Faculty Bibliography

OBJECTIVE:People with epilepsy experience increased rates of sexual dysfunction, often affecting quality of life. Sexual dysfunction may result from the underlying disorder, antiseizure or other medications, or comorbid psychosocial factors. This study evaluated the incidence and clinical associations of sexual dysfunction in adult epilepsy patients. METHODS:89 epilepsy patients 18 years and older admitted to the New York University Comprehensive Epilepsy Center epilepsy monitoring unit between 2016 and 2018 completed a survey on sexual functioning. The survey included demographic, clinical, and sexual functioning information with a validated measure of sexual function (the Arizona Sexual Experiences Scale (ASEX). RESULTS:Of 89 surveys completed, 15 (16.9 %) patients had discussed sexual functioning with a medical professional and 20 (22.5 %) reported sexual dysfunction. For the group, the mean ASEX score was 13.6 (SD 4.8). 59 (66.3 %) participants reported not being asked about sexual health by their doctor or nurse practitioner in the last year. The two independent predictors of sexual dysfunction were self-identifying as overweight/obese (OR 6.1, CI 1.4-26.5, P = 0.02) or taking strong enzyme-inducing antiseizure medications (OR 7.8, CI 1.4-44.9, P = 0.02). Other factors such as age, relationship status, duration of epilepsy, the presence of depression or anxiety, cardiovascular risk factors, and opioid/stimulant use, did not predict sexual dysfunction. SIGNIFICANCE/CONCLUSIONS:Our study showed that sexual dysfunction is common in epilepsy patients but infrequently discussed by medical professionals. Two modifiable risk factors, being overweight or taking strong enzyme-inducing antiseizure medications, were independently associated with sexual dysfunction, suggesting interventions to potentially improve sexual health.

Coronavirus disease 2019 (COVID-19) is a highly infectious pandemic caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It frequently presents with unremitting fever, hypoxemic respiratory failure, and systemic complications (e.g., gastrointestinal, renal, cardiac, and hepatic involvement), encephalopathy, and thrombotic events. The respiratory symptoms are similar to those accompanying other genetically related beta-coronaviruses (CoVs) such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East Respiratory Syndrome CoV (MERS-CoV). Hypoxemic respiratory symptoms can rapidly progress to Acute Respiratory Distress Syndrome (ARDS) and secondary hemophagocytic lymphohistiocytosis, leading to multi-organ system dysfunction syndrome. Severe cases are typically associated with aberrant and excessive inflammatory responses. These include significant systemic upregulation of cytokines, chemokines, and pro-inflammatory mediators, associated with increased acute-phase proteins (APPs) production such as hyperferritinemia and elevated C-reactive protein (CRP), as well as lymphocytopenia. The neurological complications of SARS-CoV-2 infection are high among those with severe and critical illnesses. This review highlights the central nervous system (CNS) complications associated with COVID-19 attributed to primary CNS involvement due to rare direct neuroinvasion and more commonly secondary CNS sequelae due to exuberant systemic innate-mediated hyper-inflammation. It also provides a theoretical integration of clinical and experimental data to elucidate the pathogenesis of these disorders. Specifically, how systemic hyper-inflammation provoked by maladaptive innate immunity may impair neurovascular endothelial function, disrupt BBB, activate CNS innate immune signaling pathways, and induce para-infectious autoimmunity, potentially contributing to the CNS complications associated with SARS-CoV-2 infection. Direct viral infection of the brain parenchyma causing encephalitis, possibly with concurrent neurovascular endotheliitis and CNS renin angiotensin system (RAS) dysregulation, is also reviewed.

