Vagus nerve stimulation for essential tremor: a pilot efficacy and safety trial.

OBJECTIVE: To assess the safety and efficacy of vagus nerve stimulation (VNS) for essential tremor (ET). METHODS: This was a pilot open-treatment trial at three centers, with masked videotape tremor assessments. Inclusion required a severity score of 3 or 4 on the Tremor Rating Scale (TRS) in one or both hands. At baseline, tremor was assessed with TRS and Unified Tremor Rating Assessment (UTRA), accelerometry, and a videotape protocol. The VNS device was implanted with leads placed around the left cervical vagus nerve. Stimulation was adjusted over 4 weeks before the repeat tremor assessments. Two raters masked to the study visit scored the videotapes. RESULTS: Nine subjects participated, with a mean age of 65 years and a mean age at onset of tremor of 24. Investigators rated hand tremor as mildly improved (TRS 2.3 +/- 0.7 during VNS vs 3.0 +/- 0.4 during baseline, p = 0.06). Accelerometry-measured total power improved 50.2 +/- 31.8% (p < 0.01). Videotape tremor scores were highly correlated between the masked raters and revealed no changes in tremor scores with treatment. VNS was well tolerated, with the most common adverse events being stimulation related. CONCLUSIONS: VNS was judged by investigators to mildly improve upper extremity tremor. This finding was not confirmed in videotape scoring by masked raters. VNS is not likely to have a clinically meaningful effect on ET.

Vagus nerve stimulation: analysis of device parameters in 154 patients during the long-term XE5 study.

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 < 1.1 min. RESULTS: Output current, pulse duration, frequency, and off time changed significantly between the 3- and 12-month long-term follow-ups. For the group as a whole, changes in device settings were not correlated with an improvement in efficacy. However, a significant improvement in efficacy occurred in a subgroup whose off time was reduced to < or = 1.1 min. In this group, the median reduction in seizures improved from 21% before the change in off time, to 39% after the change in off time (Wilcoxon Signed-Rank, p = 0.011). The responder rate (> 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 < or = 1.1 min off did result in significant improvements in efficacy.

Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression in rats.

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.

Suppression of harmaline-induced tremor in rats by vagus nerve stimulation.

We studied whether vagus nerve stimulation could suppress tremor in the harmaline tremor model in the rat. Animals were chronically implanted with helical leads around the left vagus nerve and a disk-shaped electrode positioned subcutaneously in the dorsal neck. Harmaline-induced tremor was recorded on a physiograph while each animal received a sequence of five 20-minute trials. Each trial consisted of five minutes of pre-stimulation baseline, five minutes of vagus nerve stimulation, and ten minutes of post-stimulation. Vagus nerve stimulation significantly suppressed harmaline-induced tremor. The suppressive effect was present within the first minute of stimulation and was reproducible across the five trials of the study. The results of this study suggest that the central generator or expression of tremor in the harmaline animal model can be suppressed by vagus nerve stimulation.

Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures.

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 EO5 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.

Seizure suppression by systemic epinephrine is mediated by the vagus nerve.

The present study investigated the seizure-suppressing effects of systemic epinephrine. Rats were injected with epinephrine, and seizures induced with pentylenetetrazol. Seizure severities were significantly reduced 15 min after 1 mg/kg of epinephrine. Severing the subdiaphragmatic vagus nerves abolished this effect, demonstrating that epinephrine-induced seizure suppression is mediated by subdiaphragmatic vagal afferents. The development of novel anti-epileptic drugs that exploit this peripheral pathway may yield new seizure treatments.

Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome.

Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from a deletion/mutation in maternal chromosome 15q11-13. The genes in 15q11-13 contributing to the full array of the clinical phenotype are not fully identified. This study examines whether a loss or reduction in the GABAA receptor beta3 subunit (GABRB3) gene, contained within the AS deletion region, may contribute to the overall severity of AS. Disrupting the gabrb3 gene in mice produces electroencephalographic abnormalities, seizures, and behavior that parallel those seen in AS. The seizures that are observed in these mice showed a pharmacological response profile to antiepileptic medications similar to that observed in AS. Additionally, these mice exhibited learning and memory deficits, poor motor skills on a repetitive task, hyperactivity, and a disturbed rest-activity cycle, features all common to AS. The loss of the single gene, gabrb3, in these mice is sufficient to cause phenotypic traits that have marked similarities to the clinical features of AS, indicating that impaired expression of the GABRB3 gene in humans probably contributes to the overall phenotype of Angelman syndrome. At least one other gene, the E6-associated protein ubiquitin-protein ligase (UBE3A) gene, has been implicated in AS, so the relative contribution of the GABRB3 gene alone or in combination with other genes remains to be established.

A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.

