Faculty Bibliography

Intractable epilepsies have an extraordinary impact on cognitive and behavioral function and quality of life, and the treatment of seizures represents a challenge and a unique opportunity. Over the past few years, considerable attention has focused on cannabidiol (CBD), the major nonpsychotropic compound of Cannabis sativa. Basic research studies have provided strong evidence for safety and anticonvulsant properties of CBD. However, the lack of pure, pharmacologically active compounds and legal restrictions have prevented clinical research and confined data on efficacy and safety to anecdotal reports. Pure CBD appears to be an ideal candidate among phytocannabinoids as a therapy for treatment-resistant epilepsy. A first step in this direction is to systematically investigate the safety, pharmacokinetics, and interactions of CBD with other antiepileptic drugs and obtain an initial signal regarding efficacy at different dosages. These data can then be used to plan double-blinded placebo-controlled efficacy trials. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Delta9 -Tetrahydrocannabinol (Delta9 -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Delta9 -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Delta9 -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the alpha3 and alpha1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Delta9 -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Rationale: For patients with medically intractable focal epilepsy, the best option for achieving seizure control is often surgical resection. In surgical planning, the potential for seizure reduction must be weighed against the risk of cognitive loss. The role that clinical and demographic factors play in predicting cognitive outcome is well established; however, little is known about the role of crosshemispheric white matter in promoting functional reorganization after surgery. In this study we measured the midsagittal crosssectional area of the corpus callosum (CC) on pre-surgical MRI to investigate whether this property is related to changes in working memory following surgery. Methods: A pre- and post-surgical neuropsychological test battery was obtained in 15 patients (9 males/6 females) who underwent temporal (n = 9), frontal (n = 4), temporal and frontal (n = 1) or parietal lobe (n = 1) resective surgery at NYU Langone Medical Center. Pre-surgical whole-brain T1-weighted 3D MRIs were acquired on all participants from the same dedicated research scanner. The midsaggital CC cross-sectional area was delineated and measured automatically on the MRI using 'yuki' (www.nitrc.org/projects/art), an automatic CC segmentation algorithm, described by Ardekani et al. 2012 (Figure 1A). The Working Memory Index (WMI) from the Wechsler Adult Intelligence Scale was used to probe change in concentration/working memory abilities (postsurgical W

Rationale: To review the efficacy and tolerability of stiripentol in the treatment of US children with Dravet syndrome. Methods: US clinicians who had prescribed stiripentol for two or more children with Dravet syndrome between 03/2005 and 03/2012 were contacted to request participation in this retrospective study. 111 Data collected included overall seizure frequency, frequency of prolonged seizures, use of rescue medications and ER/hospital visits in the year preceding stiripentol initiation, and with stiripentol therapy. We separately assessed efficacy in the following treatment groups: Group A: stiripentol without clobazam or valproate, Group B: stiripentol with clobazam but without valproate, Group C: stiripentol with valproate but without clobazam, and Group D: stiripentol with clobazam and valproate. Additionally, adverse effects were recorded. Results: Thirteen of 16 clinicians contacted for study participated and provided data on 82 children. Stiripentol was initiated a median of 6.0 years after seizure onset and 1.2 years after diagnosis of Dravet syndrome. Compared to baseline, overall seizure frequency was reduced in 2/6 in Group A, 28/35 in Group B, 8/14 in Group C and 30/48 in Group D. All children with prolonged seizure frequency greater than quarterly during the baseline period experienced a reduction in this frequency on the various treatment arms with stiripentol. Similarly, 2/4 patients in Group A, 25/25 in Group B, 5/10 in Group C and 26/33 in Group D experienced reduction in frequency of rescue medication usage and 1/1 in Group A, 12/12 in Group B, 3/5 in Group C and 18/19 in Group D had reduction in frequency of ER/hospital visits. Adverse effects were reported in 38, most commonly sedation and reduced appetite. Four patients (5%) discontinued stiripentol for adverse effects and two (2%) for lack of efficacy. Conclusions: Stiripentol is an effective and well-tolerated therapy which markedly reduced frequency of prolonged seizures in Dravet syndrome