Although responsive neurostimulation (RNS) is approved for treatment of resistant focal epilepsy in adults, little is known about response to treatment of specific cortical targets. We describe the experience of RNS targeting the insular lobe. We identified patients who had RNS implantation with at least one electrode within the insula between April 2014 and October 2015. We performed a retrospective review of preoperative clinical features, imaging, electrocardiogram (EEG), intraoperative electrocorticography (ECoG), and postoperative seizure outcome. Eight patients with at least 6 months of postimplant follow-up were identified. Ictal localization was inconclusive with MRI or scalp EEG findings. Intracranial EEG monitoring or intraoperative ECoG demonstrated clear ictal onsets and/or frequent interictal discharges in the insula. Four patients demonstrated overall 50-75% reduction in seizure frequency. Two patients did not show appreciable seizure improvement. One patient has experienced a 75% reduction of seizure frequency, and another is nearly seizure free postoperatively. There were no reported direct complications of insular RNS electrode placement or stimulation, though two patients had postoperative complications thought to be related to craniotomy (hydrocephalus and late infection). Our study suggests that insular RNS electrode placement in selected patients is relatively safe and that RNS treatment may benefit selected patients with insular epilepsy.

Schizophrenia is a psychotic disorder characterized by delusions, hallucinations, negative symptoms, as well as behavioral and cognitive dysfunction. It is a pathoetiologically heterogeneous disorder involving complex interrelated mechanisms that include oxidative stress and neuroinflammation. Neurovascular endothelial dysfunction and blood-brain barrier (BBB) hyperpermeability are established mechanisms in neurological disorders with comorbid psychiatric symptoms such as epilepsy, traumatic brain injury, and Alzheimer's disease. Schizophrenia is frequently comorbid with medical conditions associated with peripheral vascular endothelial dysfunction, such as metabolic syndrome, cardiovascular disease, and diabetes mellitus. However, the existence and etiological relevance of neurovascular endothelial dysfunction and BBB hyperpermeability in schizophrenia are still not well recognized. Here, we review the growing clinical and experimental evidence, indicating that neurovascular endotheliopathy and BBB hyperpermeability occur in schizophrenia patients. We present a theoretical integration of human and animal data linking oxidative stress and neuroinflammation to neurovascular endotheliopathy and BBB breakdown in schizophrenia. These abnormalities may contribute to the cognitive and behavioral symptoms of schizophrenia via several mechanisms involving reduced cerebral perfusion and impaired homeostatic processes of cerebral microenvironment. Furthermore, BBB disruption can facilitate interactions between brain innate and peripheral adaptive immunity, thereby perpetuating harmful neuroimmune signals and toxic neuroinflammatory responses, which can also contribute to the symptoms of schizophrenia. Taken together, these findings support the "mild encephalitis" hypothesis of schizophrenia. If neurovascular abnormalities prove to be etiologically relevant to the neurobiology of schizophrenia, then targeting these abnormalities may represent a promising therapeutic strategy.

PURPOSE: The aim of this study was to determine the relationship of fear to other auras and to gender and age using a large database. METHODS: The Epilepsy Phenome/Genome Project (EPGP) is a multicenter, multicontinental cross-sectional study in which ictal symptomatology and other data were ascertained in a standardized series of questionnaires then corroborated by epilepsy specialists. Auras were classified into subgroups of symptoms, with ictal fear, panic, or anxiety as a single category. RESULTS: Of 536 participants with focal epilepsy, 72 were coded as having ictal fear/panic/anxiety. Reviewing raw patient responses, 12 participants were deemed not to have fear, and 24 had inadequate data, leaving 36 (7%) of 512 with definite ictal fear. In univariate analyses, fear was significantly associated with auras historically considered temporal lobe in origin, including cephalic, olfactory, and visceral complaints; deja vu; and derealization. On both univariate and multivariate stepwise analyses, fear was associated with jamais vu and auras with cardiac symptoms, dyspnea, and chest tightening. Expressive aphasia was associated with fear on univariate analysis only, but the general category of aphasias was associated with fear only in the multivariate model. There was no age or gender relationship with fear when compared to the overall population with focal epilepsy that was studied under the EPGP. Patients with ictal fear were more likely to have a right hemisphere seizure focus. CONCLUSIONS: Ictal fear was strongly associated with other auras considered to originate from the limbic system. No relationship of fear with age or gender was observed.