BACKGROUND AND METHODS: Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. RESULTS: Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. CONCLUSIONS: As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.

OBJECTIVE: The purpose of this multicenter, add-on, double-blind, randomized, active-control study was to compare the efficacy and safety of presumably therapeutic (high) vagus nerve stimulation with less (low) stimulation. BACKGROUND: Chronic intermittent left vagus nerve stimulation has been shown in animal models and in preliminary clinical trials to suppress the occurrence of seizures. METHODS: Patients had at least six partial-onset seizures over 30 days involving complex partial or secondarily generalized seizures. Concurrent antiepileptic drugs were unaltered. After a 3-month baseline, patients were surgically implanted with stimulating leads coiled around the left vagus nerve and connected to an infraclavicular subcutaneous programmable pacemaker-like generator. After randomization, device initiation, and a 2-week ramp-up period, patients were assessed for seizure counts and safety over 3 months. The primary efficacy variable was the percentage change in total seizure frequency compared with baseline. RESULTS: Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group (102 patients, ages 15 to 60 year; p = 0.04). The high-stimulation group also had greater improvements on global evaluation scores, as rated by a blinded interviewer and the patient. High stimulation was associated with more voice alteration and dyspnea. No changes in physiologic indicators of gastric, cardiac, or pulmonary functions occurred. CONCLUSIONS: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior.

gamma-Aminobutyric acid type A receptors (GABA(A)-Rs) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system. The beta3 subunit is an essential component of the GABA(A)-R in many brain regions, especially during development, and is implicated in several pathophysiologic processes. We examined mice harboring a beta3 gene inactivated by gene targeting. GABA(A)-R density is approximately halved in brain of beta3-deficient mice, and GABA(A)-R function is severely impaired. Most beta3-deficient mice die as neonates; some neonatal mortality, but not all, is accompanied by cleft palate. beta3-deficient mice that survive are runted until weaning but achieve normal body size by adulthood, although with reduced life span. These mice are fertile but mothers fail to nurture offspring. Brain morphology is grossly normal, but a number of behaviors are abnormal, consistent with the widespread location of the beta3 subunit. The mice are very hyperactive and hyperresponsive to human contact and other sensory stimuli, and often run continuously in tight circles. When held by the tail, they hold all paws in like a ball, which is frequently a sign of neurological impairment. They have difficulty swimming, walking on grids, and fall off platforms and rotarods, although they do not have a jerky gait. beta3-deficient mice display frequent myoclonus and occasional epileptic seizures, documented by electroencephalographic recording. Hyperactivity, lack of coordination, and seizures are consistent with reduced presynaptic inhibition in spinal cord and impaired inhibition in higher cortical centers and/or pleiotropic developmental defects.

Functional mapping of the early stages of status epilepticus: a 14C-2-deoxyglucose study in the lithium-pilocarpine model in rat.

Continuous convulsive activity in status epilepticus generally does not occur suddenly in response to the inciting epileptogenic agent, but is rather the culmination of a stereotyped sequence of stages. Initially seizures are discrete, then undergo waxing-and-waning of convulsive/electroencephalographic severity. Following a transitional EEG-recorded fast-and-slow spiking phase, continuous fast spiking with invariant convulsive behavior ensues. We sought to map the seizure anatomic substrates corresponding to these stages, utilizing the 14C-2-deoxyglucose technique, in order to make inferences about underlying mechanisms. The lithium-pilocarpine status epilepticus model in rat was employed. Cerebral autoradiographs associated with discrete seizures revealed non-uniform cerebral metabolic activation, with rostral cortical and olfactory areas especially involved. Portions of basal ganglia were also activated, consistent with projections from seizure-activated areas. Successive stages of status entry displayed additional limbic and cortical activation, along with subcortical projection sites, so that by fast-and-slow spiking most forebrain areas were recruited. Based on these results, a model is proposed whereby cyclical seizure-attenuating mechanisms cause, in the initial stages of status entry, fluxing of seizure anatomic extents between small and large cerebral domains, with corresponding cycling of convulsive severity. In the later stages of status entry, these mechanisms become ineffective, resulting in steady-state maximal forebrain recruitment, associated with continuous and invariant convulsive behavior and electrographic fast spiking.

Functional mapping of the late stages of status epilepticus in the lithium-pilocarpine model in rat: a 14C-2-deoxyglucose study.

