Pre-operative extracranial and intracranial EEG investigation in patients with temporal lobe epilepsy: trends, results and review of pathophysiologic mechanisms

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66297/1/j.1600-0404.1988.tb08004.x.pd

Basal Temporal Language Area: Evidence from Cortical Stimulation and Surgical Ablation

TB

Zonisamide (CI-912) and Cognition: Results from Preliminary Study

Nine patients with refractory partial seizures were evaluated in a pilot study of a new anticonvulsant compound, zonisamide (l,2-benzisoxazole-3-methane-sulfonamide; CI-912). Cognitive functioning was evaluated prior to treatment with zonisamide and repeated after 12 and 24 weeks of treatment with zonisamide. At minimum steady-state plasma concentrations >30 jjug/ml, zonisamide appeared to affect specific cognitive functions such as acquisition and consolidation of new information. Previously learned material, such as vocabulary, and psychomotor performance were not affected. Verbal learning was affected, while visual-perceptual learning was unimpaired. These cognitive effects were observed in the absence of the usual clinical signs and symptoms of toxicity. A linear relationship was found between impairment of cognitive abilities and the minimum plasma concentration (r = -0.73; p < 0.05). Findings also suggest the development of tolerance to the adverse cognitive effects. RESUMEN En un estudio piloto realizado para valorar la eficacia de la zonisamida (1,2-Bencisoxazol-melanosulfonamida [CI-912]), un nuevo compuesto anticonvulsive se han evaluado unos 9 pa-cientes con ataques parciales refractarios al tratamiento. Se de-terminÓ la capacidad cognitiva anterior al tratamiento y se re-pitio 12 y 24 semanas despuÉs del tratamiento con zonisamida. Con concentraciones plasmÁticas mÍnimas estables per encima de 30 mcg/ml, la zonisamida afectÓ las funciones cognitives especÍficas tales como la adquisiciÓn y consolidaciÓn de nueva informaciÓn. El material aprendido previamente, tal como el vo-cabulario, y las funciones psicomotoras no se afectaron. El aprendizaje verbal se modificÓ mientras que el aprendizaje visuo-perfectivo no se modificÓ. Estos efectos cognitivos se ob-servaron en ausencia de los habituales signos y sÍntomas clÍnicos de toxicidad. Se encontrÓ una relaciÓn lineal entre la alteraciÓn de las posibilidades cognitivas y la concentraciÓn plasmÁtica mÍnima (r = -0.73, p < 0.05). Estos hallazgos tambiÉn sugieren el desarrollo de una tolerancia a los efectos cognitivos adversos. ZUSAMMENFASSUNG 9 Patienten mit rezidivierenden Partial-AnfÄllen wurden in einer Pilotstudie mit einer neuen antiepileptischen Substanz: Zonisamide untersucht. Die kognitiven Funktionen wurden vor der Behandlung mit Zonisamide geprtÜft und nach 12 und 24 Therapiewochen mit Zonisamide wiederholt. Bei einem Min-destplasmaspiegel von 30 mcg/ml schien Zonisamide spezifische kognitive FÄhigkeiten wie Aufnahme und Speicherung neuer In-formationen zu beeintrÄchtigen. Vorher gelernte Inhalte wie sprachliche und psychomotorische Fertigkeiten wurden nicht beeinflußt. Verbales Lernen war ebenfalls betroffen, wÄhrend visuell, perzeptives Lernen nicht verschlechtert war. Diese BeeintrÄchtigung kognitiver Funktionen wurde bei fehlenden klinischen Intoxikationszeichen beobachtet. Eine lineare Bezie-hung zwischen Verschlechterung kognitiver FÄhigkeiten und Mindest-Plasmaspiegel konnte hergestellt werden (r = -0,73; p < 0,05). Allerdings lassen die Ergebnisse auch auf eine GewÖhnung an diese unerwÜnschten Nebenwirkungen schließen.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65995/1/j.1528-1157.1987.tb03624.x.pd

Pilot Study of Zonisamide (1,2-Benzisoxazole-3-methanesulfonamide) in Patients with Refractory Partial Seizures

