Faculty Bibliography

Extensive pioneering studies performed in the hippocampus have greatly contributed to our knowledge of an endogenous cannabinoid system comprised of the molecular machinery necessary to process endocannabinoid lipid messengers and their associated cannabinoid receptors. Moreover, a foundation of knowledge regarding the function of hippocampal circuits, and its role in supporting synaptic plasticity has facilitated our understanding of the roles cannabinoids play in the diverse behaviors in which the hippocampus participates, in both normal and pathological states. In this review, we present an historical overview of research pertaining to the hippocampal cannabinoid system to provide context in which to understand the participation of the hippocampus in cognition, behavior, and epilepsy. We also examine potential roles for the hippocampal formation in mediating dysfunctional behavior, and assert that these phenomena reflect disordered physiological activity within the hippocampus and its interactions with other brain regions after exposure to synthetic cannabinoids, and the phytocannabinoids found in marijuana, such as Delta9-THC and cannabidiol. In this regard, we examine contemporary hypotheses concerning the hippocampal endocannabinoid system's participation in psychotic disorders, schizophrenia, and epilepsy, and examine cannabinoid-sensitive cellular mechanisms contributing to coherent network oscillations as potential contributors to these disorders.

Importance: Children with benign epilepsy with centrotemporal spikes (BECTS) have traditionally been considered to have a uniformly good prognosis. However, benign may be a misnomer because BECTS is linked to cognitive deficits, a more severe phenotype with intractable seizures, and the potential for sudden unexpected death in epilepsy (SUDEP). Objective: To determine if cases of BECTS are present in the North American SUDEP Registry (NASR). Design, Setting, and Participants: The NASR is a clinical and biospecimen repository established in 2011 to promote SUDEP research. The NASR database, which includes medical records, results of electroencephalographic tests, and interviews with family members of patients with epilepsy who died suddenly without other identifiable causes of death, was queried from June 3, 2011, to June 3, 2016, for cases of BECTS. The patients with epilepsy had died suddenly without other identifiable causes of death (eg, drowning, trauma, exposure to toxic substances, or suicide); SUDEP classification was determined by the consensus of 2 epileptologists. Main Outcomes and Measures: Cases of SUDEP among children who received a diagnosis of BECTS among patients reported in the NASR. Results: Three boys (median age at death, 12 years; range, 9-13 years) who received a diagnosis of BECTS by their pediatric epileptologist or neurologists were identified among 189 cases reported in the NASR. The median age of epilepsy onset was 5 years (range, 3-11 years), and the median duration of epilepsy was 4 years (range, 1-10 years). Two deaths were definite SUDEP, and 1 was probable SUDEP. Independent review of clinical and electroencephalographic data supported the diagnosis of BECTS in all 3 patients. None of the patients was prescribed antiseizure drugs, either owing to physician recommendation or mutual decision by the physician and parents. All 3 patients were found dead in circumstances typical of SUDEP. The 3 patients spanned the spectrum of BECTS severity: 1 had only a few seizures, 1 had more than 30 focal motor seizures, and 1 had 4 witnessed generalized tonic-clonic seizures and approximately 30 suspected generalized tonic-clonic seizures. Conclusions and Relevance: Sudden unexpected death in epilepsy is a very rare outcome in BECTS that clinicians should consider discussing in appropriate circumstances and possibly factoring into treatment decisions.

INTRODUCTION: Tuberous sclerosis is associated with three central nervous system pathologies: cortical/subcortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Tubers are associated with epilepsy, which is often medication-resistant and often leads to resective surgery. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be effective reducing seizure burden in some patients with tuberous sclerosis complex (TSC)-related refractory epilepsy. mTORi have also been shown to be an alternative for surgery treating SEGAs. We describe several cases of resected tubers that contained SEGA tissue without an intraventricular SEGA. METHODS: After institutional review board (IRB) protocol approval, we retrospectively reviewed the surgical-pathological data for all TSC patients who underwent cortical resections for treatment of refractory epilepsy at NYU Langone Medical Center and Tel Aviv Medical Center between 2003 and 2013. Data included demographics, epilepsy type, MRI characteristics, epilepsy outcome, and histopathological staining. RESULTS: We reviewed cortical resections from 75 patients with complete pathological studies. In three patients, cortical lesions demonstrated histopathological findings consistent with a SEGA within the resected tuber tissue, with no intraventricular SEGA. All lesions were cortically based and none had any intraventricular extension. No patient had been treated before surgery with an mTORi. Two of the three patients remain Engel grade I-II. All lesions stained positive for glial fibrillary acidic protein (GFAP), synaptophysin, and neuronal nuclear antigen (NeuN). CONCLUSION: This is the first description of cortical tubers harboring SEGA tissue. This observation though preliminary may suggest a subgroup of patients with intractable epilepsy in whom mTORi may be considered before surgical intervention.

OBJECTIVE: Amygdala enlargement (AE) is observed in patients with temporal lobe epilepsy (TLE), which has led to the suggestion that it represents a distinct TLE subtype; however, it is unclear whether AE is found at similar rates in other epilepsy syndromes or in healthy controls, which would limit its value as a marker for focal epileptogenicity. METHODS: We compared rates of AE, defined quantitatively from high-resolution T1-weighted MRI, in a large multi-site sample of 136 patients with nonlesional localization related epilepsy (LRE), including TLE and extratemporal (exTLE) focal epilepsy, 34 patients with idiopathic generalized epilepsy (IGE), and 233 healthy controls (HCs). RESULTS: AE was found in all groups including HCs; however, the rate of AE was higher in LRE (18.4%) than in IGE (5.9%) and HCs (6.4%). Patients with unilateral LRE were further evaluated to compare rates of concordant ipsilateral AE in TLE and exTLE, with the hypothesis that rates of ipsilateral AE would be higher in TLE. Although ipsilateral AE was higher in TLE (19.4%) than exTLE (10.5%), this difference was not significant. Furthermore, among the 25 patients with unilateral LRE and AE, 13 (52%) had either bilateral AE or AE contralateral to seizure onset. CONCLUSION: Results suggest that AE, as defined with MRI volumetry, may represent an associated feature of nonlesional localization related epilepsy with limited seizure onset localization value.

