Heterotopia associated with hippocampal sclerosis: an under-recognized cause of early onset epilepsy in children operated on for temporal lobe epilepsy.

PURPOSE: The aim of this study is to report on 52 children operated on for pharmacoresistant temporal lobe epilepsy, with special emphasis on histopathology and correlation with clinical features. METHODS: Charts were retrospectively analyzed. All children underwent comprehensive clinical, electrophysiological and radiological investigations before surgery. Surgical procedures were tailored according to scalp, foramen ovale and eventually depth electrode recordings. Histopathology was compared with clinical variables (χ (2) and Fisher's exact tests). Outcome was evaluated using the Engel scale. RESULTS: Developmental tumor was found in 14 cases, malformation of cortical development (MCD) in 26, isolated hippocampal sclerosis (HS) in 5 and gliosis in 7. Dual pathology (DP) affected 18 patients and the main extrahippocampal lesion consisted of microscopic sub-cortical heterotopias (HS-HT) for 15 patients who shared a particular clinical pattern: a history of febrile seizures (FS) and/or brain injury, early onset of epilepsy without latent period from FS to the first temporal seizure, and a particularly good outcome following surgery. CONCLUSION: In our pediatric temporal lobe surgery series, the prevalence for MCD and for DP was higher than in adult series. Age at seizure onset depends on pathology, and is earlier when involving the neocortex rather than only the hippocampus. We identify the association HS-HT (the most frequent DP in this series), with particular clinical features.

Pontoneocerebellar hypoplasia: definition of MR features.

We report five patients with pontoneocerebellar hypoplasia. Because the issue of cerebellar malformations is a difficult subject, we tried to define criteria for diagnosis on MRI: a thin flat pons with disappearance of the anterior curve, a small cerebellum with predominant flattening of the hemispheres and shortened cerebellar fissures, in contrast to atrophy. The posterior fossa is not enlarged. We emphasize the probable late onset of the disease in fetal life because of the demonstration of the abnormalities at US during the last trimester of the pregnancy in one patient. Prenatal diagnosis is important because of possible autosomal recessive transmission.

Immunocytochemical characterization of long-term persistent immune activation in human brain after herpes simplex encephalitis.

The clinical, virological and immunocytochemical features of three children who recovered from acute herpes simplex encephalitis (HSE) before the age of 2 years, and who developed secondary severe focal epilepsy after a symptom-free period, leading to neurosurgery 3-10 years later are described. In one child, relapse of HSE occurred immediately after surgery. In all three patients, brain sample biopsies showed abundant CD3-positive T lymphocytes with a majority of CD8 cells, and abundant activated macrophage-microglial cells, a pattern similar to that found in acute HSE. Herpes simplex virus DNA was retrieved from the tissue biopsy in one case. The long-term persistent cerebral inflammatory process observed after HSE differed from that observed in another chronic viral disease, subacute sclerosing panencephalitis. This inflammatory reaction may be a result either of low-grade viral expression or self-induced immune activation. The role of inflammation in triggering epilepsy remains hypothetical. Solving these issues should have major therapeutic implications. Herpes simplex virus DNA latency in brain may be the source of replicative HSE relapse.

Increased density of oligodendrocytes in childhood ataxia with diffuse central hypomyelination (CACH) syndrome: neuropathological and biochemical study of two cases.

We report neuropathological, biochemical and molecular studies on two patients with childhood ataxia with diffuse central nervous system hypomyelination (CACH) syndrome, a leukodystrophy recently defined according to clinical and radiological criteria. Both had severe cavitating orthochromatic leukodystrophy without atrophy, predominating in hemispheric white matter, whereas U-fibers, internal capsule, corpus callosum, anterior commissure and cerebellar white matter were relatively spared. The severity of white matter lesions contrasted with the rarity of myelin breakdown products and astroglial and microglial reactions. In the white matter, there was an increase in a homogeneous cell population with the morphological features of oligodendrocytes, in many instances presenting an abundant cytoplasm like myelination glia. These cells were negative for glial fibrillary acidic protein and antibodies PGM1 and MIB1. Some were positive for myelin basic protein, proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein, but the majority were positive for human 2'-3' cyclic nucleotide 3' phosphodiesterase and all were positive for carbonic anhydrase II, confirming that they are oligodendrocytes. Myelin protein and lipid content were reduced. The PLP gene, analyzed in one case, was not mutated or duplicated. The increased number of oligodendrocytes without mitotic activity suggests an intrinsic oligodendroglial defect or an abnormal interaction with axons or other glial cells. This neuropathological study supports the notion that CACH syndrome constitutes a specific entity.