A new anticonvulsant compound, zonisamide (1,2 benzioxazole-methanesulfonamide), was studied in 10 adults with medically refractory partial seizures. Following a single oral dose of 400 mg, peak plasma levels occurred an average of 2.8 h after dosing, and the mean clearance from plasma was 2.34 L/h. Whole blood concentrations were high than plasma concentrations because of red blood cell binding. steady-state plasma concentrations were high than predicted from a linear kinetic model. In most patients, seizure frequency was reduced after zonisamide was substituted for a standard antiepileptic drug. Dose-related reversible side effects in the central nervous and gastrointestinal system were observed. Most patients tolerated doses between 5.2 and 12.5 mg/kg/day. RÉSUMÉ Un nouveau produit anticonvulsivant, le zonisamide (1,2 benziosoxazole-methylsulfonamide) a ÉtÉ administrÉÀ 10 adultes atteints de crises partielles non contrÔlÉes par le traitement mÉdical. AprÈs une dose unique orale de 400 mg, le pic du taux plasmatique survient en moyenne 2 h 1/2 aprÉs l'ingestion, et la clairance plasmatique moyenne est de 2,34 litres par heure. les concentrations sanguines totales sont plus ÉlevÉes que les concentrations plasmatiques, en raison de la liaison aux globules rouges, les concentrations plasmatiques À l'État d'equilibre sont plus ÉlevÉes que celles que l'on peut dÉdurie d'un modÈle de cinÉtique linÉaire. Chez la plupart des patients, la frÉquence des crises a ÉtÉrÉduite par la substitution du zonisamide au traitement antiÉpileptique standard. Des effets secondaires doses-dÉpendants et rÉversibles ont ÉtÉ observÉs au niveau du systÈme nerveux central et du tube digestif. La plupart des patients ont tolÉrÉ des doses entre 5,2 et 12,5 mg/kg de poids par jour. RESUMEN En 10 adultos con ataques parciales refractarios a1 tratamiento mÉdico, se ha estudiado la acciÓn de un nuevo compuesto anticonvulsivo, la zonisamida (1,2 benzisoxazol-metanosulfonamida). Tras la ingestiÓn de una sola dosis oral de 400 mg., se alcanzaron los niveles pico en plasma en un promedio de 2.8 horas desputs de la dosis y el aclaramiento medio del plasma fuÉ de 2, 34 litros/hora. Las concentraciones en sangre fueron mÁs altas que las plasmÁticas debido a que la medicaciÓn se ligaba a los hematies. Las concentraciones plasmÁticas estables fueron mÁs altas que las previsibles de un modelo cinÉtico lineal. En la mayorÍa de los pacientes la frecuencia de los ataques se redujo despuÉs de cambiar la medicaciÓn antiepilÉptica standard por la zonisamida. TambiÉn se observaron los efectos colaterales sobre el tracto gastrointestinal y el sistema nervioso central que estaban relacionadas con la dosis y eran reversibles. La mayor parte de los pacientes tolerÓ dosis que oscilaban entre 5.2 y 12.5 mg/kg/dÍa. ZUSAMMENFASSUNG Ein neues Antikonvulsivum, Zonisamid (1,2 Benzisoxazol-Methansulfonamid) wurde bei 10 Envachsenen mit therapieresistenten PartialanfÄllen gesucht. Nach einer oralen Einzeldosis von 400 mg wurden Plasmaspitzenwerte im Durchschnitt nach 2, 8 Stunden erreicht. Die mittlere Clearance aus dem Plasma betrug 2, 34 L/Stunde. Ganzblutkonzentrationen waren hÖher als Plasmakonzentrationen aufgrund der Bindung an die roten BlutkÖrperchen. Die steady-state Plasmakonzentrationen waren hÖher als bei einem linearen kinetischen Modell zu envarten. Bei den meisten Patienten konnte die Anfallsfrequenz nach Substitution eines Standardantiepileptikums durch Zonisamid reduziert werden. Es bestanden dosisabhÄngige, reversible, zentral-nervÖse und gastrointestinale Nebenwirkungen. Die meisten Patienten tolerierten Dosen zwischen 5, 2 und 12, 5 mg/kg/Tag.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65938/1/j.1528-1157.1985.tb05407.x.pd

Polarity reversal of N20 and P23 somatosensory evoked potentials between scalp and depth recordings

From depth and scalp electrodes, we recorded MN-SSEPs of a 33-year-old man with right parietal dysfunction and refractory right temporal seizures. A depth lead with 8 electrodes was implanted deep in each parietal-temporal region. Stimulation and recording parameters followed American EEG Society guidelines. Scalp recordings had well-defined P9, P13-14, N18, N20, and P23 potentials with normal conduction times bilaterally. Depth recordings showed potentials of greater number, voltage, and coherence. P13-14 and N18 were recorded at all depth sites with latencies similar to those at the scalp. N18 had markedly greater voltage and duration near the thalamus, with multiple fast components on its ascending phase. In the deep parietal region there was a positivity corresponding to the scalp N20 and a negative potential equal in latency to scalp P23. These findings support an origin of P13-14 caudal to the thalamus, multiple thalamic and possibly rostral brain-stem generators for N18, and generation of N20 and P23 in sensory cortex or subjacent white matter.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29433/1/0000514.pd

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice