Faculty Bibliography

Sudden Unexplained Death in Childhood (SUDC) is the unexpected death of a child over age 12 months that remains unexplained after a thorough case investigation, including review of the child's medical history, circumstances of death, a complete autopsy and ancillary testing (1). First defined in 2005, SUDC cases are more often male, with death occurring during a sleep period, being found prone, peak winter incidence, associated with febrile seizure history in ~28% of cases and mild pathologic changes insufficient to explain the death (1, 2). There has been little progress in understanding the causes of SUDC and no progress in prevention. Despite reductions in sudden unexpected infant death (SUID) and other causes of mortality in childhood, the rate of SUDC has increased during the past two decades (3-5). In Ireland, SUID deaths were cut in half from 1994 to 2008 while SUDC deaths more than doubled (4). Surveillance issues, including lack of standardized certification practices, affect our understanding of the true magnitude of unexplained child deaths. Mechanisms underlying SUDC, like SUID, remain largely speculative. Limited and inconsistent evidence implicates abnormalities in brainstem autonomic and serotonergic nuclei, critical for arousal, cardiorespiratory control, and reflex responses to life-threatening hypoxia or hypercarbia in sleep (6). Abnormalities in medullary serotonergic neurons and receptors, as well as cardiorespiratory brainstem nuclei occur in some SUID cases, but have never been studied in SUDC. Retrospective, small SUDC studies with non-standardized methodologies most often demonstrate minor hippocampal abnormalities, as well as focal cortical dysplasia and dysgenesis of the brainstem and cerebellum. The significance of these findings to SUDC pathogenesis remains unclear with some investigators and forensic pathologists labeling these findings as normal variants, or potential causes of SUDC. The development of preventive strategies will require a greater understanding of underlying mechanisms.

One-third of epilepsy patients have drug-resistant epilepsy (DRE), which is often complicated by polydrug toxicity and psychiatric and cognitive comorbidities. Advances in understanding the microbiome and gut-brain-axis are likely to shed light on epilepsy pathogenesis, anti-seizure medication (ASM) resistance, and potential therapeutic targets. Gut dysbiosis is associated with inflammation, blood-brain barrier disruption, and altered neuromodulators. High-throughput and metagenomic sequencing has advanced the characterization of microbial species and functional pathways. DRE patients show altered gut microbiome composition compared to drug-sensitive patients and healthy controls. The ketogenic and modified Atkins diets can reduce seizures in some patients with DRE. These low-carbohydrate dietary therapies alter the taxonomic and functional composition of the gut microbiome, and composition varies between diet responders and nonresponders. Murine models suggest that specific phyla are necessary to confer efficacy from the diet, and antibiotic treatment may eliminate efficacy. The impact of diet might involve alterations in microbiota, promotion of select microbial interactions, and variance in brain neurotransmitter levels that then influence seizures. Understanding the mechanics of how diet manipulates seizures may suggest novel therapies. Most ASMs act on neuronal transmission via effects on ion channels and neurotransmitters. However, ASMs may also assert their effects via the gut microbiota. In animal models, the microbiota composition (eg, abundance of certain phyla) can vary with ASM active drug metabolites. Given the developing understanding of the gut microbiome in DRE, probiotics are another potential therapy. Probiotics alter the microbiota composition, and small studies suggest that these supplements can reduce seizures in some patients. DRE has enormous consequences to patients and society, and the gut microbiome holds promise as a potential therapeutic target. However, the exact mechanism and recognition of which patients are likely to be responders remain elusive. Further studies are warranted.

Physician-patient collaboration was recognized as a critical core of participatory medicine more than a century ago. However, the subsequent focus on scientific research to enable cures and increased dominance of physicians in health care subordinated patients to a passive role. This paternalistic model weakened in the past 50 years-as women, minorities, and the disabled achieved greater rights, and as incurable chronic diseases and unrelieved pain disorders became more prevalent-promoting a more equitable role for physicians and patients. By 2000, a shared decision-making model became the pinnacle for clinical decisions, despite a dearth of data on health outcomes, or the model's reliance on single patient or solo practitioner studies, or evidence that no single model could fit all clinical situations. We report about a young woman with intractable epilepsy due to a congenital brain malformation whose family and medical specialists used a collaborative decision-making approach. This model positioned the health professionals as supporters of the proactive family, and enabled them all to explore and co-create knowledge beyond the clinical realm. Together, they involved other members of the community in the decisions, while harnessing diverse relationships to allow all family members to achieve positive levels of health, despite the resistance of the seizures to medical treatment and the incurable nature of the underlying disease.

OBJECTIVE:To examine autonomic regulation of core body temperature, heart rate (HR), and breathing rate (BR) in response to moderately elevated ambient temperature or moderate physical exercise in a mouse model of Dravet syndrome (DS). METHODS:We studied video-EEG, ECG, respiration, and temperature in mice with global heterozygous Scn1a knockout (KO) (DS mice), interneuron specific Scn1a KO, and wildtype (WT) mice during exposure to increased environmental temperature and moderate treadmill exercise. RESULTS:Core body temperatures of WT and DS mice were similar during baseline. After 15 mins of heat exposure, the peak value was lower in DS than WT mice. In the following mins of heat exposure, the temperature slowly returned close to baseline level in WT, whereas it remained elevated in DS mice. KO of Scn1a in GABAergic neurons caused similar thermoregulatory deficits in mice. During exercise, the HR increase was less prominent in DS than WT mice. After exercise, the HR was significantly more suppressed in DS. The heart rate variability (HRV) was lower in DS than WT mice during baseline and higher in DS during exercise-recovery periods. SIGNIFICANCE/CONCLUSIONS:We found novel abnormalities that expand the spectrum of interictal, ictal, and postictal autonomic dysregulation in DS mice. During mild heat stress, there was a significantly blunted correction of body temperature, and a less suppression of both HR and respiration rate in DS than WT mice. These effects were seen in mice with selective KO of Scn1A in GABAergic neurons. During exercise stress, there was diminished increase in HR, followed by an exaggerated HR suppression and HRV elevation during recovery in DS mice compared to controls. These findings suggest that different environmental stressors can uncover distinct autonomic disturbances in DS mice. Interneurons play an important role in thermoregulation. Understanding the spectrum and mechanisms of autonomic disorders in DS may help develop more effective strategies to prevent seizures and SUDEP.

OBJECTIVES/OBJECTIVE:METHODS: We analyzed prospectively collected data in the Original and Offspring FHS cohorts. To determine the risk of developing epilepsy among participants with dementia and the risk of developing dementia among participants with epilepsy we used separate, nested, case-control designs and matched each case to 3 age-, sex- and FHS cohort-matched controls. We used Cox proportional hazards regression analysis, adjusting for sex and age. In secondary analysis, we investigated the role of education level and apolipoprotein ε4 allele status in modifying the association between epilepsy and dementia. RESULTS:= 0.001) compared to controls of the same educational attainment. CONCLUSIONS:There is a bi-directional association between epilepsy and dementia with either condition carrying a nearly 2-fold risk of developing the other when compared to controls.

Importance/UNASSIGNED:The true incidence of sudden unexplained death in childhood (SUDC), already the fifth leading category of death among toddlers by current US Centers for Disease Control and Prevention estimates, is potentially veiled by the varied certification processes by medicolegal investigative offices across the United States. Objective/UNASSIGNED:To evaluate the frequency of SUDC incidence, understand its epidemiology, and assess the consistency of death certification among medical examiner and coroner offices in the US death investigation system. Design, Setting, and Participants/UNASSIGNED:In this case series, 2 of 13 forensic pathologists (FPs) conducted masked reviews of 100 cases enrolled in the SUDC Registry and Research Collaborative (SUDCRRC). Children who died aged 11 months to 18 years from 36 US states, Canada, and the United Kingdom had been posthumously enrolled in the SUDCRRC by family members from 2014 to 2017. Comprehensive data from medicolegal investigative offices, clinical offices, and family members were reviewed. Data analysis was conducted from December 2014 to June 2020. Main Outcomes and Measures/UNASSIGNED:Certified cause of death (COD) characterized as explained (accidental or natural) or unexplained, as determined by SUDCRRC masked review process. Results/UNASSIGNED:In this study of 100 cases of SUDC (mean [SD] age, 32.1 [31.8] months; 58 [58.0%] boys; 82 [82.0%] White children; 92 [92.0%] from the United States), the original pathologist certified 43 cases (43.0%) as explained COD and 57 (57.0%) as unexplained COD. The SUDCRRC review process led to the following certifications: 16 (16.0%) were explained, 7 (7.0%) were undetermined because of insufficient data, and 77 (77.0%) were unexplained. Experts disagreed with the original COD in 40 cases (40.0%). These data suggest that SUDC incidence is higher than the current Centers for Disease Control and Prevention estimate (ie, 392 deaths in 2018). Conclusions and Relevance/UNASSIGNED:To our knowledge, this is the first comprehensive masked forensic pathology review process of sudden unexpected pediatric deaths, and it suggests that SUDC may often go unrecognized in US death investigations. Some unexpected pediatric deaths may be erroneously attributed to a natural or accidental COD, negatively affecting surveillance, research, public health funding, and medical care of surviving family members. To further address the challenges of accurate and consistent death certification in SUDC, future studies are warranted.