[Cortical heterotopias: animal models and human disease]. / Hétérotopies corticales: modèles animaux et pathologie humaine.

Cortical heterotopia is defined as the misplacement of a group of neurons displaced to a precise localization in the neocortex and results from perturbed migration along the glial guide, either because of glial destruction or molecular anomalies. Heterotopic neurons are rarely dispersed but are rather grouped in nodules or bands. Heterotopic masses may lie in an ependymal or subcortical localization depending on whether they result from lack of migration or an arrested migration. Heterotopias can also occur in intra-cortical or extra-cortical localizations. The cause of heterotopia remains to be elucidated. Two genes situated on chromosome X have been implicated but non-genetic forms attributable to antenatal ischemia or toxic aggression during fetal development have also been observed. The presence of heterotopia is usually associated with epilepsy and sometimes with mental retardation. Seizures may be initiated within the heterotopic region then propagate via long projections to the neocortex which may also be malformed.

Focal cortical dysplasia and hemimegalencephaly: histological and neuroimaging correlations.

BACKGROUND: The classification of cerebral cortical dysplasia is difficult and there are histological similarities between focal cortical dysplasia (FCD) and hemimegalencephaly. Objectives. To correlate the MR features and histological data of cortical dysplasias. MATERIALS AND METHODS: The MR appearances of 17 brains were examined. According to the signal intensity within the pathological area on T2-weighted (T2-W) sequences we selected two groups. RESULTS: Group 1 comprised ten patients with high signal in the dysplastic area on T2-W images. This group included five hemimegalencephalies, three frontal quadramegalencephalies, and one gyral dysplasia. The pathological hemisphere was reduced in size in one case. The cortex was thickened in all cases on T1-weighted (T1-W) images. There was loss of delineation between white matter (WM) and grey matter (GM) in all cases on both T1-W and T2-W sequences. The differential diagnosis with tumour, neoplastic-like malformation or polymicrogyria was questionable. Group 2 comprised seven patients presenting without increased signal within the dysplastic area on T2-W images. WM and GM were of similar signal intensity in six cases, and delineation between white and grey matter was absent in all cases. There were mild abnormalities on T1-W sequences in all cases. The dysplasias were limited to a lobe in five cases and a gyrus in two cases. In all cases, depiction of the malformation was a greater diagnostic problem than the differential diagnosis. CONCLUSIONS: A constant MR sign in our series was the loss of delineation between WM and GM in the dysplastic area. This correlated well with the observed histological disorganisation. Markedly high signal within the dysplastic area seems to be related to myelin abnormalities rather than glial cell abnormalities.

Distribution and submicroscopic immunogold localization of cellular prion protein (PrPc) in extracerebral tissues.

In transmissible spongiform encephalopathies (TSE), such as scrapie in animals and Creutzfeldt-Jakob disease in humans, the central event is the conversion of a host-encoded amyloidogenic protein (PrPc) into an abnormal isoform (PrPsc) that accumulates as amyloid in TSE brain. PrPc is a membrane sialoglycoprotein synthesized in the central nervous system and elsewhere. We have examined the ultrastructural localization of PrPc in numerous hamster and some human extracerebral tissues, by means of a post-embedding electron-microscopic method combined with immunogold labeling. In stomach, intestine, lung, and kidney from hamsters, and in stomach, kidney, and spleen from humans, immunogold labeling specific for PrPc is observed on various cellular substructures related to secretory pathways: Golgi apparatus, secretory globules, and plasma membrane. In mucous epithelial cells of stomach and intestine, PrPc appears to be concentrated in secretory globules, suggesting a role for PrPc in the secretory function of the digestive tract. The secretory aspect of PrPc may be a key to understanding the physiopathological mechanisms underlying TSE.

