Summary: This study better defines the way in which the thalamus controls expression of experimental generalized seizures. The effects of small intrathalamic injections of the direct GABA agonist muscimol on the thresholds of pentylenetetrazol (PTZ)‐induced seizures and on spontaneous behavior were determined in the rat and compared with the effects of injections of γ‐vinyl‐GABA (GVG), an irreversible inhibitor of GABA transaminase. Muscimol injections produced neuronal inhibition in a relatively small area of thalamus, whereas GVG injections produced inhibition in a much larger area. Muscimol injections in the midline thalamus in the vicinity of the paraventricular, paratenial, interanteromedial, intermediodorsal, and central medial nuclei facilitated PTZ myoclonic and clonic seizures and also produced sedation. These effects on seizure thresholds were attributable both to a lower PTZ threshold dose for initiation of electroencephalographic (EEG) seizure activity and to an increased probability of this EEG activity being expressed as behavioral seizures. Midline injections located more posteriorly in the thalamus also inhibited tonic seizures. Muscimol injections placed laterally, dorsally, or ventrally to this midline thalamic region had much less effect on behavior or seizures. In contrast, GVG injections in the anterior medial thalamus elevated the threshold for all PTZ seizure types and for associated EEG seizure activity but had little effect on spontaneous behavior. These findings demonstrate the existence of an important seizure regulatory system in the midline of the thalamus and a direct anatomic link between the mechanisms for regulating arousal and seizure production which may help explain the association between sleep and seizure facilitation in humans. The results of this study also show that inhibition of discrete thalamic regions modifies seizure expression, but that simultaneous inhibition of large portions of the thalamus is required for a general antiepileptic effect. RÉSUMÉ Cette étude a Dermis de mieux définir les mécanismes de contrôles par le thalamus de expression de crises généralisées expérimentales. Les effets de petites injections intrathalamiques de agoniste GABA direct, le muscimol, sur le seuil des crises induites par pentylènetétrazol (PTZ) et sur le comportement spontané ont été mesurés chez le rat, et ont été compareés avec les effets une injection de Gamma‐Vinyl‐Gaba (GVG), un inhibiteur irréversible de la gaba‐transaminase. Les injections de muscimol ont produit une inhibition neuronale dans une zone relativement petite du thalamus, alors que les injections de GVG ont produit une inhibition dans une zone beaucoup plus large. Les injections de muscimol au niveau du thalamus médian, à proximité des noyaux paraventriculaires, paraténiaux, interantéromédians, intermédiodorsaux et centro‐médians ont facilityé les crises myocloniques induites par PTZ et ont aussi entraîné une sédation. Ces effets sur le seuil épileptogène ont pu être attribués à la fois à une diminution de la dose‐seuil de PTZ pour induction une activité critique EEG, et à une augmentation de probabilityé de traduction de cette activité EEG en crises cliniques. Des injections médianes effectuées de façon plus postérieure dans le thalamus ont également inhibé les crises toniques. Les injections de muscimol placées de façon latérale, dorsale ou ventrale à cette région thalamique médiane ont eu des effets bien moindre sur le comportement et sur les crises. En revanche, les injections de GVG dans le thalamus antérieur médian ont élevé le seuil pour tous les types de crises induites par PTZ et pour activité EEG critique associée, mais n'ont eu que peu effet sur le comportement spontané Ces constatations démontrent exis‐tence un système regulateur des crises important au niveau de la région médiane du thalamus, avec un lien anatomique direct entre les mécanismes de régulation de éveil et ceux de la production des crises; ceci peut contribuer à expliquer association entre sommeil et facilitation des crises chez homme. Les résultats de cette étude montrent également que inhibition exercée au niveau de régions précises du thalamus modifie expression des crises, mais que &inhibition simultanée de parties plus étendues du thalamus est nécessaire pour obtention un effet anticonvulsivant général. RESUMEN Este estudio define mejor los mecanismos talámicos que controlan la expresión de ataques generalizados experimentales. Los efectos de pequeas inyecciones intratálamicas del muscimol (agonista directo del GABA) sobre los umbrales de los ataques inducidos por el pentilentetrazol (PTZ) y sobre el comportamiento espontáneo, fueron determinados en la rata y comparados con los efectos de inyecciones del gamma‐vinyl‐GABA (GVG), un inhibidor reversible de la GABA‐transaminasa. Las inyecciones de muscimol produjeron una inhibición neuronal en un área relativamente reducida del tálamo mientras que las inyecciones del GVG produjeron una inhibición en un área mucho más amplia. Las inyecciones de muscimol en el tálamo de línea media, próximas a los núcleos praventricular, paratenial, interanteromedial, intermediodorsal y centralmedial, facilitaron los ataques mioclónicos y clónicos del PTZ y también produjeron sedación. Estos efectos sobre los umbrales de los ataques se atribuyeron a una dosis más baja para el umbral de PTZ que provoca la iniciación de ataques de actividad epiléptica electro‐gráfica. También se atribuyeron a un aumento de la probabilidad de esta actividad en el EEG que se expresa como ataques de comportamiento. Las inyecciones mediates localizadas en áreas más posteriores del tálamo también inhibieron los ataques tónicos. Las inyecciones de muscimol en las regiones dorsal, lateral y ventral de la zona medial del tálamo produjeron efectos mucho menos aparentes sobre los ataques o sobre el comportamiento. Por el contrario, las inyecciones de GVG en la zona anteromedial del tálamo elevaron el umbral para todos los tipos de ataques del PTZ y para la actividad epiléptica asociada en el EEG, pero produjeron escasos efectos sobre el comportamiento espontáneo. Estos hallazgos demuestran la existencia de un importante sistema regulador de ataques en la zona medial del tálamo y una unión anatómica directs entre los mecanismos que regulan la vigilia y la producción de ataques que puede explicar la asociación entre el sueo y la facilitación de ataques en humanos. Los resultados de este estudio también muestran que la inhibición de discretas regiones talámicas modifica la expresión de los ataques pero que, para conseguir un efecto anticonvulsive general, se requiere, simultáneamente, una inhibición de amplias porciones del tálamo.
