Faculty Bibliography

OBJECTIVE: The Quality Standards Subcommittee of the American Academy of Neurology develops practice parameters as strategies for patient care based on analysis of evidence. For this practice parameter the authors reviewed available evidence relevant to evaluating adults presenting with an apparent unprovoked first seizure. METHODS: Relevant questions were defined and addressed by multiple searches of medical literature. Each article was then reviewed, abstracted, and classified using an established evidence scoring system. Conclusions and recommendations were based on a standard three-tiered scheme of evidence classification. RESULTS: For adults presenting with a first seizure, a routine EEG revealed epileptiform abnormalities in approximately 23% of patients, and these were predictive of seizure recurrence. A brain imaging study (CT or MRI) was significantly abnormal in 10% of patients, indicating a possible seizure etiology. Laboratory tests such as blood counts, blood glucose, and electrolyte panels were abnormal in up to 15% of individuals, but abnormalities were minor and did not cause the seizure. Overt clinical signs of infection such as fever typically predicted significant CSF abnormalities on lumbar puncture. Toxicology screening studies were limited, but report some positive tests. Recommendations: EEG should be considered as part of the routine neurodiagnostic evaluation of adults presenting with an apparent unprovoked first seizure (Level B). Brain imaging with CT or MRI should be considered as part of the routine neurodiagnostic evaluation of adults presenting with an apparent unprovoked first seizure (Level B). Laboratory tests, such as blood counts, blood glucose, and electrolyte panels (particularly sodium), lumbar puncture, and toxicology screening may be helpful as determined by the specific clinical circumstances based on the history, physical, and neurologic examination, but there are insufficient data to support or refute recommending any of these tests for the routine evaluation of adults presenting with an apparent first unprovoked seizure (Level U)

The use of antiepileptic drugs (AEDs) in pregnancy is associated with an increased risk of fetal malformations. Although it is known that AEDs may differ with respect to the type of malformations they can induce, earlier studies have generally lacked the power to demonstrate differences between AEDs in their overall teratogenic potential. Furthermore, there is an urgent need to assess the clinical teratogenic potential of the newer-generation AEDs. Epilepsy and pregnancy registries have been established to provide such information, which is essential for the rational management of women with epilepsy with childbearing potential. The registries also provide opportunities for additional studies of seizures observed during pregnancy and labor and, with the enrolled woman's consent, for separate studies on cognititve outcomes and pharmacogenetics. Although most are prospective, the existing registries vary somewhat in design, which needs to be considered when their results are compared. Some registries are driven by pharmaceutical companies (often compelled by national or international drug licensing agencies) and provide data on pregnancy outcome related to the sponsor's own product. Others are organized by independent research groups and are potentially more useful in that they publish comparative data. This review provides a critical discussion and comparison of important methodological aspects of AED and pregnancy registries along with a summary of results published so far

OBJECTIVE: We aimed to determine the likelihood of remission and its clinical predictors in adult patients meeting a strict definition of refractory epilepsy. We also wanted to investigate the influence of treatment regimen on remission. METHODS: A total of 246 patients with treatment refractory epilepsy (having at least 1 seizure per month and having not responded positively to at least 2 antiepileptic drugs) were identified in 2000 and followed for 3 years. We used Kaplan-Meier methods to estimate the rate of achieving a 6-month terminal seizure remission and Cox regression analysis to evaluate clinical predictors for seizure remission. RESULTS: The estimated 6-month terminal seizure remission rate was 19% (95% confidence interval, 14-26%) for all cases and 14% (95% confidence interval, 10-21%) when limited to those treated only with medication. Negative predictors for remission included a history of status epilepticus, younger age at intractability, number of failed drug therapies, and presence of mental retardation. No specific drug was significantly associated with remission, and frequently, no clear intervention led to terminal remission. INTERPRETATION: Fifteen percent (approximately 5% per year) of a drug refractory epilepsy population obtained a 6-month terminal seizure remission. Our results signify that no matter how many antiepileptic drug therapies have failed, there is always hope of a meaningful seizure remission in this population. Furthermore, we have elucidated four clinical predictors that can aid the epileptologist in prognostication

