Electroclinical and magnetoencephalographic analysis of epilepsy in patients with congenital bilateral perisylvian syndrome

PURPOSE: Epilepsies in four patients with congenital bilateral perisylvian syndrome (CBPS) were studied electroclinically and by magnetoencephalography (MEG) to determine whether cortical dysplasia associated with this syndrome is epileptogenic. METHODS: We studied three women and one man (mean +/- SD age 30.8 +/- 3.4 years) with a diagnosis of CBPS based on magnetic resonance imaging (MRI). All had drug-resistant epilepsy. In addition to electroclinical analysis, the distribution of equivalent-current dipoles (ECDs) analyzed from MEG signals was examined. RESULTS: Patient 1 had left-sided parietal lobe epilepsy and ECDs clustered in the left temporoparietal lobe. Patient 2 had bilateral, independent temporoparietal lobe epilepsy, and ECDs were found in both hemispheres, with clustering in the right temporoparietal lobe but not in the left hemisphere. Patient 3 presumably had parietal lobe epilepsy with unidentified focus side and ECDs clustered in the left parietal and right temporal lobes. Patient 4 had symptomatic generalized epilepsy, and ECDs were observed in both hemispheres without clustering. In the three patients who had partial epilepsy (patients 1-3), clusters of ECDs overlaid the perisylvian dysplasia and were not found elsewhere. CONCLUSIONS: Patients with CBPS may have either symptomatic partial epilepsy or symptomatic generalized epilepsy, and those with partial epilepsy are likely to have temporoparietal foci. In addition, cortical dysplasia is closely related to the generation of partial seizures and may be epileptogenic per se. However, this study did not elucidate the relationship between cortical dysplasia and CBPS-generated generalized epilepsy.     

Radiologic-pathologic correlation in focal cortical dysplasia and hemimegalencephaly in 18 children.

To describe the radiologic-pathologic correlation in children who underwent epilepsy surgery for medically intractable epilepsy with pathologically confirmed focal cortical dysplasia and hemimegalencephaly, we conducted a retrospective review on the magnetic resonance imaging and pathology of 18 children (10 boys and 8 girls). The preoperative MRIs were reviewed by one neuroradiologist who did not know the radiologic diagnosis and the pathology reports. MRI revealed focal cortical dysplasia (10), hemimegalencephaly (3), hamartomas (2), polymicrogyria (1), pial hemosiderosis (1), and no abnormality (1). Pathologic examination revealed focal cortical dysplasia (9), forme fruste of tuberous sclerosis (5), hemimegalencephaly (3), and focal cortical dysplasia with mesial temporal sclerosis (1). MRI was accurate in making the preoperative diagnosis in 16 out of 18 patients. On MRI, 12 patients had abnormal gyral formation and 12 had abnormal cortical thickness. Eleven patients manifested loss of gray-white differentiation, and 11 patients had abnormal signal on T(2)-weighted image. Pathologically, 15 patients had neuronal heterotopia, 12 had misalignment or disorientation of neurons, 11 had large neurons, and 10 had abnormal cortical lamination. The presence of ectopic and large neurons and abnormal cortical lamination may be responsible for the MRI characteristics.     

Increased expression of the neuronal glutamate transporter (EAAT3/EAAC1) in hippocampal and neocortical epilepsy

PURPOSE: To define the changes in gene and protein expression of the neuronal glutamate transporter (EAAT3/EAAC1) in a rat model of temporal lobe epilepsy as well as in human hippocampal and neocortical epilepsy. METHODS: The expression of EAAT3/EAAC1 mRNA was measured by reverse Northern blotting in single dissociated hippocampal dentate granule cells from rats with pilocarpine-induced temporal lobe epilepsy (TLE) and age-matched controls, in dentate granule cells from hippocampal surgical specimens from patients with TLE, and in dysplastic neurons microdissected from human focal cortical dysplasia specimens. Immunolabeling of rat and human hippocampi and cortical dysplasia tissue with EAAT3/EAAC1 antibodies served to corroborate the mRNA expression analysis. RESULTS: The expression of EAAT3/EAAC1 mRNA was increased by nearly threefold in dentate granule cells from rats with spontaneous seizures compared with dentate granule cells from control rats. EAAT3/EAAC1 mRNA levels also were high in human dentate granule cells from patients with TLE and were significantly elevated in dysplastic neurons in cortical dysplasia compared with non-dysplastic neurons from postmortem control tissue. No difference in expression of another glutamate transporter, EAAT2/GLT-1, was observed. Immunolabeling demonstrated that EAAT3/EAAC1 protein expression was enhanced in dentate granule cells from both rats and humans with TLE as well as in dysplastic neurons from human cortical dysplasia tissue. CONCLUSIONS: Elevations of EAAT3/EAAC1 mRNA and protein levels are present in neurons from hippocampus and neocortex in both rats and humans with epilepsy. Upregulation of EAAT3/EAAC1 in hippocampal and neocortical epilepsy may be an important modulator of extracellular glutamate concentrations and may occur as a response to recurrent seizures in these cell types.     

