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NMDA receptor alterations in neurons from pediatric cortical dysplasia tissue

André, Véronique M; Flores-Hernández, Jorge; Cepeda, Carlos; Starling, Amaal J; Nguyen, Snow; Lobo, Mary Kay; Vinters, Harry V; Levine, Michael S; Mathern, Gary W
The subunit composition of glutamate receptors affects their functional properties, and could contribute to abnormal electrophysiology in pediatric cortical dysplasia (CD). We examined electrophysiological responses and subunit assembly of N-methyl-D-aspartate (NMDA) receptors in acutely dissociated normal-appearing pyramidal and cytomegalic neurons from CD tissue and normal-appearing pyramidal neurons from non-CD tissue. In most cytomegalic and approximately 30% of normal-appearing pyramidal neurons from CD tissue, NMDA currents showed decreased Mg(2+) sensitivity compared with neurons from non-CD tissue. Ifenprodil had less effect in CD compared with non-CD neurons, indicating a functional loss of NR2B subunits. NMDA-evoked current density was decreased in cytomegalic compared with normal-appearing neurons. Single-cell reverse transcriptase polymerase chain reaction showed that all non-CD neurons expressed NR2B subunit mRNA. By comparison, 22% of pyramidal neurons in CD tissue lacked NR2B mRNA. Immunofluorescence showed a decrease in NR2B subunit expression in cytomegalic neurons and a subset of normal-appearing pyramidal neurons from CD tissue. Taken together, these results demonstrate the presence of NMDA receptors with altered subunit composition and Mg(2+) sensitivity that could contribute to functional abnormalities in CD.
PMID: 15054078
ISSN: 1047-3211
CID: 5013752

Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes

Jonas, R; Nguyen, S; Hu, B; Asarnow, R F; LoPresti, C; Curtiss, S; de Bode, S; Yudovin, S; Shields, W D; Vinters, H V; Mathern, G W
OBJECTIVE:To compare hemispherectomy patients with different pathologic substrates for hospital course, seizure, developmental, language, and motor outcomes. METHODS:The authors compared hemispherectomy patients (n = 115) with hemimegalencephaly (HME; n = 16), hemispheric cortical dysplasia (hemi CD; n = 39), Rasmussen encephalitis (RE; n = 21), infarct/ischemia (n = 27), and other/miscellaneous (n = 12) for differences in operative management, postsurgery seizure control, and antiepilepsy drug (AED) usage. In addition, Vineland Adaptive Behavior Scale (VABS) developmental quotients (DQ), language, and motor assessments were performed pre- or postsurgery, or both. RESULTS:Surgically, HME patients had the greatest perioperative blood loss, and the longest surgery time. Fewer HME patients were seizure free or not taking AEDs 1 to 5 years postsurgery, but the differences between pathologic groups were not significant. Postsurgery, 66% of HME patients had little or no language and worse motor scores in the paretic limbs. By contrast, 40 to 50% of hemi CD children showed near normal language and motor assessments, similar to RE and infarct/ischemia cases. VABS DQ scores showed +5 points or more improvement postsurgery in 57% of patients, and hemi CD (+12.7) and HME (+9.1) children showed the most progress compared with RE (+4.6) and infarct/ischemia (-0.6) cases. Postsurgery VABS DQ scores correlated with seizure duration, seizure control, and presurgery DQ scores. CONCLUSIONS:The pathologic substrate predicted pre- and postsurgery differences in outcomes, with hemimegalencephaly (but not hemispheric cortical dysplasia) patients doing worse in several domains. Furthermore, shorter seizure durations, seizure control, and greater presurgery developmental quotients predicted better postsurgery developmental quotients in all patients, irrespective of pathology.
PMID: 15159467
ISSN: 1526-632x
CID: 5018702

Five or more acute postoperative seizures predict hospital course and long-term seizure control after hemispherectomy

Koh, Susan; Nguyen, Snow; Asarnow, Robert F; LoPresti, Christine; Yudovin, Sue; Shields, W Donald; Vinters, Harry V; Mathern, Gary W
PURPOSE/OBJECTIVE:Acute postoperative seizures (APOSs) are those that occur in the first 7 to 10 days after surgery, and previous studies in temporal lobe epilepsy patients support the notion that APOSs may foretell failure of long-term seizure control. It is unknown whether APOSs also predict seizure outcome or hospital course after hemispherectomy. METHODS:Hemispherectomy patients (n = 114) were studied retrospectively and subdivided into the following groups: No APOSs, 1 to 5 APOSs, or >5 APOSs. Intensive care unit (ICU) nursing staff or family members reported and described the APOS events. APOS categories were compared with pre- and postsurgery clinical variables abstracted from the medical record. RESULTS:APOSs occurred in 22.6% of hemispherectomy patients. Compared with the 0 and 1 to 5 APOS groups, patients with >5 APOS showed (a) longer seizure durations before surgery, (b) longer hospitalizations, (c) later oral food intake, (d) more frequent lumbar punctures, (e) worse seizure control at 0.5 and 1 year after surgery, (f) more antiepileptic drug (AED) use at 2 and 5 years after surgery, and (g) higher reoperation rate. No similar differences were found between the 0 and 1 to 5 APOS groups. The day of the APOS, whether the APOS was typical of preoperative seizures, and postsurgery scalp EEG did not predict long-term seizure control. APOS patients in the 1 to 5 and >5 groups had lower pre- and postsurgery Vineland developmental quotients compared with those without an APOS. CONCLUSIONS:Hemispherectomy patients with >5 APOSs had a more prolonged and complicated hospital course and worse postsurgery seizure control, more AED use, and higher reoperation rate than did patients with 0 or 1 to 5 APOSs. Thus the number of APOSs was a predictor of postsurgery seizure control and can be used to counsel patients and families about prognosis after hemispherectomy.
PMID: 15101834
ISSN: 0013-9580
CID: 5013762

