David G. Vossler

Multiple Subpial Transections for Partial Seizures in Sensorimotor Cortex

We report six patients with complex partial seizures arising from the primary sensorimotor cortex who underwent invasive long-term ictal electroencephalogram/video monitoring and brain mapping and then multiple subpial transections. Although four patients demonstrated no abnormalities on magnetic resonance imaging, each patient showed moderate to marked gliosis in cortex biopsied from the site of ictal onset. Extensive preoperative and postoperative neuropsychological tests demonstrated no functional deficits resulting from surgery. Only one patient failed to derive significant postoperative seizure improvement, and he subsequently underwent additional subpial sectioning without further significant improvement. We propose a modification for this surgical technique and hypothesize that these patients may represent a syndrome of central cortical epilepsy.

Serum and CSF Glutamine Levels in Valproate‐related Hyperammonemic Encephalopathy

Summary:  Purpose: To investigate ammonia and glutamine levels in valproate (VPA)‐related hyperammonemic encephalopathy (VHE).

Cataplexy and monoamine oxidase deficiency in Norrie disease

Norrie disease (ND) is an X-linked recessive disorder causing ocular atrophy, mental retardation, deafness, and dysmorphic features. Virtually absent monoamine oxidase (MAO) type-A and -B activity has been found in some boys with chromosome deletions. We report the coexistence of cataplexy and abnormal REM sleep organization with ND. Three related boys, referred for treatment of medically refractory atonic spells and apneas, underwent extended EEG-video-polysomnographic monitoring. They demonstrated attacks of cataplexy and inappropriate periods of REM sleep during which they were unarousable. One boy also had generalized tonic-clonic seizures. Previous testing revealed that all three have complete ND gene deletions. In all subjects, platelet MAO-B activity was absent, serum serotonin levels were markedly increased, and plasma catecholamine levels were normal. Data from the canine narcolepsy syndrome model implicate abnormal catecholaminergic and cholinergic activities in the pathogenesis of cataplexy. Our findings suggest that abnormal MA0 activity or an imbalance between serotonin and other neurotransmitter levels may be involved in the pathogenesis of human cataplexy.

Ictal stuttering A sign suggestive of psychogenic nonepileptic seizures

Objective: To determine if ictal stuttering (IS) is more common among patients with psychogenic nonepileptic seizures (PNES) than patients with epileptic seizures (ES). Methods: The authors prospectively reviewed the medical records, EEG-video recordings, and Minnesota Multiphasic Personality Inventory-2 (MMPI-2) scores of consecutive adults of normal intelligence diagnosed with either PNES or ES. Results: A total of 230 (117 PNES and 113 ES) patients were studied. PNES patients were older (p = 0.029), more likely to be female (p < 0.001), and had a shorter duration of seizure disorder (p < 0.001) than ES cases. Ten (8.5%) PNES subjects and no ES cases demonstrated IS. The proportion of patients with IS in these two groups was significantly different (p = 0.004). PNES patients with IS were of similar age as but had an even shorter (p = 0.010) duration of seizure disorder (mean = 3.0 years) than those without IS. Scores on the hypochondriasis, depression (D), and hysteria scales of the MMPI-2 were significantly higher among PNES subjects than in ES patients (p ≤ 0.002). However, seven PNES patients with IS had a lower mean score on the D scale than did 98 PNES cases without stuttering (p = 0.005). This produced a more sharply defined “conversion V” appearance on the MMPI-2 graph in the stutterers. Conclusions: Ictal stuttering was present in 8.5% of 117 consecutive patients with psychogenic nonepileptic seizures, but was not observed in a consecutive series of 113 adults with epileptic seizures. Patients with psychogenic nonepileptic seizures with ictal stuttering had a shorter duration of seizure disorder and a more prominent conversion profile on the Minnesota Multiphasic Personality Inventory than either patients with psychogenic nonepileptic seizures without stuttering or subjects with epileptic seizures.

Intracranial EEG in Temporal Lobe Epilepsy: Location of Seizure Onset Relates to Degree of Hippocampal Pathology

Summary:  Purpose: To determine whether the specific location of electrographic seizure onset in the temporal lobe is related to hippocampal pathology in temporal lobe epilepsy (TLE).

Zonisamide for the treatment of myoclonic seizures in progressive myoclonic epilepsy: an open-label study

PURPOSE To examine the safety and efficacy of zonisamide in treating myoclonic seizures associated with progressive myoclonic epilepsy (PME), in an open-label setting. METHODS Thirty patients with refractory PME (aged > or = 5 years), who were taking up to three antiepileptic drugs, received adjunctive zonisamide (< or = 6 mg/kg/day) therapy for 16 weeks. Myoclonic seizures were recorded daily over a 24-hour period or in 10-minute epochs in the morning, afternoon, and evening. Safety was assessed via adverse events (AEs); efficacy was measured by the percentage of patients experiencing a > or = 50% decrease in myoclonic seizure frequency from baseline. RESULTS Treatment-related AEs, experienced by 53% (n = 16/30) of patients, led to five patients discontinuing zonisamide. The most common AEs were decreased appetite, somnolence, and asthenia. Overall, 36% of patients (n = 10/28) had a > or = 50% reduction in myoclonic seizure frequency. CONCLUSIONS These results suggest that zonisamide may be useful in the treatment of patients with PME. However, due to the size and open-label character of this study, further research is required.