Nodular heterotopia: a neuropathological study of 24 patients undergoing surgery for drug-resistant epilepsy

Purpose:   Despite the availability of detailed electroclinical and imaging data, only a few neuropathological studies of nodular heterotopia have been published. The aim of this study was to describe the neuropathological features of various types of nodular heterotopia obtained from patients undergoing surgery for intractable epilepsy.
Methods: Specimens of heterotopic nodules taken from 24 patients were neuropathologically investigated using routine and immunocytochemical procedures, and the data were compared with magnetic resonance imaging (MRI), electroclinical findings, and surgical outcomes.
Results: The neuropathological data distinguished two groups. Group 1 (14 patients, 78% in Engel class 1) had similar characteristics regardless of the size, number, or location of the nodules, with both projecting and local circuit neurons in the nodules intermingled with glial cells. Thirteen patients had focal cortical dysplasia. The nodules were identified by MRI in all cases. In group 2 (10 patients, 90% in Engel class 1), all of the nodules were within the temporal lobe and associated with hippocampal sclerosis or gangliogliomas. They were very small (undetected by MRI) and mainly formed by projecting neurons with no evidence of glial cells. All of the patients had cortical dysplasia.
Discussion: The distinctive neuropathological features of the nodules in the two groups suggest different etiopathogenetic mechanisms. In group 2, the presence of nodular formations in association with cortical dysplasia and either hippocampal sclerosis or ganglioglioma raises a question concerning so-called dual pathology in the temporal lobe.     

Altered layer-specific gene expression in cortical samples from patients with temporal lobe epilepsy

Purpose: Neuropathologic investigations frequently reveal the presence of architectural cortical dysplasia in patients with temporal lobe epilepsy (TLE), sometimes as an isolated finding but more commonly associated with hippocampal sclerosis (HS) and white matter abnormalities. The histologic pattern and the developmental origin of these alterations are not clear, and their diagnostic criteria are poorly defined. The aim of this study was to investigate the expression patterns of layer‐specific genes in cortical specimens from patients with TLE presenting different subtypes of cortical malformations in order to elucidate the disorganization of the laminar architecture of such epileptogenic abnormalities and provide evidence to enable a more objective neuropathologic diagnosis. Methods: We analyzed the expression patterns of CUX2, RORBETA, ER81, NURR1, and CTGF genes, respectively specific markers of layers II–III, IV, V, VI, and VIb, in surgical samples by means of in situ hybridization and compared them with those observed in control cortices. The pathologic samples included typical architectural dysplasia (group 1); temporal lobe sclerosis, a variant of architectural dysplasia (group 2); and white matter heterotopic neuronal aggregates, namely small lentiform nodules (group 3). These abnormalities may have been associated or not with HS. Key Findings: All of the genes had a laminar expression pattern in normal cortices, whereas groups 1 and 2 showed alterations mainly involving layers V and VI, and highlighted by the altered distribution of ER81‐ and NURR1‐positive cells. The expression of ER81 and NURR1 genes was different among the groups, and atypical coexpression of NURR1 and CUX2 mRNA was detected in the neurons making up the small lentiform nodules. Significance: These findings indicate that defects in cortical organization involving the deeper cortical neurons may be a common etiopathogenic mechanism in group 1 and 2 cortical dysplasia, whether isolated or associated with HS, and that developmental disorders may also be present in the white matter (group 3). They also provide evidence that the layer‐specific genes can be usefully used to investigate the neuropathology of human cortical dysplasia.     

