Faculty Bibliography

PURPOSE: Nonrandomized studies of the relationship of antiepileptic drugs (AEDs) with sudden unexpected death in epilepsy (SUDEP) may be susceptible to confounding by tonic-clonic seizure frequency, polypharmacy, and other potential risk factors for SUDEP. We evaluated the risk of SUDEP with lamotrigine (LTG) compared to active comparators and placebo in randomized controlled clinical trials conducted by GlaxoSmithKline (GSK) between 1984 and 2009. METHODS: Among 7,774 subjects in 42 randomized clinical trials, there were 39 all-cause deaths. Ten deaths occurred >2 weeks after discontinuation of study medication and were excluded. Narrative summaries of deaths were independently reviewed by three clinical experts (TT, LH, DF), who were blinded to randomized treatment arm. The risk of definite or probable SUDEP was compared between treatment arms for each trial type (placebo-controlled, active-comparator, crossover), using exact statistical methods. KEY FINDINGS: Of 29 on-treatment deaths, eight were definite/probable SUDEP, four were possible SUDEP, and 17 were non-SUDEP. The overall, unadjusted rate of definite/probable SUDEP for LTG was 2.2 events per 1,000-patient years (95% confidence interval [95% CI] 0.70-5.4). The odds ratios (OR) for on-treatment, definite/probable SUDEP in LTG arms relative to comparator arms, adjusted for length of exposure and trial, were the following: placebo-controlled, OR 0.22 (95% CI 0.00-3.14; p = 0.26); active-comparator, OR 2.18 (95% CI 0.17-117; p = 0.89); and placebo-controlled cross-over, OR 1.08 (95% CI 0.00-42.2; p = 1.0). SIGNIFICANCE: There was no statistically significant difference in rate of SUDEP between LTG and comparator groups. However, the CIs were wide and a clinically important effect cannot be excluded.

OBJECTIVES: To determine continuous EEG (cEEG) patterns that may be unique to anti-NMDA receptor (NMDAR) encephalitis in a series of adult patients with this disorder. METHODS: We evaluated the clinical and EEG data of 23 hospitalized adult patients with anti-NMDAR encephalitis who underwent cEEG monitoring between January 2005 and February 2011 at 2 large academic medical centers. RESULTS: Twenty-three patients with anti-NMDAR encephalitis underwent a median of 7 (range 1-123) days of cEEG monitoring. The median length of hospitalization was 44 (range 2-200) days. Personality or behavioral changes (100%), movement disorders (82.6%), and seizures (78.3%) were the most common symptoms. Seven of 23 patients (30.4%) had a unique electrographic pattern, which we named "extreme delta brush" because of its resemblance to waveforms seen in premature infants. The presence of extreme delta brush was associated with a more prolonged hospitalization (mean 128.3 +/- 47.5 vs 43.2 +/- 39.0 days, p = 0.008) and increased days of cEEG monitoring (mean 27.6 +/- 42.3 vs 6.2 +/- 5.6 days, p = 0.012). The modified Rankin Scale score showed a trend toward worse scores in patients with the extreme delta brush pattern (mean 4.0 +/- 0.8 vs 3.1 +/- 1.1, p = 0.089). CONCLUSIONS: Extreme delta brush is a novel EEG finding seen in many patients with anti-NMDAR encephalitis. The presence of this pattern is associated with a more prolonged illness. Although the specificity of this pattern is unclear, its presence should raise consideration of this syndrome.

Sudden Unexpected Death in Epilepsy (SUDEP) is the most common cause of epilepsy related mortality in treatment resistant epilepsy. Most SUDEPs occur after one or more seizure(s) during sleep. Nocturnal seizures may go unrecognized. Respiratory depression in the peri-ictal period is one of the primary potential causes of SUDEP. Ictal and postictal apnea is often overlooked because it is not routinely assessed, but appears common and has been a recent focus of SUDEP research. We report a 37 year-old man who had central apnea as the initial manifestation of partial complex seizures associated with oxygen desaturation. This important pathophysiological consequence of a nocturnal complex seizure was identified by respiratory monitoring during a combined video EEG and sleep study. Diagnostic and therapeutic implications are discussed.

Clinical trials as part of antiepileptic drug development are increasingly expensive and complex, with many pitfalls that can derail even promising drugs and devices. Although a third of patients remain resistant to treatment, the availability of more than 20 approved antiepileptic drugs can reduce the incentive to enrol in trials of unproven agents, for which safety is not assured. The challenge of recruiting patients drives investigators to regions of the world where treatment options are more limited. This increases complexity and has potential implications for quality of the trial data. Furthermore, the availability of so many approved treatments raises questions about the ethics and safety of placebo-controlled trials in patients with epilepsy. Novel trial designs, such as time-to-event adjunctive therapy and historical-control monotherapy, might be more acceptable to patients and their doctors because they restrict exposure to placebo or ineffective treatments.

It has been suggested that alerting caregivers to seizure occurrence so they can deliver post-ictal care may be an effective way to prevent sudden unexpected death in epilepsy (SUDEP). We report two cases of SUDEP referred for an expert medical-legal review for which immediate post-ictal intervention was ineffective. In both patients, prompt resuscitation procedures by medical personnel after seizures failed to prevent SUDEP. These cases demonstrate that some seizures may lead to death even with expert intervention almost immediately after the seizure occurs. It is possible that for some SUDEP cases, seizures may trigger an irreversible cascade of cardiopulmonary and cerebral changes that lead to death. Further studies in the pathophysiology of SUDEP may help identify alternative prevention strategies.

Many studies have shown that patients with Alzheimer's disease (AD) are at increased risk for developing seizures and epilepsy. However, reported prevalence and incidence of seizures and relationship of seizures to disease measures such as severity, outcome, and progression vary widely between studies. We performed a literature review of the available clinical and epidemiological data on the topic of seizures in patients with AD. We review seizure rates and types, risk factors for seizures, electroencephalogram (EEG) studies, and treatment responses. Finally, we consider limitations and methodological issues. There is considerable variability in the reported prevalence and incidence of seizures in patients with AD-with reported lifetime prevalence rates of 1.5-64%. More recent, prospective, and larger studies in general report lower rates. Some, but not all, studies have noted increased seizure risk with increasing dementia severity or with younger age of AD onset. Generalized convulsive seizures are the most commonly reported type, but often historical information is the only basis used to determine seizure type and the manifestation of seizures may be difficult to distinguish from other behaviors common in demented patients. EEG has infrequently been performed and reported. Data on treatment of seizures in AD are extremely limited. Similarly, the relationship between seizures and cognitive impairment in AD is unclear. We conclude that the literature on seizures and epilepsy in AD, including diagnosis, risk factors, and response to treatment suffers from methodological limitations and gaps.