Faculty Bibliography

OBJECTIVE:To determine the impact of socioeconomic status (SES) on sudden unexpected death in epilepsy (SUDEP) rates. METHODS:We queried all decedents presented for medico-legal investigation at 3 medical examiner (ME) offices across the country (New York City, Maryland, San Diego County) in 2009 to 2010 and 2014 to 2015. We identified all decedents for whom epilepsy/seizure was listed as cause/contributor to death or comorbid condition on the death certificate. We then reviewed all available reports. Decedents determined to have SUDEP were included for analysis. We used median income in the ZIP code of residence as a surrogate for SES. For each region, zip code regions were ranked by median household income and divided into quartiles based on total population for 2 time periods. Region-, age-, and income-adjusted epilepsy prevalence was estimated in each zip code. SUDEP rates in the highest and lowest SES quartiles were evaluated to determine disparity. Examined SUDEP rates in 2 time periods were also compared. RESULTS:< 0.0001). CONCLUSION/CONCLUSIONS:ME-investigated SUDEP incidence was significantly higher in people with the lowest SES compared to the highest SES. The difference persisted over a 5-year period despite decreased overall SUDEP rates.

PURPOSE/OBJECTIVE:A phase I feasibility study to determine the accuracy of identifying seizures based on audio recordings. METHODS:We systematically generated 166 audio clips of 30 s duration from 83 patients admitted to an epilepsy monitoring unit between 1/2015 and 12/2016, with one clip during a seizure period and one clip during a non-seizure control period for each patient. Five epileptologists performed a blinded review of the audio clips and rated whether a seizure occurred or not, and indicated the confidence level (low or high) of their rating. The accuracy of individual and consensus ratings were calculated. RESULTS:The overall performance of the consensus rating between the five epileptologists showed a positive predictive value (PPV) of 0.91 and a negative predictive value (NPV) of 0.66. The performance improved when confidence was high (PPV of 0.96, NPV of 0.70). The agreement between the epileptologists was moderate with a kappa of 0.584. Hyperkinetic (PPV 0.92, NPV 0.86) and tonic-clonic (PPV and NPV 1.00) seizures were most accurately identified. Seizures with automatisms only and non-motor seizures could not be accurately identified. Specific seizure-related sounds associated with accurate identification included disordered breathing (PPV and NPV 1.00), rhythmic sounds (PPV 0.93, NPV 0.80), and ictal vocalizations (PPV 1.00, NPV 0.97). CONCLUSION/CONCLUSIONS:This phase I feasibility study shows that epileptologists are able to accurately identify certain seizure types from audio recordings when the seizures produce sounds. This provides guidance for the development of audio-based seizure detection devices and demonstrate which seizure types could potentially be detected.

OBJECTIVE:To assess relative rates and clinical features of patients with genetic generalized epilepsy (GGE), focal epilepsy (FE), and developmental encephalopathic epilepsy (DEE) in the North American SUDEP Registry (NASR). METHODS:We identified all adjudicated definite, definite plus, and probable sudden unexpected death in epilepsy (SUDEP) cases (n = 262) and determined epilepsy type (GGE, FE, or DEE) from medical record review including history, imaging and EEG results, genetics, and next-of-kin interviews. RESULTS:Of the 262 SUDEP cases, 41 occurred in GGE, 95 in FE, 24 in DEE, and 102 were unclassifiable. GGE cases comprised 26% of NASR cases with an epilepsy syndrome diagnosis. The relative frequency of FE:GGE was slightly lower (2.3:1) than in population cohorts (2.1-6:1). Compared to patients with FE, patients with GGE had similar (1) ages at death and epilepsy onset and rates of (2) terminal and historical antiseizure medication adherence; (3) abnormal cardiac pathology; (4) illicit drug/alcohol use histories; and (5) sleep state when SUDEP occurred. CONCLUSIONS:GGE cases were relatively overrepresented in NASR. Because GGEs are less often treatment-resistant than FE or DEE, seizure type rather than frequency may be critical. Many people with GGE predominantly have generalized tonic-clonic seizures (GTCS) when they have uncontrolled or breakthrough seizures, whereas patients with FE more commonly experience milder seizures. Future mechanistic SUDEP studies should assess primary and focal-to-bilateral GTCS to identify potential differences in postictal autonomic and arousal disorders and to determine the differential role that lifestyle factors have on breakthrough seizures and seizure types in GGE vs FE to effectively target SUDEP mechanisms and prevention.

Excess mortality due to epilepsy is greatest among young adults. However, the relative proportions of sudden unexpected death in epilepsy (SUDEP) and other epilepsy-related causes of death are not well defined. We prospectively adjudicated cause of death in all 18- to 45-year-olds with a history of seizure/epilepsy who underwent medicolegal investigation in San Diego County between 2014 and 2017. We identified 108 decedents with definite or probable epilepsy; 62% died from an epilepsy-related cause. SUDEP accounted for 42.6% (N = 46) of deaths, which were usually unwitnessed deaths, at home in bed. Other frequent causes of death were drug overdose (N = 23), suicide (N = 8), trauma (N = 8), and drowning (N = 6). SUDEP autopsies were similar to those of decedents from other causes. Most deaths in young adults with epilepsy that undergo medico-legal investigation are epilepsy-related, and SUDEP is the leading cause. Improved seizure control can potentially save many lives.