Circular RNAs (circRNAs) regulate mRNA translation by binding to microRNAs (miRNAs), and their expression is altered in diverse disorders, including cancer, cardiovascular disease, and Parkinson's disease. Here, we compare circRNA expression patterns in the temporal cortex and hippocampus of patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and healthy controls. Nine circRNAs showed significant differential expression, including circRNA-HOMER1, which is expressed in synapses. Further, we identified miRNA binding sites within the sequences of differentially expressed (DE) circRNAs; expression levels of mRNAs correlated with changes in complementary miRNAs. Gene set enrichment analysis of mRNA targets revealed functions in heterocyclic compound binding, regulation of transcription, and signal transduction, which maintain the structure and function of hippocampal neurons. The circRNA-miRNA-mRNA interaction networks illuminate the molecular changes in MTLE, which may be pathogenic or an effect of the disease or treatments and suggests that DE circRNAs and associated miRNAs may be novel therapeutic targets.

We compared sudden unexpected death in epilepsy (SUDEP) diagnosis rates between North American SUDEP Registry (NASR) epileptologists and original death investigators, to determine degree and causes of discordance. In 220 SUDEP cases with post-mortem examination, we recorded the epileptologist adjudications and medical examiner- and coroner- (ME/C) listed causes of death (CODs). COD diagnosis concordance decreased with NASR's uncertainty in the SUDEP diagnosis: highest for Definite SUDEP (84%, n = 158), lower in Definite Plus (50%, n = 36), and lowest in Possible (0%, n = 18). Rates of psychiatric comorbidity, substance abuse, and toxicology findings for drugs of abuse were all higher in discordant cases than concordant cases. Possible SUDEP cases, an understudied group, were significantly older, and had higher rates of cardiac, drug, or toxicology findings than more certain SUDEP cases. With a potentially contributing or competing COD, ME/Cs favored non-epilepsy-related diagnoses, suggesting a bias toward listing CODs with structural or toxicological findings; SUDEP has no pathognomonic features. A history of epilepsy should always be listed on death certificates and autopsy reports. Even without an alternate COD, ME/Cs infrequently classified COD as "SUDEP." Improved collaboration and communication between epilepsy and ME/C communities improve diagnostic accuracy, as well as bereavement and research opportunities.

PURPOSE/OBJECTIVE:Surgical planning for people with drug resistant non-lesional focal epilepsy can be challenging. Prior studies focus on cases that are only MRI-negative or MRI-negative with PET-positive imaging, but little is known about outcomes in patients with non-lesional findings on both MRI and PET imaging. In this study, we investigate 5-year surgical outcomes in patients who underwent epilepsy surgery for drug resistant MRI/PET-negative focal epilepsy. METHODS:We collected clinical and testing data on 131 consecutive patients with drug resistant non-lesional epilepsy who were presented at a multidisciplinary epilepsy surgery conference at the New York University Comprehensive Epilepsy Center between 2010 and 2014, and identified those who underwent epilepsy surgery in order to review 5-year surgical outcomes. RESULTS:There were 103 with non-lesional MRI studies, and of these, 22 had corresponding non-lesional PET imaging. 14 MRI/PET-negative patients pursued a surgical treatment option and 9 underwent resections after intracranial EEG. At 5 years, 77.8 % of patients had favorable (ILAE class 1 and 2) outcomes. Most (77.8 %) had focal cortical dysplasia type Ia (FCDIa) on pathology. CONCLUSION/CONCLUSIONS:These findings suggest that with careful planning and patient selection, surgery for patients with drug resistant MRI/PET-negative focal epilepsy can be successful.

Drug-resistant focal epilepsy (DRFE) in children can impair cognition and behavior, and lead to premature death. Increased pediatric epilepsy surgery numbers reflect the improvements in seizure control and long-term developmental outcomes. Yet, many children with DRFE are not candidates for surgical resection due to overlap of the seizure network with eloquent cortex or multiple seizure-onset zones, making surgery dangerous or ineffective. In adults, responsive neurostimulation (RNS System) therapy is safe and effective treatment for DRFE with one or two seizure foci, especially when the seizure focus is in eloquent cortex. We present six pediatric patients with DRFE who underwent RNS implantation. Our outcomes demonstrate safety, decreased clinical seizure frequency, as well as improved functional status and quality of life. Changes in the clinical seizure semiology and frequency occurred in conjunction with adjustments to the stimulation parameters, supporting the efficacy of responsive neuromodulation in children.