Inhibitory Circuits in Human Dysplastic Tissue

Summary: Purpose : Different types of epilepsies and seizures depend on the nature and location of the primary disturbance and are presumably mediated by different physiopathological mechanisms. We immunocytochemically investigated possible changes in the inhibitory -aminobutyric acid (GABA)ergic system in specimens taken from four patients who underwent surgery for intractable epilepsy and presented two different types of focal cortical dysplasia in the temporal lobe.
Methods : The patients were selected on the basis of electro-clinical, imaging, and routine neuropathological data: two had Taylor focal dysplasia, and two had non-Taylor dysplasia (microdysgenesia). The study was performed using antibodies against parvalbumin (PV), glutamic acid decarboxylase (GAD), and GABA-transporter 1 (GAT1).
Results : In the patients with Taylor dysplasia, laminar disorganization of the cortex was associated with the presence of giant neurons and ballooned cells; there was a reduced number of PV-positive neurons and terminals, the giant neurons were surrounded by clusters of PV- and GAD-positive terminals, and there was an overall reduction in GAT1. Despite the presence of cortical laminar disorganization, no giant or ballooned cells were found in the patients with non-Taylor microdysgenesia; there was a marked decrease in PV and GAD immunoreactive elements, with a patchy distribution of GAD and GAT1 immunoreactivity but no clustering of PV and GAD terminals.
Conclusions : These results suggest that the two forms of cortical dysplasia are characterized by different and selective morphofunctional alterations in the GABAergic system.     

Multicenter study of occipital lobe epilepsy in childhood: clinical characteristics

We investigated the clinical characteristics of 54 patients with childhood onset occipital lobe epilepsy (OLE). There were 25 patients of symptomatic OLE (cortical dysplasia, post encephalitis or encephalopathy, brain tumor and so on), and 29 cases of cryptogenic OLE. Eighteen patients had positive visual symptoms such as flash light, bright spots and sparks of light, 23 patients had negative ones such as scotoma, hemianopia and amaurosis and 10 patients had other complicated visual symptoms such as change of the shape or colors. Young children complained of simple visual phenomena. The youngest patient who could explain visual symptom was 3 years old. All 3 patients with visual field defects had cortical dysplasia in occipital lobe. Ictal SPECT study showed wide hyperperfusion areas in the temporo-parieto-occipital lobe in most of patients with abnormal MRI findings. CBZ and VPA were prescribed in most cases, and were effective in 65% and 60% of the patients, respectively. Seizure prognosis was relatively good. Seizures disappeared in 56% of the patients with symptomatic OLE and 79% of those with cryptogenic OLE.     

Temporo-mesial extraventricular neurocytoma and cortical dysplasia in focal temporal lobe epilepsy

We describe a 17-year-old boy with a left extraventricular temporo-mesial neurocytoma associated with cortical dysplasia causing focal pharmacoresistant temporal lobe epilepsy. He presented with a long history of medically refractory, temporal complex partial seizures. MRI showed a left temporo-mesial lesion suspect to be a low-grade tumor. Based on the pre-operative non-invasive neurophysiological studies, the patient underwent a left tailored temporal antero-mesial resection. Histopathological examination showed an extraventricular neurocytoma associated with architectural dysplasia (Type 1a) of the temporal pole. The patient was seizure-free at 2 years follow-up. Extraventricular neurocytomas must be considered in the differential diagnosis of the plethora of low-grade tumors associated with focal epilepsy that typically involve the temporal lobe, and are frequently associated with focal cortical dysplasia.     

Recurrent intractable seizures in children with cortical dysplasia adjacent to dysembryoplastic neuroepithelial tumor

