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Summary Purpose: We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy. Methods: Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation. Results: One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and “most severe” seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events. Discussion: Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.

Summary: Purpose:γ-Aminobutyric acid receptor (GABAAr) subunit β3–deficient mice model Angelman syndrome by displaying impaired learning, abnormal EEG with interictal spikes and slowing, myoclonus, and convulsions. The β3-subunit deficiency causes a failure of intrathalamic reticular nucleus inhibition, leading to abnormally synchronized thalamocortical oscillations. We postulated that this pathophysiology underlies the abnormal cortical EEG and triggers interictal spikes and seizures, but extrathalamic regions also contribute to interictal spikes and seizures, so that the EEG slowing should reveal an absence-like response profile, whereas spikes and seizures have dual responsiveness to absence and partial-seizure drugs. Methods: Recording electrodes were implanted over the parietal cortices of wild-type, heterozygotes, and homozygous null mice. In each experiment, EEG was recorded for 45 min, either drug or vehicle administered, and EEG recorded for another 3 h. Each EEG was scored for slow-wave activity, interictal spikes, and seizures by a reader blinded to treatments. Results: Interictal spiking and percentage of time in EEG slowing in heterozygotes were increased by the proabsence drug baclofen (GABAB-receptor agonist), whereas CGP 35348 (GABAB-receptor antagonist) had the opposite effect. The antiabsence drug ethosuximide markedly suppressed EEG slowing and interictal spiking in heterozygote and null mice. Broad-spectrum clonazepam and valproate were more effective on interictal spiking than on EEG slowing, and fosphenytoin suppressed only interictal spiking. Conclusions: The results suggest that this model of Angelman syndrome, although not expressing typical absence seizures, is characterized by hypersynchronous thalamocortical oscillations that possess absence-like pharmacologic responsiveness and promote EEG slowing, interictal spikes, and convulsive seizures.

Summary: Purpose: Early animal studies of the therapeutic mechanisms of vagus nerve stimulation (VNS) suggested that seizure suppression requires maximal activation of small, unmyelinated vagal C fibers. However, effective therapeutic stimulation parameters appear to be subthreshold for these fibers in humans, and there are no clinical reports of the autonomic side effects that would be expected if these fibers were maximally activated. We report here that selective destruction of C fibers with capsaicin does not affect VNS-induced seizure suppression in rats. Methods: Rats were pretreated with capsaicin or vehicle in three injections over a 2-day period. A cuff electrode was later implanted on the left cervical vagus nerve. Two days after surgery, VNS was given to half of the capsaicin- and vehicle-treated rats. The remaining rats were connected to the stimulator but did not receive VNS. Thirty seconds after VNS onset, seizures were induced by pentylenetetrazol (PTZ), and seizure severity was measured. Two days later, the reciprocal VNS treatment was given, and PTZ-induced seizure severity was again measured. Results: VNS effectively reduced seizure severity in both capsaicin- and vehicle-treated rats as compared with their non-VNS baselines. Conclusions: These results indicate that activation of vagal C fibers is not necessary for VNS-induced seizure suppression.

Summary: Purpose: To determine the long-term efficacy of vagus nerve stimulation (VNS) for refractory seizures. VNS is a new treatment for refractory epilepsy. Two short-term double-blind trials have demonstrated its safety and efficacy, and one long-term study in 114 patients has demonstrated a cumulative improvement in efficacy at 1 year. We report the largest prospective long-term study of VNS to date. Methods: Patients with six or more complex partial or generalized tonic-clonic seizures enrolled in the pivotal EOS study were prospectively evaluated for 12 months. The primary outcome variable was the percentage reduction in total seizure frequency at 3 and 12 months after completion of the acute EO5 trial, compared with the preimplantation baseline. Subjects originally randomized to low stimulation (active-control group) were crossed over to therapeutic stimulation settings for the first time. Subjects initially randomized to high settings were maintained on high settings throughout the 12-month study. Results: The median reduction at 12 months after completion of the initial double-blind study was 45%. At 12 months, 35% of 195 subjects had a >50% reduction in seizures, and 20% of 195 had a >75% reduction in seizures. Conclusions: The efficacy of VNS improves during 12 months, and many subjects sustain >75% reductions in seizures.

