Faculty Bibliography

Advances in MRI have transformed the in vivo detection of brain abnormalities in neurological disease. However, many subtle structural abnormalities remain undetected, especially in individual patients, where clinical relevance is highest. We present a quantitative, multifeature morphometry approach combined with machine learning algorithms for detecting structural cortical abnormalities in epilepsy patients with focal cortical dysplasia (FCD). FCD is a malformation of cortical development and is the most common etiology in pediatric epilepsy and the second most common etiology in adults with treatment resistant epilepsy. Lesions may occur anywhere in cortex. Seizure freedom after surgery is reported at 66% with a detected lesion, but only 29% in MRI-negative patients. Yet, 70% to 80% of histologically confirmed FCD cases go undetected by visual inspection of the MRI. Sixty-one controls and 23 MRI-negative patients in whom no focal lesion was detected during routine visual radiological analysis and 7 MRI-positive patients were scanned before surgery at 3 T using a T1-weighted MRI sequence. All patients subsequently underwent intracranial EEG monitoring and resection of the epileptic focus and pathology confirmed FCD. Morphometric routines with surface-based spherical averaging techniques were used to align anatomical structures between individual brains and to calculate 6 features at each vertex, including cortical thickness, gray-white contrast, local gyrification, sulcal depth, Jacobian distance, and curvature. A logistic regression classifier was trained on normal control data and the data from the FCD region of MRI-positive patients to classify, in MRI-negative patients, vertices into lesional and nonlesional. The logistic regression approach correctly classified lesions within the resection zone in 14 out of the 24 (58%) MRInegative patients. The overall false positive rate (by vertex) was never greater than 1.05%. Quantitative MRI can aid in the presurgical detection of FCD lesions, even !

BACKGROUND: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. RESULTS: EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. CONCLUSIONS: EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.

Rationale: Tuberous Sclerosis Complex (TSC) is a multisystem autosomal dominant disease caused by inactivating mutations in TSC1 or TSC2 genes. The most common neurological symptoms in TSC include treatment-resistant epilepsy, mental retardation and autism. There is now accumulating evidence that pro-inflammatory cytokines, produced and released mainly by reactive astrocytes and activated microglia, are implicated in a wide range of chronic neurological disorders, including refractory epilepsy. The purpose of this study was to evaluate the degree of inflammation in TSC brain lesions in human, with the hypothesis that activated glial cells and pro-inflammatory cytokines will be increased in both cortical tubers and peri-tuberal brain (PTB), possibly contributing to widespread network dysfunction. Methods: Human TSC specimens (n=10; ages 0-7 years) were prospectively collected following epilepsy surgery at NYULMC. Region-matched control autopsy brain samples from cases with normal neurological history were obtained from the Maryland Brain and Tissue Bank (n=7; ages 0-8 years). Tissue samples were collected and handled in accordance with the NYULMC Institutional Review Board. Fresh frozen specimens were used to prepare protein extracts for Western blotting. Blots were probed with the astrocytic and microglial markers GFAP and Iba1, as well as with the proinflammatory cytokines interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha). To determine statistical significance (p<0.05), oneway ANOVA followed by Student's t-test were used. Results: GFAP and Iba1 levels were significantly elevated in both tubers (343+/-115% of control, n=5; p<0.05 for GFAP, and 346+/-35% of control, n=5; p<0.0001 for Iba1) and PTB (225+/-37% of control, n=5; p<0.001 for GFAP, and 247+/-37% of control, n=5; p<0.001 for Iba1). The inactive pro-IL-1beta was highly upregulated in tubers (319+/-114% of control, n=6; p<0.05) and in PTB (228+/-70% of control, n=4; p<0.001), and this was accompanied by a commensur!

Rationale: The Generalized Tonic-Clonic Convulsion (GTCC) has been described as a stereotyped seizure consisting of a symmetric tonic posture, followed by vibratory and clonic phases - defined as movements at a frequency of >5 Hz and <5 Hz respectively. We examined how frequently the classic GTCC occurs in a population and what factors, if any, contributed to deviations from this pattern. Methods: We reviewed the video EEG of 100 consecutive inpatients of the NYU Comprehensive Epilepsy Center that had bilateral limb movements as part of their seizure semiology. Each seizure was reviewed by 2 reviewers; any records in which the patient was obscured on the video were excluded from further analysis. Any seizure with bilateral symmetric tonic, vibratory and clonic phases in that order was categorized as "typical GTCC" (tGTCC), if one phase was absent, asymmetric or in the wrong order of progression it was considered "atypical GTCC" (aGTCC), if two phases were absent it was not a GTCC (nGTCC). All aGTCC were reviewed by at least 3 reviewers. Results: 104 seizures (41 from women) from 100 patients were reviewed, 2 patients were excluded due to obscured video. 45 had a tGTCC while 15 were aGTCC, and 42 were nGT

Rationale: The Generalized Tonic-Clonic Convulsion (GTCC) is often associated with post-ictal electrographic slowing, and at times suppression. The mechanism of post-ictal EEG suppression is not known but may reflect involvement of bilateral subcortical networks. We examined the electrographic activity occurring after seizures with bilateral movement to determine if there are post-ictal features unique to the GTCC. Methods: We reviewed the video EEG of 100 consecutive inpatients of the NYU Comprehensive Epilepsy Center that had bilateral movement as part of their seizure semiology. Each seizure was reviewed by 2 reviewers; any records in which the patient was obscured on the video were excluded from further analysis. Any seizure with bilateral symmetric tonic, vibratory and clonic phases (defined as bilateral movement > and < 5 Hz respectively) in that order was categorized as "typical GTCC" (tGTCC). If one phase was absent, asymmetric or the progression was different, it was considered an "atypical GTCC" (aGTCC). If two phases were absent it was not a GTCC (nGTCC). All aGTCC were reviewed by at least 3 reviewers. The post-ictal EEG was categorized as: "suppression", defined as background voltage <10uV; "slowing" defined as decreased amplitude and/or frequency compared to baseline while still >10uV; or "no change from baseline." Results: 104 seizures from 100 patients were reviewed, 5 patients were excluded due to obscured video or EEG, leaving 97 seizures reviewed. 41 were tGTCC, 14 were aGTCC and 42 were nGT

Despite the expanding treatment options in the past two decades, a third of patients with epilepsy remain treatment resistant, and there is a continued need for new therapies. After many years of repeated success, several late-stage clinical development programs for antiseizure drugs have seen unexpected failures to demonstrate superiority of the experimental drug over placebo, which has led to a re-examination of how clinical trials are conducted in this heterogeneous and often unpredictable condition. There are numerous sources of variability in epilepsy trials that can reduce effect size. Methods to improve diagnostic accuracy and outcome assessment are needed to ensure that promising compounds have the best chance to get to patients. 2013 Future Science Ltd