The differential contribution of medial-temporal lobe regions to verbal declarative memory is debated within the neuroscience, neuropsychology, and cognitive psychology communities. We evaluate whether the extent of surgical resection within medial-temporal regions predicts longitudinal verbal learning and memory outcomes. This single-center retrospective observational study involved patients with refractory temporal lobe epilepsy undergoing unilateral anterior temporal lobe resection from 2007 to 2015. Thirty-two participants with Engel Classes 1 and 2 outcomes were included (14 left, 18 right) and followed for a mean of 2.3 years after surgery (+/-1.5 years). Participants had baseline and postsurgical neuropsychological testing and high-resolution T1-weighted MRI scans. Postsurgical lesions were manually traced and coregistered to presurgical scans to precisely quantify resection extent of medial-temporal regions. Verbal learning and memory change scores were regressed on hippocampal, entorhinal, and parahippocampal resection volume after accounting for baseline performance. Overall, there were no significant differences in learning and memory change between patients who received left and right anterior temporal lobe resection. After controlling for baseline performance, the extent of left parahippocampal resection accounted for 27% (p = .021) of the variance in verbal short delay free recall. The extent of left entorhinal resection accounted for 37% (p = .004) of the variance in verbal short delay free recall. Our findings highlight the critical role that the left parahippocampal and entorhinal regions play in recall for verbal material.

Background Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. Methods We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. Findings We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2.3, 95% CI 1.7-3.2, p=9.1 x 10(-8); familial non acquired focal epilepsy 3.6, 2.7-4.9, p=1.1 x 10(17)). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5.8 x 10(-8)) that were lower than expected from a random sampling of genes. Interpretation We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection I between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future.

Transcranial electric stimulation aims to stimulate the brain by applying weak electrical currents at the scalp. However, the magnitude and spatial distribution of electric fields in the human brain are unknown. We measured electric potentials intracranially in ten epilepsy patients and estimate electric fields across the entire brain by leveraging calibrated current-flow models. When stimulating at 2 mA, cortical electric fields reach 0.4 V/m, the lower limit of effectiveness in animal studies. When individual whole-head anatomy is considered, the predicted electric field magnitudes correlate with the recorded values in cortical (r=0.89) and depth (r=0.84) electrodes. Accurate models require adjustment of tissue conductivity values reported in the literature, but accuracy is not improved when incorporating white matter anisotropy or different skull compartments. This is the first study to validate and calibrate current-flow models with in vivo intracranial recordings in humans, providing a solid foundation to target stimulation and interpret clinical trials.

BACKGROUND: Acute unprovoked idiopathic fatal pulmonary embolism (IFPE) causes sudden death without an identifiable thrombogenic risk. We aimed to investigate the underlying genomic risks of IFPE through whole exome sequencing (WES). METHODS: We reviewed 14years of consecutive out-of-hospital fatal pulmonary embolism records (n=1478) from the ethnically diverse population of New York City. We selected 68 qualifying IFPE cases for WES. We compared the WES data of IFPE cases to those of 9332 controls to determine if there is an excess of rare damaging variants in the genome using ethnicity-matched controls in collapsing analyses. FINDINGS: We found nine of the 68 decedents (13.2%) who died of IFPE had at least one pathogenic or likely pathogenic variant in one of the three anti-coagulant genes: SERPINC1 (Antithrombin III), PROC, and PROS1. The odds ratio of developing IFPE as a variant carrier for SERPINC1 is 144.2 (95% CI, 26.3-779.4; P=1.7x10-7), for PROC is 85.6 (95% CI, 13.0-448.9; P=2.0x10-5), and for PROS1 is 56.4 (95% CI, 5.3-351.1; P=0.001). The average age-at-death of anti-coagulant gene variant carriers is significantly younger than that of non-carriers (28.56years versus 38.02years; P=0.01). INTERPRETATION: This study showed the important role of severe thrombophilia due to natural anti-coagulant deficiency in IFPE. Evaluating severe thrombophilia in out-of-hospital fatal PE beyond IFPE is warranted.

BACKGROUND: Cohesinopathies are rare neurodevelopmental disorders arising from a dysfunction in the cohesin pathway, which enables chromosome segregation and regulates gene transcription. So far, eight genes from this pathway have been reported in human disease. STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. This work aimed to identify the phenotype ascribed to STAG1 mutations. METHODS: Among patients referred for intellectual disability (ID) in genetics departments worldwide, array-comparative genomic hybridisation (CGH), gene panel, whole-exome sequencing or whole-genome sequencing were performed following the local diagnostic standards. RESULTS: A mutation in STAG1 was identified in 17 individuals from 16 families, 9 males and 8 females aged 2-33 years. Four individuals harboured a small microdeletion encompassing STAG1; three individuals from two families had an intragenic STAG1 deletion. Six deletions were identified by array-CGH, one by whole-exome sequencing. Whole-exome sequencing found de novo heterozygous missense or frameshift STAG1 variants in eight patients, a panel of genes involved in ID identified a missense and a frameshift variant in two individuals. The 17 patients shared common facial features, with wide mouth and deep-set eyes. Four individuals had mild microcephaly, seven had epilepsy. CONCLUSIONS: We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a STAG1 deletion or point mutation. This first series reporting the phenotype ascribed to mutation in STAG1 highlights the importance of data sharing in the field of rare disorders.