Despite the introduction of many second-generation antiepileptic drugs (AEDs) in the past 15 years, a third of patients with epilepsy remain refractory to available treatments, and newer and more effective therapies are needed. Although our understanding of the mechanisms of drug resistance is fragmented, novel AED targets have been identified, and models of refractory epilepsy have been developed that can help to select candidate compounds for development. There are more than 20 compounds with potential antiepileptic activity in various stages of clinical development, and for many of these promising clinical trial results are already available. Several incentives justify further investment into the discovery of newer and more effective AEDs. Moreover, developments in clinical trial methodology enable easier completion of proof-of-concept studies, earlier definition of the therapeutic potential of candidate compounds, and more efficient completion of trials for various epilepsy indications

PURPOSE: The goal of this study is to (1) provide clinically useful, previously unpublished comparative analyses of seizure-freedom rates for newer antiepileptic drugs (AEDs), and (2) recommend a standard for data presentation and analysis. METHODS: Data were reviewed from placebo-controlled adjunctive trials in refractory patients of gabapentin (GPN), lamotrigine (LTG), topiramate (TOP), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), zonisamide (ZNS), and pregabalin (PGB). Seizure-freedom analyses in these publications, if included at all, consistently included both patients who completed the trial, and those who dropped out prior to completion (last observation carried forward, LOCF). This has the potential to increase reported seizure-free outcomes. Pharmaceutical companies were contacted for the provision of unpublished seizure-free data in the patients who completed the entire study. RESULTS: In most cases, LOCF analysis produced a higher rate of seizure freedom compared to complete analysis. A total of 0%-1.1% of the LOCF population was seizure-free in the GPN trials (complete data not available). For the remaining AEDs, seizure-freedom results in the LOCF versus complete populations were: 0.7% versus 0.8% (LTG trial); 12% versus 2.6% (OXC trial); 3.6%-6.4% versus 3.9%-7.1% (LEV trial); 3.7%-7.9% versus 1.3%-1.4% (PGB trial); and 6.0% versus 3.0% (ZNS trial, minus titration period). CONCLUSIONS: By employing LOCF, a clinically unrealistic picture of seizure-free rates may be reported. Access to complete data is informative, as it includes only those patients who were able to tolerate the drug at doses that produced seizure freedom. Ideally, data from both ITT and complete analyses should be made available

PURPOSE: Carisbamate, a novel neuromodulatory agent with antiepileptic properties, was evaluated in patients with photoparoxysmal responses to intermittent photic stimulation (IPS) in this multicenter, non-randomized, single-blind, placebo-controlled, proof-of-concept study. METHODS: Eighteen Caucasian patients (14 females, 4 males) with a mean age of 30 years (range: 16-51 years) underwent standardized IPS under three eye conditions (during eye closure, eyes closed and eyes open) at hourly intervals for up to 8h after receiving placebo (Day 1), carisbamate (Day 2) and placebo (Day 3). Carisbamate was given at single doses of 250-1000 mg. All patients received one or two concomitant antiepileptic drugs, most commonly valproate. RESULTS: Carisbamate produced a dose-dependent reduction in photosensitivity in the 13 evaluable patients, with abolishment of photoparoxysmal responses in 3 patients and clinically significant suppression of such responses in 7 additional patients. Photosensitivity was abolished or reduced in all five patients in the 1000-mg dose group. The onset of carisbamate occurred rapidly, with clinically significant suppression achieved before or near the time peak plasma drug levels were reached. The duration of action was dose-related and long-lasting, with clinically significant reductions of photosensitivity observed for up to 32 h after doses of 750 or 1000 mg. Carisbamate was generally well tolerated, with dizziness and nausea reported more frequently after active drug than placebo. CONCLUSION: This study shows that carisbamate exhibits dose-related antiepileptic effects in the photosensitivity model. Randomized, controlled studies of carisbamate in epilepsy patients inadequately controlled by their existing AED therapy are warranted