Rationale: While the ionotropic glutamate receptors (iGluRs) have been extensively studied, little is known about the role of metabotropic glutamate receptors (mGluRs) in seizure generation and epileptogenesis associated with altered brain development, including Tuberous Sclerosis Complex (TSC) and focal cortical dysplasia (FCD). Animal model studies show that Group I mGluRs, including mGluR1 and mGluR5, are pro-convulsive, while specific mGluR antagonists are effective in suppressing seizure activity. Furthermore, experimental deletion of Tsc1 impairs mGluR-dependent long-term depression. We hypothesized that Group I mGluRs are expressed at higher levels in TSC and FCD compared to controls, which may significantly contribute to altered synaptic function, network excitability and information processing in these patients. Methods: Cortical samples from TSC (n= 5; ages 0.9-5 years) and non-TSC epilepsy patients (n=5; ages 21.5-37 years) were obtained during brain surgery for treatment of pharmaco-resistant epilepsy at NYU Langone Medical Center. The cases were further diagnosed as either TSC or FCD Type Ia by standard neuropathological examination. Age-matched and region-matched control specimens from cases with normal neurological history (n=6; ages 2-24 years) were obtained from University of Maryland Brain and Tissue Bank. The study was approved by the local Institutional Review Board. Frozen cortical samples were used to separate the membrane fraction and blots were probed for mGluR1 (1:1000) and mGluR5 (1:1000). Mean expression levels were compared among groups and statistical significance (p<0.05) was established using two-tailed t-tests. Results: mGluR1 expression was significantly upregulated relative to controls in both TSC (270+40% of control; p<0.05) and FCD cortex (136+10% of control; p<0.05), with higher levels in TSC relative to FCD (p<0.05). mGluR5 was also significantly elevated in TSC (370+34% of control; p<0.01) and FCD (321+25% of control; p<0.001), with no significant differen!

Rationale: SUDEP is the most common epilepsy-related cause of death in persons with epilepsy. Evidence supports that increased SUDEP awareness and education can be translated into significantly reduced rates of epilepsy-related deaths. However, there is a lack of consensus regarding how health care practitioners should address SUDEP with patients, and a lack of evidence regarding patient educational interventions. The purpose of this study was to describe various health care providers' practices regarding discussion of SUDEP with their patients. Methods: Separate focus groups were conducted, each involving epileptologists (n=19), neurologists (n=16), or advanced practice nurses (n=8). The focus group moderator asked participants questions pertaining to reasons for and for not discussing SUDEP, and how they discuss SUDEP. Focus group data were analyzed via content analysis per each practitioner group, and comparisons were then made across groups. Data were organized via themes in order to answer the research questions. Results: Table 1 depicts final themes and definitions. Across all disciplines, reasons for discussing SUDEP included Practical Accountability, Moral Accountability, Proactivity, and Reactivity. For nurses only, an additional reason was Patient Advocacy. In terms of when not to discuss SUDEP, for all disciplines involved, and especially the physicians, the theme Not at First emerged. Additional themes that emerged for this question included, in the case of neurologists and epileptologists, Moral Accountability and Out of Options. Ways in which SUDEP is discussed included, in all groups, Discussion and Written Materials. In addition, prevalent in all groups was the finding that procedures for discussing SUDEP with patients and families need to be somewhat standardized, though the discussion should always be tailored to fit the patient's context. As well, more informative written materials should be developed. Conclusions: These results provide an initial view of the way in which var!