Epilepsy in Schizencephaly: Abnormal Cortical Organization Studied by Somatosensory Evoked Potentials

Summary: Median nerve short‐latency somatosensory evoked potentials (MN‐SSEP) are recorded from the scalp to assess parietal lobe function and from the cortex to identify primary sensory and motor areas before epilepsy surgery. Nevertheless, the origins of many of the MN‐SSEP waveforms and the reliability of this technique for localizing the central sulcus are not definitively known. We studied a child with a unilateral, closed, right parietal schizencephalic cleft and frequent simple partial seizures before the child underwent cortical resection. The sensory examination, neuroimaging, and electrical brain stimulation findings indicated a normal thalamus and an abnormal parietal lobe. Scalp‐recorded MN‐SSEPs showed intact widespread N18 potentials bilaterally, but absent right, although normal left parietal N20 and P27 waveforms. Cortically recorded MN‐SSEPs could not localize the central sulcus owing to an absence of the expected negative potential over the right postcentral gyrus and the presence of waves with abnormal latencies over the precentral cortex. These findings suggest that: (a) the N18 potential probably originates at or below the level of the thalamus, (b) the N20 and P27 peaks are most likely generated by parietal cortex or white matter, and (c) cortically recorded MN‐SSEPs can fail to localize the central sulcus before epilepsy surgery when congenital anomalies exist in the parietal lobe.

Nonepileptic seizures of physiologic origin

Abstract Because patients with NES are often misdiagnosed and treated as though they have ES, health care services may be inappropriately utilized. No accurate data are available regarding the prevalence of undiagnosed NES in the population. Using EEG-video monitoring, with supplementary physiologic parameters when indicated, we determined that 32% of 231 patients referred for a diagnosis of intractable seizures actually had NES. Patients with psychNES constituted 24% of the total group. Eighteen patients had physNES. Of the latter, 28% also had a known or suspected diagnosis of epilepsy. We reviewed the many physiologic causes of NES. In our experience, combining EEG-audio-video monitoring with other polygraphic techniques has been relatively simple and has allowed more appropriate or effective treatment in all patients with physNES.

AES Position Statement on Generic Substitution of Antiepileptic Drugs

Among the older antiepileptic drugs (AEDs), generic substitutes have been available for many years. Phenobarbital, synthesized in 1912, has long been available in generic form, and brand-name Luminal was discontinued in the United States decades ago. Phenytoin, developed in 1938, was prescribed for decades as extended-release Dilantin Kapseals (Pfizer, Inc., New York), but it has largely been replaced by generic extended-release products. After approval in the United States of carbamazepine in 1974 and valproic acid in 1978, the branded forms had many years of patent exclusivity, but generic alternatives later became available. Beginning in 1993 with felbamate, a series of approximately 20 new brand-name AEDs were approved by the U.S. Food and Drug Administration (FDA). Patent duration after FDA approval of these newer AEDs varied, but all approved before 2005 are now available as generics. Typically, generic drugs are less expensive than the branded original, which encourages, or may mandate, the substitution of generics for the brand product to reduce pharmaceutical costs. For any drug, bioavailability is defined as the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action (1). In order for a generic AED to be approved by the FDA, manufacturers are required to show pharmaceutical equivalence and to demonstrate bioequivalence of the generic form to the original brand-name product. Pharmaceutical equivalence requires that the drug product contains the same active ingredient, dosage form and strength, and route of administration. However, it may differ in inactive ingredients (e.g., binders, excipients), manufacturing process, and physical appearance (1). Bioequivalence (BE) is achieved if the product exhibits no substantial difference in the rate and extent of drug absorption. BE is tested in single-dose pharmacokinetic generally involving 24 to 36 healthy subjects under both fed and fasting conditions (1). Statistically, the BE standard requires that the entire 90% confidence interval (CI) of the log-transformed ratios of the test/reference for the maximum plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC) fall within the bounds of 80% to 125%. This is based on the judgment that a difference <20% between products would not result in a clinically-significant problem. Therefore, the test product is not significantly less than reference (T/R = 80%) and a reference product is not significantly less than test (T/R = 80%). As all data are expressed as T/R, this becomes 100/80 or 125%. In a recent analysis of 258 BE studies of AEDs the 80% to 125% BE rule resulted in <15% variability in AUC and Cmax in 99% and 89%, respectively (2).

Core elements of epilepsy diagnosis and management: expert consensus from the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty

ABSTRACT Background: Although epilepsy is relatively common, only a limited number of specialized epilepsy centers exist in the United States. Therefore, epilepsy diagnosis and management frequently occur in the community setting. This can complicate patient management and suboptimal care is a potential concern. Delayed recognition and inadequate treatment increase the risk of subsequent seizures, brain damage, disability, and death from seizure-related injuries. To identify core elements of epilepsy management that should be offered to all patients, the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty assessed current practical issues and identified practices to improve patient care and outcomes. Scope: This paper presents a consensus opinion formed from a survey of 26 current LEAD faculty members, who answered 105 questions about epilepsy diagnosis and patient evaluation, treatment decisions, lifelong monitoring, and the management of special patient subgroups. Consensus agreement was concluded when ≥50% of the faculty provided the same answer. The results were compiled and areas of consensus are included in this report. The recommendations provided in this commentary are limited by the scope of the survey. Findings: Consensus was reached on several minimum standard patient management practices. Primary among these minimum standards of care is the need for diagnosis including a detailed medical history, neurological examination, discussions with caregivers, and diagnostic tests including electroencephalograms and magnetic resonance imaging. As the overall goals of therapy include seizure freedom, minimizing side effects, and improving quality of life and long-term safety, therapy decisions should consider parameters that affect these goals, including potential adverse effects of therapy. Antiepileptic drug selection should consider coexisting conditions for possible exacerbation of disease and potential drug–drug interactions. Conclusions: The core elements of epilepsy management identified here suggest minimum standards that can be used across all settings to improve consistency and quality of epilepsy diagnosis and care.