Summary: Purpose: We studied the efficacy and safety of bilateral subthalamic deep brain stimulation (DBS) for refractory partial-onset epilepsy in two cases. Methods: This was an open treatment pilot study for subjects who had failed numerous medications and had seizure injuries. Seizure counts and adverse events were collected during a 3-4 month baseline, and for 26-32 months after DBS surgery, with AEDs held constant. Results: Case 1, age 45, with bitemporal seizures, had about half the seizure frequency but still fell with injuries. Case 2, age 46, with left frontal encephalomalacia, had a frequency reduction of about one-third, but a more meaningful reduction of seizure severity and injuries. Conclusions: Subthalamic DBS partly reduced partial-onset seizures, but the quality of life was more affected by seizure-related injuries.

We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy.Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation.One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and "most severe" seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events.Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.

Summary: Repeated electrical stimulation was delivered to the amygdala in a paradigm of electrogenic limbic status epilepticus induction in rats. We observed four distinct initial behavioral states associated with prolonged spiking, comprising an ordered hierarchy of severity: immobile, exploratory, minor convulsive, and clonic convulsive. The EEG and behavioral topography of the initial prolonged seizure state behaviorally and electrographically resembled the acute seizures that occurred earlier during induction. Onset of status epilepticus on limbic induction appears to represent not a new type of seizure activity, but instead the extended version of repeated brief limbic-onset seizures as seizure-terminating mechanisms gradually become ineffective. These prolonged seizure states can therefore be used to study the anatomy and mechanisms of brief limbic seizures. We also examined the temporal progression of amygdala-induced prolonged-seizure states. At one end of the severity spectrum, immobile-associated spiking was prone to terminate early, within 90 min, accompanied by normalization of behavior. At the other end of the spectrum, clonic convulsive status epilepticus slowly decreased in behavioral severity together with a change in EEG from fast to slow spiking. Exploratory status epilepticus was characterized by incessant explorationlike behavior that could last hours and was associated with slow periodic spikecomplexes on EEG. The long-term course consisted either of slow devolution, with eventual cessation of spiking, or of spontaneous late ascension to convulsive status. Prolonged-seizure states may thus be considered to fall not only within an anatomiclbehavioral hierarchy of severity, but also within a temporal physiologic progression. RESUME Les auteurs ont administre des stimulations electriques repetitives au niveau amygdalien dans un protocole d'induction d'etat de ma1 epileptique limbique chez le rat. IIs ont observe 4 etats comportementaux initiaux distincts associes avec des decharges prolongees de pointes, avec une hierarchie dans la severite: etat immobile, exploratoire, etat confulsif mineur et etat convulsif clonique. La topographie EEG et comportementale de I'etat critique prolonge initial ressemblait sur le plan comportemental et electrographique aux crises aigues qui etaient survenues plus tot pendant I'induction. L'installation de l'etat de mal epileptique apres induction limbique parait representer non un type d'activite critique mais plutot une version etendue de breves crises a debut limbique repetees, au fur et a mesure que les mecanismes de terminaison des crises deviennent inefficaces. Ces etats de crises prolongees peuvent donc etre utilises pour etudier l'anatomie et les mecanismes de crises limbiques breves. La progression temporelle des etats critiques prolonges induits au niveau de I'amygdale a egalement eteetudiee. Pour les manifestations les moins severes, les pointes associees a l'immobilite avaient tendance a se terminer rapidement, en moins de 90 minutes avec normalisation du comportement. A I'autre extremite du spectre de severite I'etat de ma1 epileptique clonique convulsif a diminue progressivement en severite sur le plan comportemental, parallelement a une modification de I'EEG passant de pointes rapides a des pointes lentes. L'etat de ma1 epileptique exploratoire etait caracterise par un comportement exploratoire incessant qui pouvait durer des heures et qui etait associe avec des complexes de pointes-ondes