IMPORTANCE: Sudden unexpected death in epilepsy (SUDEP) is a common cause of mortality in patients with the disease, but it is unknown how neurologists disclose this risk when counseling patients. OBJECTIVE: This study aimed at examining SUDEP discussion practices of neurologists in the U.S. and Canada. DESIGN: An electronic, web-based survey was sent to 17,558 neurologists in the U.S. and Canada. Survey questions included frequency of SUDEP discussion, reasons for discussing/not discussing SUDEP, timing of SUDEP discussions, and perceived patient reactions. We examined factors that influence the frequency of SUDEP discussion and perceived patient response using multivariate logistic regression. PARTICIPANTS: The participants of this study were neurologists who completed postgraduate training and devoted >5% of their time to patient care. RESULTS: There was a response rate of 9.3%; 1200 respondents met eligibility criteria and completed surveys. Only 6.8% of the respondents discussed SUDEP with nearly all (>90% of the time) of their patients with epilepsy/caregivers, while 11.6% never discussed it. Factors that independently predicted whether SUDEP was discussed nearly all of the time were the following: number of patients with epilepsy seen annually (OR=2.01, 95% CI=1.20-3.37, p<0.01) and if the respondent had a SUDEP case in the past 24months (OR=2.27, 95% CI=1.37-3.66, p<0.01). A majority of respondents (59.5%) reported that negative reactions were the most common response to a discussion of SUDEP. Having additional epilepsy/neurophysiology training was associated with an increased risk of a perceived negative response (OR=1.36, 95% CI=1.02-1.82, p=0.038), while years in practice (OR=0.85, 95% CI=0.77-0.95, p<0.005) and seeing both adults and children were associated with a decreased likelihood of negative response (OR=0.15, 95% CI=0.032-0.74, p=0.02). CONCLUSIONS: U.S. and Canadian neurologists rarely discuss SUDEP with all patients with epilepsy/caregivers though discussions are more likely among neurologists who frequently see patients with epilepsy or had a recent SUDEP in their practice. Perceived negative reactions to SUDEP discussions are common but not universal; more experienced neurologists may be less likely to encounter negative reactions, suggesting that there may be ways to frame the discussion that minimizes patient/caregiver distress.

OBJECTIVES: Patients with tuberous sclerosis complex (TSC) frequently have autism spectrum disorders and neuropsychiatric disorders. Subependymal giant cell astrocytomas (SEGAs) have been reported to occur in 5-20% of patients with TSC; however, the relationship between SEGAs and neuropsychiatric disorders in TSC remains unknown. We utilized a large multicenter database to study associations between SEGAs and neuropsychiatric disorders in patients with TSC. METHODS: Associations between the presence of SEGAs and neuropsychiatric disorders were examined in a retrospective review of 916 patients enrolled in the TSC Natural History Database Project (Tuberous Sclerosis Alliance). RESULTS: Among the 916 TSC patients, 226 had SEGAs (25%) and 155 had autism spectrum disorder (ASD) (17%). Compared to patients without SEGAs, patients with SEGAs were 1.83 (95% confidence interval [CI] 1.26-2.66) times more likely to have ASD. No significant relationship was found between SEGAs and intellectual disability, attention-deficit/hyperactive disorder, or major depressive disorder. SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. These data show that SEGAs are associated with ASD in patients with TSC, suggesting that the pathologic changes leading to SEGA formation may also predispose patients to ASD. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Septal nuclei, located in basal forebrain, are strongly connected with hippocampi and important in learning and memory, but have received limited research attention in human MRI studies. While probabilistic maps for estimating septal volume on MRI are now available, they have not been independently validated against manual tracing of MRI, typically considered the gold standard for delineating brain structures. We developed a protocol for manual tracing of the human septal region on MRI based on examination of neuroanatomical specimens. We applied this tracing protocol to T1 MRI scans (n=86) from subjects with temporal epilepsy and healthy controls to measure septal volume. To assess the inter-rater reliability of the protocol, a second tracer used the same protocol on 20 scans that were randomly selected from the 72 healthy controls. In addition to measuring septal volume, maximum septal thickness between the ventricles was measured and recorded. The same scans (n=86) were also analysed using septal probabilistic maps and Dartel toolbox in SPM. Results show that our manual tracing algorithm is reliable, and that septal volume measurements obtained via manual and automated methods correlate significantly with each other (p<.001). Both manual and automated methods detected significantly enlarged septal nuclei in patients with temporal lobe epilepsy in accord with a proposed compensatory neuroplastic process related to the strong connections between septal nuclei and hippocampi. Septal thickness, which was simple to measure with excellent inter-rater reliability, correlated well with both manual and automated septal volume, suggesting it could serve as an easy-to-measure surrogate for septal volume in future studies. Our results call attention to the important though understudied human septal region, confirm its enlargement in temporal lobe epilepsy, and provide a reliable new manual delineation protocol that will facilitate continued study of this critical region.