Faculty Bibliography

OBJECTIVE: To describe the phenomenology of monitored sudden unexpected death in epilepsy (SUDEP) occurring in the interictal period where death occurs without a seizure preceding it. METHODS: We report a case series of monitored definite and probable SUDEP where no electroclinical evidence of underlying seizures was found preceding death. RESULTS: Three patients (two definite and one probable) had SUDEP. They had a typical high SUDEP risk profile with longstanding intractable epilepsy and frequent generalized tonic-clonic seizures (GTCS). All patients had varying patterns of respiratory and bradyarrhythmic cardiac dysfunction with profound electroencephalography (EEG) suppression. In two patients, patterns of cardiorespiratory failure were similar to those seen in some patients in the Mortality in Epilepsy Monitoring Units Study (MORTEMUS). SIGNIFICANCE: SUDEP almost always occur postictally, after GTCS and less commonly after a partial seizure. Monitored SUDEP or near-SUDEP cases without a seizure have not yet been reported in literature. When nonmonitored SUDEP occurs in an ambulatory setting without an overt seizure, the absence of EEG information prevents the exclusion of a subtle seizure. These cases confirm the existence of nonseizure SUDEP; such deaths may not be prevented by seizure detection-based devices. SUDEP risk in patients with epilepsy may constitute a spectrum of susceptibility wherein some are relatively immune, death occurs in others with frequent GTCS with one episode of seizure ultimately proving fatal, while in others still, death may occur even in the absence of a seizure. We emphasize the heterogeneity of SUDEP phenomena.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of epilepsy-related mortality. We hypothesized that electrocardiography (ECG) features may distinguish SUDEP cases from living subjects with epilepsy. Using a matched case-control design, we compared ECG studies of 12 consecutive cases of SUDEP over 10 years and 22 epilepsy controls matched for age, sex, epilepsy type (focal, generalized, or unknown/mixed type), concomitant antiepileptic, and psychotropic drug classes. Conduction intervals and prevalence of abnormal ventricular conduction diagnosis (QRS >/=110 msec), abnormal ventricular conduction pattern (QRS <110 msec, morphology of incomplete right or left bundle branch block or intraventricular conduction delay), early repolarization, and features of inherited cardiac channelopathies were assessed. Abnormal ventricular conduction diagnosis and pattern distinguished SUDEP cases from matched controls. Abnormal ventricular conduction diagnosis was present in two cases and no controls. Abnormal ventricular conduction pattern was more common in cases than controls (58% vs. 18%, p = 0.04). Early repolarization was similarly prevalent in cases and controls, but the overall prevalence exceeded that of published community-based cohorts.

INTRODUCTION: Tuberous Sclerosis Complex (TSC) has an incidence of 1/6,000 in the general population. Overall care may be very complex and costly. We examine trends in healthcare utilization and outcomes of TSC patients over the last decade. METHODS: The National Inpatient Sample (NIS) database for inpatient hospitalizations was searched for admission of patients with TSC. RESULTS: During 2000-2010, the NIS captured 5655 TSC patients. The majority patients were admitted to teaching hospitals (71.7%). Over time, the percentage of craniotomies performed per year remained stable (p = 0.351). Relevant diagnoses included neuro-oncologic pathology (5.4%), hydrocephalus (6.5%), and epilepsy (41.2%). Hydrocephalus significantly increased length of stay and hospital charges. A higher percentage of patients who underwent craniotomy had hydrocephalus (29.8% versus 5.3%; p < 0.001), neuro-oncologic pathology (43.5% versus 3.4%; p < 0.001), other cranial pathologies (4.2% versus 1.2%; p < 0.001), and epilepsy (61.4% versus 40.1%; p < 0.001). CONCLUSION: Our study identifies aspects of inpatient healthcare utilization, outcomes, and cost of a large number of patients with TSC. These aspects include related diagnoses and procedures that contribute to longer length of stay, increased hospital cost, and increased in-hospital mortality, which can inform strategies to reduce costs and improve care of patients with TSC.