periodiques lents sur I'EEG. L'evolution a long terme a ete representee soit par une diminution progressive, avec cessation finale de la production des pointes, soit par la transformation spontanee, tardive, en etat de ma1 convulsif. Des etats critiques prolonges peuvent donc etre consideres non seulement comme entrant dans une hierarchie anatomique et comportementale de severite, mais aussi en fonction de leur progression physiologique dans le temps. RESUMEN Se ha aplicado una estimulacion electrica repetida en la amigdala en un modelo de status epilepticus electrogenico inducido en ratas. Los autores han observado cuatro comportamientos iniciales distintos asociados a descargas de puntas prolongadas que comprendian, jeraquicamente, segun la severidad: inmovilidad, actitud exploratoria, convulsiones menores y convulsiones clinicas. El EEG y la topografia del comportamiento del prolongado estado de ataques inicial se parecia, desde el punto de vista del comportamiento y electrograficamente, a los ataques agudos que aparecieron precozmente durante la induccion. El comienzo del status, tras la induccion limbica, no parece representar un nuevo tipo de actividad epileptica. Mas bien consiste en una version ampliada de ataques de comienzo limbico, breves y repetidos, a medida que los mecanismos de control de los ataques se hacen gradualmente ineficaces. Estos estados prolongados de ataques pueden utilizarse en el estudio de la anatomia y de los mecanismos de ataques limbicos breves. La progresion en el tiempo de los estados de ataques prolongados inducidos en la amigdala ha sido tambien examinada. En un extremo del espectro de severidad, las puntas asociadas a la inmovilidad del animal tenian tendencia a terminar precozmente (en unos 90 minutos) y se asociaron a una normalizacion del comportamiento. En el otro extremo del espectro, el status convulsivo clonico declino lentamente en la severidad del comportamiento a la vez que se observo un cambio en el EEG desde puntas rapidas a mas lentas. El status epilepticus exploratorio se caracterizo por un comportamiento incesante de exploracion del ambient que podia durar horas y se asocio a complejos de puntas lentas periodicas en el EEG. El curso, a large plazo, consistio en una resolucion lenta con interrupcion eventual de las puntas o en una ascension lenta y espontanea al estado convulsivo que puede considerarse como un fallo no solo de la jerarquia anatomico-compartamental de severidad sino tambien de la progresion fisiologica en el tiempo. ZUSAMMENFASSUNG Bei einem Paradigma des elektrogenen limbischen Status epilepticus bei Ratten wurden den Amygdala wiederholte elektrische Reize appliziert. Wir beobachteten 4 verschiedene initiale Verhaltenszustande, die mit verlangertan Spike-Ausbruchen einhergingen und eine Hierarchie im Schweregrad darstellten: Einen immobilen Zustand, einen exploratorischen Zustand, einen kleineren konvulsiven und einen klonisch-konvulsiven Zustand. EEG und Verhaltenstopographie des anfanglichen verlangerten Anfallsstatus ahnelten verhaltensmaβig und elektrographisch den akuten Anfallen, die fruh wahrend der Induktion auftraten. Der Beginn des Status epilepticus bei limbischer Induktion scheint keinen neuen Anfallstyp darzustellen, sondern eine ausgedehnte Version von wiederholten kurzen, im limbischen System beginnenden Anfallen, wenn die anfallsbeendigenden Mechanismen schrittweise unwirksam werden. Diese verlangerten Anfallsstaten konnen deshalb dazu dienen, Andtomie und Mechanismen von kurzen limbischen Anfallen zu untersuchen. Der zeitliche Verlauf von Amygdalon-induzierten verlangerten Anfallsstaten wurde ebenfalls untersucht. Am einen Ende des Schwerespektrums neigte das mit Immobilitat einhergehende Auftreten von Spikes zu einer fruhen Beendigung innerhalb von 90 Minuten, begleitet von einer Verhaltensnormalisierung. Am anderen Ende des Spektrums zeigten klonische konvulsive epileptische Staten eine allmahliche Abnahme im Schweregrad der Verhaltensanderung zusammen mit einer Anderung im EEG von schnellen zu langsamen Spikefolgen. Der exploratorische Status epilepticus war durch ein andauendes Exploratorionsverhalten charakterisiert, das uber Stunden anhalten konnte und mit langsamen periodischen Spike-Komplexem im EEG einherging. Der Langzeitverlauf bestand entweder in einem langsamen Ende mit evt. Nachlassen der Spike-Aktivitat oder in einem spontanen spaten Auftreten eines konvulsiven Status. Verlangerte Anfallsstaten konnen somit nicht nur hinsichtlich einer anatomischen bzw. verhaltensmaβigen Hierarchie des Schweregrades betrachtet werden, sondern auch hinsichtlich einer zeitlichen physiologischen Entwicklung.

