNA had been ruled out.ResultsA homozygous c.242_249delins7 (p.Pro81fs) mutation in exon 3 of ARFGEF2 was identified in the siblings. The alteration is a combination of 2 missense mutations (c.242C > A and c.247G > T) and a frameshift mutation (c.249delA) resulting in a premature stop codon. The clinical phenotype was characterized by dystonic quadriplegia, marked developmental delay, obstructive cardiomyopathy, recurrent infections and feeding difficulties. Degenerative features included early regression, acquired microcephaly and cerebral atrophy. Brain MRI revealed bilateral periventricular heterotopia, small corpus callosum, cerebral and hippocampal atrophy and hyperintensity in the putamen.ConclusionMutations in ARFGEF2 can be anticipated based on characteristic clinical and imaging features.     

神经元移行异常的临床特征和诊断

目的探讨神经元移行异常(NMD)的临床特征和诊断依据。方法对37例NMD患儿的临床、影像和实验室资料进行分析,并进行随访。结果37例NMD中无脑回—巨脑回21例,主要临床表现为智力低下(20例)、癫痫(14例)和脑性偏瘫(6例),头围小于正常同龄儿是一重要体征,占80％(17／21);无脑回—巨脑回合并其他畸形8例;灰质异位5例,主要表现为癫痫(4例);脑裂畸形3例,脑性偏瘫为其主要临床特征(2例)。16例脑电图中12例异常,全导阵发不规则尖棘慢波、慢波10例。本组随访18例,癫痫患儿14例,经抗癫痫药物治疗后均难以控制发作,运动发育有改善但语言发育障碍4例。结论NMD的临床特征以智力低下、癫痫及脑性偏瘫为主,头颅MRI是诊断本病的最佳检查方法。