Faculty Bibliography

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer's disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches.

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 !

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

PURPOSE: To review the efficacy and tolerability of stiripentol in the treatment of U.S. children with Dravet syndrome. METHODS: U.S. clinicians who had prescribed stiripentol for two or more children with Dravet syndrome between March 2005 and 2012 were contacted to request participation in this retrospective study. Data collected included overall seizure frequency, frequency of prolonged seizures, and use of rescue medications and emergency room (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. In addition, adverse effects were recorded. KEY FINDINGS: 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 use 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. SIGNIFICANCE: Stiripentol is an effective and well-tolerated therapy that markedly reduced frequency of prolonged seizures in Dravet syndrome.

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.

Object In this paper the authors' goal was to identify preoperative variables that predict long-term seizure freedom among patients with mesial temporal sclerosis (MTS) after single-stage anterior temporal lobectomy and amygdalohippocampectomy (ATL-AH). Methods The authors retrospectively reviewed 116 consecutive patients (66 females, mean age at surgery 40.7 years) with refractory seizures and pathologically confirmed MTS who underwent ATL-AH with at least 2 years of follow-up. All patients underwent preoperative MRI and video-electroencephalography (EEG); 106 patients (91.4%) underwent Wada testing and 107 patients (92.2%) had neuropsychological evaluations. The authors assessed the concordance of these 4 studies (defined as test consistent with the side of eventual surgery) and analyzed the impact of preoperative variables on seizure freedom. Results The median follow-up after surgery was 6.7 years (mean 6.9 years). Overall, 103 patients (89%) were seizure free, and 109 patients (94%) had Engel Class I or II outcome. Concordant findings were highest for video-EEG (100%), PET (100%), MRI (99.0%), and Wada testing (90.4%) and lowest for SPECT (84.6%) and neuropsychological testing (82.5%). Using binary logistic regression analysis (seizure free or not) and Cox proportional hazard analysis (seizure-free survival), less disparity in the Wada memory scores between the ipsilateral and contralateral sides was associated with persistent seizures. Conclusions Seizure freedom of nearly 90% can be achieved with ATL-AH in properly selected patients with MTS and concordant preoperative studies. The low number of poor outcomes and exclusion of multistage patients limit the statistical power to determine preoperative variables that predict failure. Strong Wada memory lateralization was associated with excellent long-term outcome and adds important localization information to structural and neurophysiological data in predicting outcome after ATL-AH for MTS.

Object In patients with tuberous sclerosis complex (TSC), the tuber-to-brain proportion (TBP) is a marker of seizure severity and cognitive function. However, few studies have quantified the TBP. Furthermore, authors of these studies have measured the TBP at only a single time point, despite the fact that tuber cells were found to express proliferation markers, suggesting that they may be dynamic lesions. Authors of the present study used a semi-automated tuber segmentation program to determine whether the TBP changes over time. Methods Axial FLAIR MR images were retrospectively identified for patients with TSC who had undergone imaging at the authors' institution between February 1998 and June 2009. Using FireVoxel software, the TBP was measured for each patient at a minimum interval of 2 years. Results Twelve patients meeting the study inclusion criteria were identified. The mean TBP was 1.88% (range 0.38%-3.70%). Eight patients demonstrated minimal changes and 3 patients demonstrated small increases in TBP. The remaining patient exhibited a decrease of 1.00%, which correlated with a visible decrease in the size of 2 cerebellar lesions. Conclusions Semi-automated brain segmentation is a valuable tool in the longitudinal study of tubers. A subset of patients with TSC, particularly those with cerebellar lesions, may exhibit changes in the TBP over time.