BACKGROUND:Early accounts of forced thought were reported at the onset of a focal seizure, and characterized as vague, repetitive, and involuntary intellectual auras distinct from perceptual or psychic hallucinations or illusions. Here, we examine the neural underpinnings involved in conceptual thought by presenting a series of 3 patients with epilepsy reporting intrusive thoughts during electrical stimulation of the left lateral prefrontal cortex (PFC) during invasive surgical evaluation. We illustrate the widespread networks involved through two independent brain imaging modalities: resting state functional magnetic resonance imaging (fMRI) (rs-fMRI) and task-based meta-analytic connectivity modeling (MACM). METHODS:We report the clinical and stimulation characteristics of three patients with left hemispheric language dominance who demonstrate forced thought with functional mapping. To examine the brain networks underlying this phenomenon, we used the regions of interest (ROI) centered at the active electrode pairs. We modeled functional networks using two approaches: (1) rs-fMRI functional connectivity analysis, representing 81 healthy controls and (2) meta-analytic connectivity modeling (MACM), representing 8260 healthy subjects. We also determined the overlapping regions between these three subjects' rs-fMRI and MACM networks through a conjunction analysis. RESULTS:We identified that left PFC was associated with a large-scale functional network including frontal, temporal, and parietal regions, a network that has been associated with multiple cognitive functions including semantics, speech, attention, working memory, and explicit memory. CONCLUSIONS:We illustrate the neural networks involved in conceptual thought through a unique patient population and argue that PFC supports this function through activation of a widespread network.

There have been few studies of agreement between seizure descriptions obtained from patients and observers. We investigated 220 patients and observers who completed structured questionnaires about patients' semiological seizure features at the initial clinical visit. Inter-rater reliability was assessed using Cohen's kappa and indices of positive and negative agreement. Patients and observers had excellent agreement on the presence of memory impairment and generalized shaking and stiffness during seizures. In addition, patients under-reported seizure descriptions more easily observed externally, whereas observers under-reported change in patient location at seizure end. These findings may guide interpretation of clinical histories obtain in epilepsy care.

Slow-oscillations and spindle activity during non-REM sleep have been implicated in memory consolidation. Closed-loop acoustic stimulation has previously been shown to enhance slow oscillations and spindle activity during sleep and improve verbal associative memory. We assessed the effect of closed-loop acoustic stimulation during a daytime nap on a virtual reality spatial navigation task in 12 healthy human subjects in a randomized within-subject crossover design. We show robust enhancement of slow-spindle activity during sleep. However, no effects on behavioral performance were observed when comparing real versus sham stimulation. To explore whether memory enhancement effects were task-specific and dependent on nocturnal sleep, in a second experiment with 19 healthy subjects, we aimed to replicate a previous study which used closed-loop acoustic stimulation to enhance memory for word pairs. Methods were as close as possible to the original study, except we used a double-blind protocol, in which both subject and experimenter were unaware of the test condition. Again, we successfully enhanced slow-spindle power, but again did not strengthen associative memory performance with stimulation. We conclude that enhancement of slow-spindle oscillations may be insufficient to enhance memory performance in spatial navigation or verbal association tasks, and provide possible explanations for lack of behavioral replication.SIGNIFICANCE STATEMENT Prior studies have demonstrated that a closed-loop acoustic pulse paradigm during sleep can enhance verbal memory performance. This technique has widespread scientific and clinical appeal due to its non-invasive nature and ease of application. We tested with a rigorous double-blind design whether this technique could enhance key sleep rhythms associated sleep-dependent memory performance. We discovered that we could reliably enhance slow and spindle rhythms, but did not improve memory performance in the stimulation condition compared to sham condition. Our findings suggest that enhancing slow-spindle rhythms is insufficient to enhance sleep-dependent learning.

Dynamic interactions between remote but functionally specialized brain regions enable complex information processing. This intercortical communication is disrupted in the neural networks of patients with focal epilepsy, and epileptic activity can exert widespread effects within the brain. Using large-scale human intracranial electroencephalography recordings, we show that interictal epileptiform discharges (IEDs) are significantly coupled with spindles in discrete, individualized brain regions outside of the epileptic network. We found that a substantial proportion of these localized spindles travel across the cortical surface. Brain regions that participate in this IED-driven oscillatory coupling express spindles that have a broader spatial extent and higher tendency to propagate than spindles occurring in uncoupled regions. These altered spatiotemporal oscillatory properties identify areas that are shaped by epileptic activity independent of IED or seizure detection. Our findings suggest that IED-spindle coupling may be an important mechanism of interictal global network dysfunction that could be targeted to prevent disruption of normal neural activity.

We report 13 SUDEP cases in the North American SUDEP Registry with both psychogenic nonepileptic seizures (PNES) and epileptic seizures (ES) among a consecutive series of 231 cases (excluding epileptic encephalopathies). On average, cases of PNES + ES died at a younger age (23 ± 11 years) than the ES-only cohort (30 ± 14 years), and died an average of 3 years after PNES diagnosis. We found no statistically significant confounding cardiac, respiratory, or psychiatric comorbidities and equal rates of anti-seizure medication adherence, although there was a trend for higher rates of psychiatric disorders in the PNES group. Our findings confirm that patients with comorbid ES and PNES can die from SUDEP and that there may be a high-risk period after the diagnosis of PNES is made in patients with comorbid ES. Such patients should be closely monitored and provided with coordinated care of both their epilepsy and psychiatric disorder(s).