PURPOSE: An emerging approach in medical genetics is to identify de novo mutations in patients with severe early-onset genetic disease that are absent in population controls and in the patient's parents. This approach, however, frequently misses post-zygotic "mosaic" mutations that are present in only a portion of the healthy parents' cells and are transmitted to offspring. METHODS: We constructed a mosaic transmission screen for variants that have an ~50% alternative allele ratio in the proband but are significantly less than 50% in the transmitting parent. We applied it to two family-based genetic disease cohorts consisting of 9 cases of sudden unexplained death in childhood (SUDC) and 338 previously published cases of epileptic encephalopathy. RESULTS: The screen identified six parental-mosaic transmissions across the two cohorts. The resultant rate of ~0.02 identified transmissions per trio is far lower than that of de novo mutations. Among these transmissions were two likely disease-causing mutations: an SCN1A mutation transmitted to an SUDC proband and her sibling with Dravet syndrome, as well as an SLC6A1 mutation in a proband with epileptic encephalopathy. CONCLUSION: These results highlight explicit screening for mosaic mutations as an important complement to the established approach of screening for de novo mutations.Genet Med advance online publication 30 December 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.155.

Interactions between the hippocampus and the cortex are critical for memory. Interictal epileptiform discharges (IEDs) identify epileptic brain regions and can impair memory, but the mechanisms by which they interact with physiological patterns of network activity are mostly undefined. We show in a rat model of temporal lobe epilepsy that spontaneous hippocampal IEDs correlate with impaired memory consolidation, and that they are precisely coordinated with spindle oscillations in the prefrontal cortex during nonrapid-eye-movement (NREM) sleep. This coordination surpasses the normal physiological ripple-spindle coupling and is accompanied by decreased ripple occurrence. IEDs also induce spindles during rapid-eye movement (REM) sleep and wakefulness-behavioral states that do not naturally express these oscillations-by generating a cortical 'down' state. In a pilot clinical examination of four subjects with focal epilepsy, we confirm a similar correlation of temporofrontal IEDs with spindles over anatomically restricted cortical regions. These findings imply that IEDs may impair memory via the misappropriation of physiological mechanisms for hippocampal-cortical coupling, which suggests a target for the treatment of memory impairment in epilepsy.

Our objective was to define the EEG features during sleep of children with neurodevelopmental disorders due to copy number gains of 15q11-q13 (Dup15q). We retrospectively reviewed continuous EEG recordings of 42 children with Dup15q (mean age: eight years, 32 with idic15), and data collected included background activity, interictal epileptiform discharges, sleep organization, and ictal activity. Three patterns were recognized: This is the first report of electroencephalographic patterns during sleep of children with Dup15q reporting alpha-delta rhythms, CSWS, and high amplitude fast frequencies. Alpha-delta rhythms are described in children with dysautonomia and/or mood disorders and CSWS in children with developmental regression. The significance of these findings in cognitive function and epilepsy for the children in our cohort needs to be determined with follow-up studies.

A dominant theory, based on electrophysiological and lesion evidence from nonhuman primate studies, posits that the dorsolateral prefrontal cortex (dlPFC) stores and maintains working memory (WM) representations. Yet, neuroimaging studies have consistently failed to translate these results to humans; these studies normally find that neural activity persists in the human precentral sulcus (PCS) during WM delays. Here, we attempt to resolve this discrepancy. To test the degree to which dlPFC is necessary for WM, we compared the performance of patients with dlPFC lesions and neurologically healthy controls on a memory-guided saccade task that was used in the monkey studies to measure spatial WM. We found that dlPFC damage only impairs the accuracy of memory-guided saccades if the damage impacts the PCS; lesions to dorsolateral dlPFC that spare the PCS have no effect on WM. These results identify the necessary subregion of the frontal cortex for WM and specify how this influential animal model of human cognition must be revised. SIGNIFICANCE STATEMENT: High-level cognition depends on working memory (WM) as a critical building block, and many symptoms of psychiatric disorders may be the direct result of impaired WM. Canonical theory posits a critical role for the dorsolateral prefrontal cortex (dlPFC) in WM based on studies of nonhuman primates. However, we find that spatial WM in humans is intact after dlPFC damage unless it impacts the more caudal PCS. Therefore, the human dlPFC is not necessary for spatial WM and highlights the need for careful translation of animal models of human cognition.