Faculty Bibliography

OBJECTIVE:To investigate the cumulative probability of death and the standardised mortality ratio (SMR) in an adult drug-resistant epilepsy (DRE) population. METHODS:In two separate centres during 2003-2006, we identified a total of 433 patients with DRE defined as at least one seizure per month and failure of at least two antiepileptic drugs. These patients were subsequently followed for a total follow-up of 6 years. We examined the cumulative probability of death, using Kaplan-Meier methodology, and the SMR based on mortality data from the Social Security Death Index. Clinical predictors of death were evaluated using Cox regression analysis. RESULTS:The cumulative probability of death was 8.7% (95% CI 6.2% to 12.1%) at 6 years. The overall SMR was 2.4 (95% CI 1.7 to 3.3). It was 3.1; 95% CI 2.0 to 4.6 in subjects with remote or progressive aetiology and 1.7; 95% CI 0.8 to 2.8 in subjects with unknown aetiology. The SMR was significantly increased in those with a known remote aetiology (2.5; 95% CI (1.4 to 3.8)). Older age at enrolment and symptomatic generalised epilepsy syndrome were significant predictors of death. DISCUSSION/CONCLUSIONS:Mortality is increased in this drug-resistant population; largely driven by those with a known epilepsy aetiology. The increased mortality remains even after exclusion of those with a progressive aetiology. Previous studies of incident epilepsy cohorts revealed increased mortality that declines to near-normal levels after the first several years, but in our DRE cohort, mortality remains elevated despite a median duration of epilepsy of 25 years at study entry.

OBJECTIVES: To assess the efficacy and tolerability of add-on pregabalin controlled-release formulation (PGB-CR) (doses of 165 or 330 mg/day) in patients with partial-onset seizures (POS). METHODS: This was a randomized, double-blind (DB), parallel-group study of PGB-CR once-daily as adjunctive treatment in adults with treatment-resistant partial seizures. After an 8-week baseline period, eligible patients were randomized (1:1:1) to placebo, PGB-CR 165 mg, or PGB-CR 330 mg for 14 weeks, including a 2-week dose escalation. Primary endpoint was the loge -transformed 28-day seizure rate for all POS with observable component during the full 14-week double-blind treatment phase. Secondary endpoints included the 50% responder rate and percent change from baseline in 28-day POS rate. RESULTS: Three hundred twenty-three patients were randomized and received treatment; placebo (n = 110), PGB-CR 330 mg (n = 100), PGB-CR 165 mg (n = 113); and 287 (88.9%) completed the trial. The primary efficacy analysis result, expressed as percent reduction from placebo, was 13.1% and 1.0% for PGB-CR 330 mg and PGB-CR 165 mg, respectively, and was not statistically significant (p = 0.091, 0.908). The proportion of 50% responders was similar for placebo (35.8%) and 165 mg PGB-CR (37.8%) and nominally higher for 330 mg PGB-CR (45.9%, p = 0.125 compared to placebo). The LS mean estimates of the percent change from baseline for placebo (-5.7%) was nominally smaller than 165 mg PGB-CR (-15.0%, p = 0.540) and 330 mg PGB-CR (-31.5%, p = 0.079); however, the median percent changes from baseline were not as well differentiated (placebo, -35.4%; 165 mg PGB-CR, -38.0%; 330 mg PGB-CR -43.4%). Rates of adverse events (AEs) were low for placebo and study drug; the most frequent reported AEs were dizziness, somnolence, and fatigue, consistent with the immediate-release formulation. SIGNIFICANCE: Results from this trial did not demonstrate that PGB-CR is effective in reducing seizure frequency below that of placebo. Both doses of PGB-CR were shown to be safe and well-tolerated.

There is an urgent need for preclinical translational efforts to be realized as breakthroughs in therapy for the many patients with life-altering conditions affecting the CNS. Despite intensive efforts, few transformative therapies have emerged, and many new potential therapies that looked promising in preclinical development have failed in the clinic. In this Perspective, we suggest that if preclinical scientists partner early with clinical scientists, they can begin to envision the pathway forward for their work through clinical trials. Options might include determining the populations to be treated, issues of dose selection, timing of intervention, duration of intervention, and the availability of biomarkers. In addition, understanding other factors that impact the likelihood that a proof-of-concept trial can be performed, as well as other critical issues, will altogether increase the attractiveness of the project to investors and partners and will also increase the likelihood that the intervention will succeed in the clinic.

OBJECTIVE: There is not yet a clear consensus on the incidence of sudden unexpected death in epilepsy (SUDEP) or the extent of its burden on public health. In this systematic review, we seek to summarize the incidence of SUDEP and its age distribution, as well as the years of potential life lost and cumulative risks of SUDEP for persons with epilepsy. METHODS: We conducted a systematic search for epidemiologic studies of sudden death in epilepsy and rated their quality of evidence. We pooled data from comparable higher quality population-based studies of SUDEP incidence across all age groups, calculating the overall incidence of SUDEP per 100,000 population, and per 1,000 people with epilepsy. Using standard formulas, we also calculated the years of potential life lost and cumulative risks associated with SUDEP. RESULTS: SUDEP has an estimated overall crude annual incidence rate of 0.81 cases per 100,000 population, or 1.16 cases per 1,000 patients with epilepsy. Comparing years of potential life lost from SUDEP with selected other neurologic diseases, SUDEP ranks second only to stroke. SIGNIFICANCE: Despite limitations to the data on which our analysis is based, we conclude that the public health burden of SUDEP, which has previously been underappreciated, is substantial and deserves much more attention from clinicians, researchers, and the public health community. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Translation of successful target and compound validation studies into clinically effective therapies is a major challenge, with potential for costly clinical trial failures. This situation holds true for the epilepsies-complex diseases with different causes and symptoms. Although the availability of predictive animal models has led to the development of effective antiseizure therapies that are routinely used in clinical practice, showing that translation can be successful, several important unmet therapeutic needs still exist. Available treatments do not fully control seizures in a third of patients with epilepsy, and produce substantial side-effects. No treatment can prevent the development of epilepsy in at-risk patients or cure patients with epilepsy. And no specific treatment for epilepsy-associated comorbidities exists. To meet these demands, a redesign of translational approaches is urgently needed.

On April 30th, 2011 the National Institute of Neurological Disorders and Stroke (NINDS) held a workshop to identify key problems in recent epilepsy clinical trials and propose approaches to address the barriers that impede development of new therapeutic options for epilepsy. Preliminary recommendations were made for selection criteria for subjects entered into epilepsy trials that maximize the scientific impact of the trial and increase the ability to recruit appropriate subjects efficiently and safely. These recommendations were further refined by the authors following the workshop, and subsequently shared with all NINDS workshop participants and with the participants of the 2011 AED XI workshop on epilepsy trials (approximately 200 participants) for further comment. The working group agreed to a final set of criteria that include updated considerations of subject age, clinical semiology, EEG and imaging results, use of prior and current therapies, co-occurring conditions, and suicidality, among others.

Integrated data from three double-blind, randomized, placebo-controlled trials were analyzed to evaluate the efficacy and tolerability of ezogabine (EZG; US adopted name)/retigabine (RTG; international non-proprietary name) when used in combination with >/=1 sodium channel blocking antiepileptic drug (AED), >/=1 non-sodium channel blocking AED, or >/=1 AED from both the sodium channel and non-sodium channel mechanistic groups. Efficacy and tolerability appeared to be similar across all three groups of patients.

To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Delta9 -Tetrahydrocannabinol (Delta9 -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Delta9 -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Delta9 -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the alpha3 and alpha1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Delta9 -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.