Cerebral hemispherectomy in pediatric patients with epilepsy: comparison of three techniques by pathological substrate in 115 patients

Cook, Shon W; Nguyen, Snow T; Hu, Bin; Yudovin, Sue; Shields, W Donald; Vinters, Harry V; Van de Wiele, Barbara M; Harrison, Rick E; Mathern, Gary W
OBJECT/OBJECTIVE:Cerebral hemispherectomy for intractable seizures has evolved over the past 50 years, and current operations focus less on brain resection and more on disconnection. In addition, cases involving cortical dysplasia and Rasmussen encephalitis are being identified and surgically treated in younger individuals. Few studies have been conducted to compare whether there are perioperative differences based on hemispherectomy technique and/or pathological substrate in pediatric patients with epilepsy. METHODS:In this study the authors compared, stratified by disease, anatomical (37 cases) and Rasmussen functional hemispherectomy (32 cases) with a new modified lateral hemispherotomy (46 cases). Pathological processes included cortical dysplasia (55 cases), Rasmussen encephalitis (21 cases), infarction/ischemia (27 cases), and other/miscellaneous (12 cases). The authors found differences in perioperative clinical factors based on operative technique and/or pathological substrate. In terms of technique, the lateral hemispherotomy was associated with the least intraoperative blood loss, shortest intensive care unit stay, and lowest complication rate. The anatomical hemispherectomy was associated with the longest hospital stay, delayed oral food intake, highest postsurgery fevers, and the highest incidence of shunt requirement. The functional hemispherectomy was associated with the highest reoperation rate for recurrent seizures (25%). In terms of pathology, patients with cortical dysplasia were the youngest at surgery, suffered the greatest amount of blood loss, and required the longest operative/anesthesia times compared with the other pathologically defined groups. Postoperative seizure control (range 0.5-2 years) was not statistically different according to technique or disease process and was similar to that in cases of pediatric temporal lobe epilepsy. CONCLUSIONS:The authors found differences in perioperative risks and hospital course but not postsurgery seizure control, which vary by hemispherectomy technique and/or disease process. The modified lateral hemispherotomy approach offers various advantages related to operative blood loss and reoperation compared with anatomical and functional hemispherectomies that are especially relevant in younger patients with cortical dysplasia and Rasmussen encephalitis with small and/or malformed ventricles.
PMID: 14758940
ISSN: 0022-3085
CID: 5013742

Enhanced expression of a specific hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) in surviving dentate gyrus granule cells of human and experimental epileptic hippocampus

Bender, Roland A; Soleymani, Sheila V; Brewster, Amy L; Nguyen, Snow T; Beck, Heinz; Mathern, Gary W; Baram, Tallie Z
Changes in the expression of ion channels, contributing to altered neuronal excitability, are emerging as possible mechanisms in the development of certain human epilepsies. In previous immature rodent studies of experimental prolonged febrile seizures, isoform-specific changes in the expression of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCNs) correlated with long-lasting hippocampal hyperexcitability and enhanced seizure susceptibility. Prolonged early-life seizures commonly precede human temporal lobe epilepsy (TLE), suggesting that transcriptional dysregulation of HCNs might contribute to the epileptogenic process. Therefore, we determined whether HCN isoform expression was modified in hippocampi of individuals with TLE. HCN1 and HCN2 expression were measured using in situ hybridization and immunocytochemistry in hippocampi from three groups: TLE with hippocampal sclerosis (HS; n = 17), epileptic hippocampi without HS, or non-HS (NHS; n = 10), and autopsy material (n = 10). The results obtained in chronic human epilepsy were validated by examining hippocampi from the pilocarpine model of chronic TLE. In autopsy and most NHS hippocampi, HCN1 mRNA expression was substantial in pyramidal cell layers and lower in dentate gyrus granule cells (GCs). In contrast, HCN1 mRNA expression over the GC layer and in individual GCs from epileptic hippocampus was markedly increased once GC neuronal density was reduced by >50%. HCN1 mRNA changes were accompanied by enhanced immunoreactivity in the GC dendritic fields and more modest changes in HCN2 mRNA expression. Furthermore, similar robust and isoform-selective augmentation of HCN1 mRNA expression was evident also in the pilocarpine animal model of TLE. These findings indicate that the expression of HCN isoforms is dynamically regulated in human as well as in experimental hippocampal epilepsy. After experimental febrile seizures (i.e., early in the epileptogenic process), the preserved and augmented inhibition onto principal cells may lead to reduced HCN1 expression. In contrast, in chronic epileptic HS hippocampus studied here, the profound loss of interneuronal and principal cell populations and consequent reduced inhibition, coupled with increased dendritic excitation of surviving GCs, might provoke a "compensatory" enhancement of HCN1 mRNA and protein expression.
PMCID:3100807
PMID: 12890777
ISSN: 1529-2401
CID: 5013732