Antenatal thalamic lesions in the newborn: two anatomoclinical cases.

We report two cases of antenatal bilateral thalamic lesions constituted by neuronal loss, gliosis and mineralized glial or neuronal cells. No etiology could be found. Neuroradiological findings were poorly correlated with histological changes. These cases are compared with the few previously reported cases of the same condition. We strongly recommend extensive etiological investigation as recurrence occurred in one family.

Expression of the adrenoleukodystrophy protein in the human and mouse central nervous system.

The gene mutated in X-linked adrenoleukodystrophy (ALD), a progressive demyelinating disease, codes for a protein (ALDP) involved in very-long-chain fatty acid (VLCFA) transport. The expression of ALDP and of two peroxisomal enzymes involved in beta-oxidation of VLCFA, acyl-CoA oxidase, and catalase was studied in human and mouse brain. The pattern of expression was similar in both species. While acyl-CoA oxidase and catalase are found in all types of CNS cells, including neurons and oligodendrocytes, ALDP expression is restricted mostly to the white matter and endothelial cells. ALDP is highly expressed in astrocytes and microglial cells in vivo and in regenerating oligodendrocytes in vitro. In contrast, in vivo, ALDP is detected in much fewer oligodendrocytes and quantitative Western blot analysis confirmed the lower abundance of ALDP in these cells than in astrocytes. Only oligodendrocytes localized in corpus callosum, internal capsules, and anterior commissure express ALDP at levels comparable to those seen in astrocytes. In ALD, demyelination is first detected in these white matter regions, suggesting that the ALD gene mutation selectively affects those oligodendrocytes strongly expressing ALDP. Because of their failure to express ALDP, microglia and astrocytes may also contribute to demyelination in ALD patients.

Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein.

The agent responsible for transmissible spongiform encephalopathies (TSEs) is thought to be a malfolded, protease-resistant version (PrPres) of the normal cellular prion protein (PrP). The interspecies transmission of bovine spongiform encephalopathy (BSE) to mice was studied. Although all of the mice injected with homogenate from BSE-infected cattle brain exhibited neurological symptoms and neuronal death, more than 55 percent had no detectable PrPres. During serial passage, PrPres appeared after the agent became adapted to the new host. Thus, PrPres may be involved in species adaptation, but a further unidentified agent may actually transmit BSE.

Early hemispherectomy in a case of hemimegalencephaly.

We report a case with hemimegalencephaly and catastrophic epilepsy treated early at 4 months by functional hemispherectomy. The boy had intractable continuous epilepsy, with seizures every 10 min, hemiparesis and absence of psychomotor acquisition. Three years after hemispherectomy, the boy is seizure free and has a mild psychomotor delay. Hemiparesis and hemianopsia are unchanged. Early hemispherectomy, before 6 months of age, may control severe epilepsy and preserve the development of higher cortical functions in the nonhemimegalencephalic hemisphere.

[Corpus callosum agenesis and parasagittal interhemispheric cyst]. / Agénésie du corps calleux et kyste interhémisphérique paramédian.

We report the association of a corpus callosum agenesis with a parasagittal interhemispheric cyst, without cortical malformation. This rare malformation is related to an early disorder in embryogenesis. The importance of the anatomic abnormalities compared with the good clinical status is remarkable. MR findings avoid misdiagnosis with a medial interhemispheric cyst associated to corpus callosum agenesis in which the prognosis is unpredictable.

Opercular malformations: clinical and MRI features in 11 children.

Opercular malformations are rare and complex brain malformations for which only very fragmented neuropathological descriptions have been reported. They are related to an abnormal development of both sylvian fissure and frontoparietal operculum. We report a retrospective clinical and MRI study of 11 patients presenting with opercular malformations. A congenital pseudobulbar syndrome was observed in six cases, various motor disorders in seven cases, mental retardation in six cases and epilepsy in four cases. The purpose of this study is to evaluate the main features of opercular malformations in children and to try to characterise this entity on the basis of its clinical features and MRI pattern.