The purpose of this study was to identify the pathologic features that predict postoperative outcome in children with cortical dysplasia adjacent to dysembryoplastic neuroepithelial tumors. We reviewed the records of children with dysembryoplastic neuroepithelial tumor who underwent epilepsy surgery and who had at least 1 year of surgical follow-up. We divided the dysembryoplastic neuroepithelial tumors into three pathology classes (simple, complex, and nonspecific), categorized adjunctive cortical dysplasia into four types, and compared histopathology with seizure outcomes. We identified 26 children with dysembryoplastic neuroepithelial tumors. Dysembryoplastic neuroepithelial tumors were complex in 19 patients (73%), simple in 6 (23%), and nonspecific in 1 (4%). Cortical dysplasia was adjacent to dysembryoplastic neuroepithelial tumors in 18 patients. Six patients had type IA cortical dysplasia, 5 had type IB, 3 had type IIA, and 1 had type IIB. The 3 remaining patients had repeated surgeries; of these, 2 patients had cortical dysplasias of type IA/IB and 1 was type IIA/IIB. Eight (39%) of 18 patients with dysembryoplastic neuroepithelial tumors and cortical dysplasia required further surgery for recurrent intractable seizures (P < .05), whereas none of 8 patients without cortical dysplasia required additional surgery. Of 13 patients with type I cortical dysplasia, only 4 had a poor seizure outcome, whereas all 5 patients with type II had a poor seizure outcome postoperatively (P < .05). Children with dysembryoplastic neuroepithelial tumor and cortical dysplasia often had recurrent intractable seizures postoperatively and required further epilepsy surgery. Cortical dysplasia adjacent to dysembryoplastic neuroepithelial tumor can play a role in the epileptogenicity of dysembryoplastic neuroepithelial tumor. Complete resection of a dysembryoplastic neuroepithelial tumor and its adjacent cortical dysplasia should be considered.     

难治性癫痫46例患者大脑半球或多脑叶切除标本的临床病理学分析

目的 研究难治性癫痫患者大脑半球或多脑叶切除标本的临床病理学特点.方法 对2005-2009年在首都医科大学宣武医院接受大脑半球(行功能性大脑半球切除术)或多脑叶切除的46例难治性癫痫患者临床病理学资料进行回顾性分析.结果 46例患者的平均发病年龄3.9岁,平均病程为10.2年.其中行大脑半球切除33例,多脑叶切除13例,且颞叶全部受累.组织学分型:继发性瘢痕脑回31例,皮质发育畸形7例,中枢神经系统感染8例.31例瘢痕脑回标本镜下可见皮质结构消失、神经元减少、反应性胶质细胞增生及淀粉样小体出现;此外还可观察到含铁血黄素(13例)、钙化(9例)以及岛状分布的神经元(5例).瘢痕脑回均伴不同程度的皮质发育不良,并有7例伴海马硬化.7例脑回发育畸形中,局灶性皮质发育不良(FCD)5例(其中FCDⅠB型3例,FCDⅠA型1例,FCDⅡA型1例),多小脑回畸形及穿通脑畸形各1例.8例中枢神经系统感染中Rasmussen脑炎5例、巨细胞病毒性脑炎1例、结核性脑膜炎1例、囊虫感染1例.结论 大脑半球或多脑叶切除的脑组织病理学主要是多种原因(比如外伤、缺氧等)引起的继发性瘢痕脑回,颞叶病变明显.中枢神经系统感染以Rasmussen脑炎为主,皮质发育畸形主要以FCDⅠB型为主.

Abstract：

Objective To investigate the clinicopathologic features of the brain tissue from multilobar resection or hemispherectomy for refractory epilepsy. Methods The clinical and pathologic findings of 46 cases seen at Xuanwu hospital from 2005 to 2009 were reviewed retrospectively. Results The mean age of seizure onset and disease duration were 3.9 years and 10.2 years, respectively. There were 33 cases of hemispherectomy and 13 cases of multilobar resection. Temporal lobe abnormality was seen in all cases. The pathologic subgroups were as follows: ulegyria (31/46), malformation of cortical development (MCD, 7/46 ) and infection (8/46). Microscopic examination of ulegyria showed cortical architectural disturbances, neuronal loss, reactive gliosis and appearance of corpora amylacea. We also noted deposition of hemosiderin (13 cases), calcification (9 cases) and island-like neurons (5 cases). All ulegyria cases were accompanied by varying degree of cortical dysplasia, and hippocampus sclerosis were identified in 7 cases. MCD comprised of 5 cases of focal cortical dysplasia ( FCD), including 3 cases of FCDⅠB, 1 case of FCDⅡA and 1 case of FCDⅠA, 1 case of polymicrogyria and 1 case of porencephaly. Among 8 infection eases, there were 5 cases of Rasmussen encephalitis ( RE), l case of cysticercosis, 1 case of tuberculous meningitis and l case of Cytomegalovirus encephalitis. Conclusions The most common pathological category of specimens from hemispherectomy or multilobar resection is ulegyria with obvious temporal lobe abnormality. This is followed by MCD ( with FCDⅠB as the main type) and central nervous system infection (RE as the most frequent abnormality).