Summary: Purpose: To determine the effect of changes in device settings and duty cycle (on and off times) on the efficacy of vagus nerve stimulation (VNS) for refractory epilepsy. In the long-term XE5 study of VNS for intractable epilepsy, the median reduction in seizure frequency improved significantly after 1 year of follow-up. A central question is whether device changes improve efficacy. We analyzed the effects of device parameter changes on seizure frequency in 154 subjects who completed the study and who had complete data for analysis. Methods: Retrospective analysis of device changes during the XE5 long-term study of VNS. During the XE5 long-term follow-up study, the subject's device settings were modified within a Food and Drug Administration (FDA)-approved range of output current, pulse duration, frequency, on time, and off time. Significant changes in device settings occurred after 3 months. We investigated the relationship between percentage reduction in seizures and changes in device parameters between the 3- and 12-month visits. Within-group comparisons were performed for those who continued on standard on/off cycle of 30 s on and 5 min off, and those with the most common off times of 3, 1.8, and 50% reduction in seizures) also significantly improved from 19 to 35% (McNemar's test, p = 0.046). Conclusions: The data from this retrospective analysis indicate that device changes were not the primary determinant of increased efficacy at 12 months of long-term follow-up. In general, patients who remained on the original settings of 30 s on and 5 min off continued to respond or improve in their response over the 1-year period. However, some patients may benefit from reductions in off time (increases in duty cycle). In a subgroup initially resistant to VNS, a change in off time to ≤1.1 min off did result in significant improvements in efficacy.

Gabapentin (GBP) has shown antiepileptic efficacy and good tolerance in clinical trials. Much remains to be learned about its clinical use. As a participating center in the US Gabapentin Study Group, we report observations that have practical implications for patient management. Twenty-three patients with intractable partial-onset seizures initiated open-label treatment after a blinded placebo-controlled add-on dose efficacy study. In the titration phase, GBP and concurrent antiepileptic drugs (AEDs) were adjusted to achieve optimal efficacy on maximally tolerated GBP doses. Nine patients had no significant improvement in seizure control and discontinued GBP. The remaining 14 patients were observed while treated long-term with stable-dose GBP and concurrent AEDs. Improvement was maintained as long as patients were followed: < or = 4 years. The protocol-allowed upper dose limit, 2,400 mg/day, was well tolerated by 16 of 23 patients, indicating that higher doses may be tolerated. GBP discontinuation did not cause rebound increases in seizure frequency. The most common adverse events (AEs) (in 14 of 23) were similar to those induced by concurrent AEDs and responded to reduction of concurrent AEDs. Many patients reported positive psychostimulatory effects. These observations extend previous findings indicating that GBP is an effective and well-tolerated drug for treatment of partial-onset seizures.

Summary: The pathophysiologic and clinical significance of periodic lateralized epileptiform discharges (PLEDs) is unclear; whether PLEDs represent an ictal condition that should be treated remains uncertain. We performed FDG-positron emission computed tomography (FDG-ET) in a patient with PLEDs at 3 days, 18 days, and 10 weeks after onset. During left temporal PLEds, the initial scan showed intense hypermetabolism of the left mesiotemporal region. The second scan, performed when PLEDs were resolving, displayed reduced hypermetabolism. The follow-up scan, when PLEDs had resolved, showed left temporal hypometabolism. These findings, together with clinical evidence from the literature, are compatible with the interpretation that PLEDs represent partial status epilepticus (SE); whether vigorous therapy is required to prevent neuronal damage from this focal seizure activity remains uncertain.