Since 2010, the Food and Drug Administration has approved the use of four new anti-epilepsy drugs (AEDs) for the treatment of epilepsy in the USA: clobazam (Onfi), ezogabine (Potiga), perampanel (Fycompa), and eslicarbazepine (Aptiom) as well as two extended release formulations, topiramate ER (Qudexy XR and Trokendi) and oxcarbazepine ER (Oxtellar). This not only provides practitioners ample choice to match medication profiles to their patients' preferences and co-morbidities better, but also challenges us to be proficient in the use of all. In addition to providing a brief overview of these new medications and of the current medical management of epilepsy, this review discusses new data regarding vitamin D and AED-related osteoporosis, pregnancy registries, suicidality, marijuana-related compounds for epilepsy, and the recently published guidelines on the approach and management of a first unprovoked seizure in adults and guidelines for when to stop AEDs.

OBJECTIVE: We studied the frequency of auras in generalized epilepsy (GE) using a detailed semistructured diagnostic interview. METHODS: In this cross-sectional study, participants with GE were drawn from the Epilepsy Phenome/Genome Project (EPGP). Responses to the standardized diagnostic interview regarding tonic-clonic (grand mal) seizures were then examined. This questionnaire initially required participants to provide their own description of any subjective phenomena before their "grand mal seizures." Participants who provided answers to these questions were considered to have an aura. All participants were then systematically queried regarding a list of specific symptoms occurring before grand mal seizures, using structured (closed-ended) questions. RESULTS: Seven hundred ninety-eight participants with GE were identified, of whom 530 reported grand mal seizures. Of these, 112 (21.3%) reported auras in response to the open-ended question. Analysis of responses to the closed-ended questions suggested that 341 participants (64.3%) experienced at least one form of aura. CONCLUSIONS: Auras typically associated with focal epilepsy were reported by a substantial proportion of EPGP subjects with GE. This finding may support existing theories of cortical and subcortical generators of GE with variable spread patterns. Differences between responses to the open-ended question and closed-ended questions may also reflect clinically relevant variation in patient responses to history-taking and surveys. Open-ended questions may underestimate the prevalence of specific types of auras and may be in part responsible for the underrecognition of auras in GE. In addition, structured questions may influence participants, possibly leading to a greater representation of symptoms.

OBJECTIVE: One mechanism that may be responsible for drug resistance in epilepsy is the upregulation of P-glycoprotein (P-gp), a drug efflux pump, at the epileptogenic focus. In this study, we sought to evaluate the potential of a recently developed P-gp PET radiotracer, [(11)C]N-desmethyl-loperamide ([(11)C]dLop), for measuring P-gp function in the rat brain. METHODS: The precursor to [(11)C]dLop was synthesized in two steps from commercially available starting materials and subsequently radiolabeled in one step using [(11)C]methyl iodide. [(11)C]dLop was then administered to two groups of rats, controls (n = 4) and those treated with a P-gp inhibitor (n = 8). Cyclosporin A (CsA, 50 mg/kg, n = 3) and tariquidar (TQ, 20 mg/kg, n = 5) were both used as P-gp inhibitors. MicroPET brain scans were performed for 120 min with arterial blood sampling. A one-tissue compartment model was used to estimate the distribution volume of radiotracer as the outcome measure of P-gp function. RESULTS: Plasma levels of parent [(11)C]dLop decreased rapidly to <0.1 mean standardized uptake value (SUV) at 60 min. In controls, brain uptake of [(11)C]dLop was very low (<0.1 mean SUV). In contrast, the mean SUVs were significantly higher in rats treated with CsA (0.51) or TQ (0.22). Estimation of distribution volumes was stable by 70 min. Estimated distribution volumes were significantly larger after P-gp inhibition (CsA = 7.3, TQ = 4.7) compared to controls (no inhibitor = 2.1). CONCLUSIONS: The rat brain demonstrates significantly increased uptake of [(11)C]dLop after P-gp inhibition. [(11)C]dLop is a substrate of P-gp, and will serve as a promising radiotracer for studying P-gp function in the future.