Migrating partial seizures in infancy: a malignant disorder with developmental arrest.

Fourteen infants of both sexes had a previously unreported epileptic condition characterized by nearly continuous multifocal seizures. The first seizures occurred at a mean age of 3 months, without antecedent risk factors. At 1 to 10 months, the seizures became very frequent. They were partial with variable clinical expression, and the EEG showed that the discharges randomly involved multiple independent sites, moving from one cortical area to another in consecutive seizures. Although their topography varied, the EEG ictal pattern of each seizure was very similar. It consisted of rhythmic alpha or theta activity which spread to involve an increasing area of the cortical surface. Patients regressed developmentally and became quadriplegic with severe axial hypotonia. Three patients died at age 7 months and at age 7 and 8 years, respectively. Seizures were controlled in only 2 patients, and only 3 children resumed psychomotor development. Extensive investigation failed to determine an etiology, and there was no familial recurrence. Neuropathological examination of the brain in two cases showed only severe hippocampal neuronal loss and accompanying gliosis.

An unusual presentation of focal cortical dysplasia.

In a case of histologically proved focal cortical dysplasia, there was an absence of cortex-white matter delineation in the right parietooccipital area only on the T2-weighted images. This pattern correlated with the gross and histologic findings obtained on the resected cerebral tissue.

Ultrastructural localization of cellular prion protein (PrPc) in synaptic boutons of normal hamster hippocampus.

The cellular prion protein (PrPc) is a membrane sialoglycoprotein synthesized in the central nervous system and extraneural tissues. Its post-translational modification produces an accumulation of abnormal isoform PrPsc found in brains of transmissible neurodegenerative disorders in animals (scrapie and bovine spongiform encephalopathy) and humans (Kuru, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome). One major unanswered question relative to PrPc concerns its physiological role in brain neurons, depending largely on the limited knowledge of its subcellular localization. Using a highly-sensitive immunogold electron microscopy technique, we reported that in the hamster dentate gyrus, the synaptic boutons constituted the submicroscopic site where PrPc was observed. This detection was obtained with 2 highly-specific polyclonal antibodies for prion protein. PrPc localization was assigned, both on structural basis and on its co-localization with synaptophysin. The presence of PrPc in synaptic terminals should provide additional informations on its possible role in neuronal transmission and on the implication of synapses in the pathogenesis of spongiform encephalopathies.

Dysembryoplastic neuroepithelial tumors in two children with neurofibromatosis type 1.

Dysembryoplastic neuroepithelial tumors (DNT) occur mainly in children and are always clinically associated with intractable complex partial seizures. In the first report, which included 39 cases, the patients had no neurological deficit and no stigmata of phacomatosis. In contrast, we observed a DNT in 2 children with a neurofibromatosis type 1. The first patient developed intractable complex partial seizures at age 9 years and was operated at the age of 13 years. Neuroimaging study showed multifocal involvement with three separated lesions in the frontal, parietal and temporal lobes. The second patient was a 16-year-old boy with 5-year history of severe and refractory epilepsy. Magnetic resonance imaging identified a right temporal lesion and the patient underwent a right temporal lobectomy. This unusual association of two cases of DNT with neurofibromatosis type 1 raises the question of whether this association is specific or fortuitous.

Clinical, biochemical, and molecular analysis of a maternally inherited case of Leigh syndrome (MILS) associated with the mtDNA T8993G point mutation.

We report a new case of Leigh disease (subacute necrotizing encephalomyelopathy) in a girl with mitochondrial DNA (mtDNA) mutation in the ATPase6 gene at nucleotide position 8993. Sequence analysis of mtDNA revealed a T-to-G transversion at nucleotide position 8993 in the ATPase6 gene. Southern blot restriction analysis of patient muscle mtDNA showed only a mutant pattern for the mutation 8993. Molecular analysis of seven subjects from the family showed that except for the father they all carried the 8993 mtDNA mutation in all studied tissues, with high percentages in the two symptomatic children and even in one asymptomatic boy.