Pilocarpine administration to lithium chloride-pretreated rats results initially in discrete convulsive seizures, each behaviorally and electroencephalographically terminated, which then progress to convulsive activity with waxing-and-waning behavioral and electrographic severity; finally, a continuous convulsive state ensues, associated electrographically with continuous fast spiking. This stage does not last indefinitely but is followed by a dramatic electrographic change to periodic epileptiform discharges. The purpose of the present study was to determine with the 14C-2-deoxyglucose functional mapping technique what changes occur in the seizure anatomic substrate during and after this transition, in order to enable inferences about underlying mechanisms. Behavior associated with early and late continuous fast spiking consisted of head twitching; corresponding deoxyglucose autoradiographs displayed seizure-induced intense glucose utilization in most forebrain areas; extranigral brainstem was normal. At 2-3 h of status, fast spiking became interrupted by flat periods; periodic complexes soon dominated the electroencephalogram. Behaviorally, convulsive severity increased. Despite this dramatic electrographic evolution, little change in generalized forebrain metabolic hyperactivation occurred, except that the zona incerta/pretectal/superior colliculus complex displayed markedly increased activity. Deoxyglucose studies in late stages of periodic epileptiform discharges established a sequence of further changes. In late periodic discharges with clonic jerks, at 4 h after status entry, generalized forebrain hyperactivation still prevailed, but to a lesser degree than in early periodic discharges with clonic jerks. At a still later stage, late periodic discharges, subtle convulsive, autoradiographs revealed constriction of the seizure-activated anatomic substrate: hyperactivation was lost in most of neocortex and thalamus, and in caudal olfactory structures, cortical amygdala, and entorhinal areas, but retained in deep occipital cortex and many limbic areas. In the last stage, late periodic discharges, electrical, not associated with convulsive behavior, autoradiographs revealed residual activation in only Ammon's horn; in contrast, much of the forebrain displayed below-normal glucose utilization. These results demonstrate that in the later stages of status epilepticus, the transition from fast spiking to periodic complexes is not associated with a reduction in the seizure anatomic substrate. The electrographic entity of periodic epileptiform discharges is not anatomically or behaviorally homogeneous, but proceeds through successive stages characterized initially by a reduction of glucose utilization within generalized seizure-activated forebrain, then a contraction of the seizure anatomic substrate. Possible mechanisms underlying the transition to periodic complexes are discussed.

Mapping of limbic seizure progressions utilizing the electrogenic status epilepticus model and the 14C-2-deoxyglucose method.

We have previously described a model of limbic status epilepticus in which chronic prolonged seizure states of immobile, exploratory, minor convulsive or clonic convulsive behavior are induced by intracerebral electrical stimulation; these states appear to belong to the same behavioral progression as kindled seizures. We postulated that the underlying seizure substrates, as mapped by the 14C-2-deoxyglucose method, should reflect a corresponding anatomic progression of discharge spread. Status epilepticus was induced in rat by pulsed-train current delivered for up to 90 min to one of several subcortical areas. Autoradiographs revealed that most of the observed patterns of seizure-induced metabolic activation comprised a hierarchical sequence, such that progressively more extensive patterns subsumed anatomic territories activated in less extensive patterns, thus allowing inferences as to the progression of discharge spread. In this sequence, the basolateral amygdala ipsilateral to the induction electrode was among the first structures to be activated. In successively larger activation patterns a small unilateral network related to basolateral amygdala was involved; this evolved through a transitional state to a unilateral extensive limbic pattern; which in turn was succeeded by bilateral extensive limbic activation. This hierarchical sequence culminated in a neocortical activation pattern, in which most of the forebrain was involved in intense seizure-induced activation. Seizure behaviors increased in severity in correspondence with the underlying seizure-activated anatomic substrate. In contrast, patterns of seizure activation were observed which did not fit within the early stages of the above sequence, although analysis indicates that the later stages of spread may be shared. The study of these patterns and those reported in the literature indicates that although limbic seizure networks may be anatomically distinct at their origination, further expansion is characterized by overlap; upon assumption of extensive patterns of activation the number of nuclei participating is so vast that the identity of the limbic originator is lost and common convulsive manifestations occur.

Rising dose study of safety and tolerance of flunarizine.

In a recent NIH-sponsored parallel-group placebo-controlled blinded study of flunarizine for the treatment of partial-onset seizures, the flunarizine serum concentration was controlled to a constant level among patients in order to reduce response variability. Flunarizine was found to exhibit modest anti-epileptic efficacy. A potential criticism of this study is that the chosen controlled concentration was too low to determine optimal efficacy. As a participating center in this study we investigated the effect of higher doses of open-label flunarizine on seizure frequency in 16 patients with refractory partial seizures. Following the completion of the blinded placebo/flunarizine phase, all patients were initiated at the flunarizine dose calculated to result in a serum concentration of 60 ng.ml-1. The dose was subsequently increased each 8-12 weeks to a maximum of 2.7 times the initial dose. On the initial maintenance flunarizine dose, seizure control was improved, with an average seizure reduction of 47% compared to pre-blinded-phase baseline. When higher doses were administered, adverse reactions were more common yet improved seizure control did not occur in most patients. These findings complement those of the concentration-controlled NIH study and suggest that appropriate flunarizine doses were utilized in that study.