Abstract We describe a case of GNAO1‐associated epilepsy and chorea in a patient with a de novo pathogenic mutation. This patient is unique in being the first reported male with this phenotype, and we propose that this genetic variant may represent a mutation hotspot that characterizes a unique phenotype. This 5.2‐years‐old boy presented with seizures, chorea, and severe global developmental delay. Brain imaging showed progressive diffuse cerebral atrophy. EEG monitoring revealed multifocal and diffuse discharges, along with generalized‐onset seizures. Genetic testing found a de novo pathogenic variant in the GNAO1 gene (c.607G>A; p.Gly203Arg). A review of the literature showed two other patients with similar phenotype and the same genetic variant. In contrast, other patients with neurological involvement had private mutations in the GNAO1 gene. The neurological phenotypes associated with GNAO1 mutations appear to lie on a spectrum, and it is possible that the c.607G>A (p.Gly203Arg) variant characterizes a phenotype with both severe epilepsy and chorea. [ Published with video sequence on www.epilepticdisorders.com ]
Voltage‐gated sodium channels have been implicated in numerous inherited paroxysmal disorders of the nervous system, muscle, and heart. Our goal is to provide a framework that helps neurologists understand the clinical and treatment implications of sodium channel variants they encounter in clinical practice. This will be accomplished through our objectives of (1) recognizing the relationship between location of a missense sodium channel gene variant and its effect on channel function, and (2) categorizing clinical phenotype based on functional effect of a variant. The relationship between location, function, and treatment response is also discussed. These interactions can be illustrated by the sodium channelopathies seen in people with epilepsy but generalize beyond that disorder. Ann Neurol 2018;83:1–9
Electrical stimulation mapping (ESM) is the clinical standard for functional localization with subdural electrodes (SDE). As stereoelectroencephalography (SEEG) has emerged as an alternative option, we compared functional responses, afterdischarges (ADs), and unwanted ESM-induced seizures (EISs) between the two electrode types.
Posterior quadrant disconnection (PQD) has been described as a treatment for patients with refractory posterior quadrant subhemispheric epilepsy. Surgical outcomes are difficult to interpret because of limited literature.To provide insight regarding the operative technique and postsurgical seizure freedom in young pediatric patients who underwent surgical disconnection for the treatment of posterior quadrant subhemispheric epilepsy at our institution.The authors retrospectively analyzed a series of 5 patients who underwent PQD between 2019 and 2021. Charts were reviewed for preoperative workup including noninvasive/invasive testing, operative reports, and postoperative follow-up data which included degree of seizure freedom, completion of disconnection, and complications.Five patients were included in this series. The median age at seizure onset was 12 months (range 3-24 months), and the median age at surgery was 36 months (range 22-72 months). Histopathology confirmed focal cortical dysplasia in 3 of 5 patients (2 patients with type IB; 1 with type IIID). The average length of follow-up after surgery was 16.8 months (range 12-24 months). All patients underwent complete disconnection of the posterior quadrant without complications. Four of 5 patients (80%) had Engel score of I, while the remaining patient had an Engel score of IIB.Our early results demonstrate that complete PQD can be successful at providing excellent seizure freedom and functional outcomes in carefully selected young pediatric patients who have concordant seizure semiology, noninvasive/invasive testing, and imaging findings with primary seizure onset zone within the ipsilateral posterior quadrant. Meticulous surgical planning and thorough understanding of the surgical anatomy and technique are critical to achieving complete disconnection.
Objective: The purpose of this work is to characterize the effectiveness and therapeutic doses of carbamazepine (CBZ) in children with localization-related epilepsy. Methods: Treatment to initial CBZ monotherapy and doses associated with 1-year seizure freedom were examined in 100 consecutive children with partial epilepsy. Results: Of the 100 patients studied, 55 became seizure-free on CBZ monotherapy, 10 did not tolerate CBZ within the first 3 months of therapy owing to either hypersensitivity or intolerable side effects, and 35 continued to have seizures. In children age <12, over 95% responded at doses below 17.5 mg/kg/day; in children age >12, over 95% responded at below 15 mg/kg/day. Conclusions: We suggest that other antiepileptic treatments be considered when seizures continue in children taking carbamazepine doses between 15 and 17.5 mg/kg/day even if side effects are absent.