A new, non-pharmacologic model of convulsive status epilepticus induced by electrical stimulation: behavioral/electroencephalographic observations and response to phenytoin and phenobarbital.

Much remains to be learned about mechanisms underlying entry into, and temporal progression of, status epilepticus (SE). This report describes a non-pharmacologic model of generalized convulsive SE in rat. Pulsed trains of suprathreshold electric current, were administered bilaterally to either of four rostral forebrain sites: orbital cortex, medial precentral cortex, deep prepiriform cortex, or rostral caudate-putamen (n = 8 per site). This induction method resulted in 30/32 animals attaining limb-clonic convulsive SE within a mean of 30-35 min for each forebrain site, with no differences between sites. Subsequent SE proceeded without further interventions, permitting observation of the natural course of progression. A stereotyped behavioral/electrographic sequence occurred, characterized by devolution. Behaviorally, animals progressed from predominantly limb clonus to head clonus, then to subtle twitching, and finally to electrical SE before cessation of spikes. The corresponding electrographic progression was from fast and slow spiking to periodic epileptiform discharges (PEDs). In 20 animals surviving to 48 h, pathologic damage affected mainly limbic sites; damage was related to total convulsive time rather than to clonic activity. High-dose phenobarbital but not phenytoin suppressed SE when given during orbital cortex-induced limb-clonic SE. These findings are compatible with human observations and indicate that this model will enable investigations of generalized SE mechanisms and evaluation of new therapeutic agents for refractory SE.

Efficacy and tolerance of long-term, high-dose gabapentin: additional observations.

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.

Dezinamide for partial seizures: results of an n-of-1 design trial.

BACKGROUND: Dezinamide (DZM, ADD 94057) is a potential antiepileptic drug that binds to the voltage-sensitive sodium channel and showed preliminary evidence of efficacy and safety in an open-label study. METHODS: Our double-blind, placebo-controlled trial at two sites used an n-of-1 (single-patient) design. All 15 patients had medically intractable partial-onset seizures and were comedicated with phenytoin (PHT) only. Treatment was for six 5-week periods (three active paired with three placebo in random sequence). Assuming nonlinear kinetics, we used an initial pharmacokinetic profile to estimate dosages for reaching target plasma concentrations of DZM. RESULTS: Statistically significant seizure reduction was found by both a randomization test (p = 0.0025) and a signed rank test (p = 0.048). Median seizure frequency decreased 37.9%, and 40% of patients had > 50% seizure reduction, both compared with placebo. Pharmacokinetic predictions were not accurate; mean plasma concentrations fell well below target values. Plasma PHT concentrations increased (mean = 17.1%) during DZM treatment. The most common adverse experiences were fatigue, light-headedness, and abnormal gait; five patients required DZM dosage reductions. CONCLUSIONS: DZM showed minimal clinical toxicity and significant efficacy despite lower plasma concentrations than predicted by pharmacokinetics. This trial establishes the suitability of the n-of-1 design to investigational antiepileptic drug trials.

Markedly increased mesiotemporal lobe metabolism in a case with PLEDs: further evidence that PLEDs are a manifestation of partial status epilepticus.

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-PET) 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.

Interictal spiking increases 2-deoxy[14C]glucose uptake and c-fos-like reactivity.

Although interictal spikes are thought to share pathophysiological mechanisms with partial-onset seizure discharges, positron emission tomographic studies of the interictal state have paradoxically shown focal hypometabolism whereas seizures produce hypermetabolism. To address this question, we performed functional mapping studies in an interictal spiking model in the rat. Recording screw electrodes were inserted through the skull bone so as to depress underlying cortex. Interictal spiking was subsequently induced by systemic administration of bicuculline methiodide. 2-deoxy[14C]glucose studies revealed increased glucose utilization in superficial and middle cortical layers at spiking screw sites. Nonspiking screw sites in the same animals and in controls did not show increased uptake. Convulsive seizures caused additional 2-deoxy[14C]glucose uptake at screw sites and in widespread forebrain areas. c-fos immunoreactivity occurred in superficial cortex at interictal spiking, but not nonspiking, sites. Convulsive seizures induced widespread forebrain c-fos immunoreactivity. These data suggest interictal epileptiform activity occurs in cells adjacent to cortical injury; these activate deeper layers via local connections. Interictal and ictal epileptiform states share common mechanisms, as both induce glucose hypermetabolism and immediate-early gene product activation. Possible reasons for failure to detect hypermetabolism in interictal human subjects are discussed.