Faculty Bibliography

Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis

Experimental evidence and clinical observations indicate that brain inflammation is an important factor in epilepsy. In particular, induction of interleukin-converting enzyme (ICE)/caspase-1 and activation of interleukin (IL)-1beta/IL-1 receptor type 1 axis both occur in human epilepsy, and contribute to experimentally induced acute seizures. In this study, the anticonvulsant activity of VX-765 (a selective ICE/caspase-1 inhibitor) was examined in a mouse model of chronic epilepsy with spontaneous recurrent epileptic activity refractory to some common anticonvulsant drugs. Moreover, the effects of this drug were studied in one acute model of seizures in mice, previously shown to involve activation of ICE/caspase-1. Quantitative analysis of electroencephalogram activity was done in mice exposed to acute seizures or those developing chronic epileptic activity after status epilepticus to assess the anticonvulsant effects of systemic administration of VX-765. Histological and immunohistochemical analysis of brain tissue was carried out at the end of pharmacological experiments in epileptic mice to evaluate neuropathology, glia activation and IL-1beta expression, and the effect of treatment. Repeated systemic administration of VX-765 significantly reduced chronic epileptic activity in mice in a dose-dependent fashion (12.5-200 mg/kg). This effect was observed at doses >/= 50 mg/kg, and was reversible with discontinuation of the drug. Maximal drug effect was associated with inhibition of IL-1beta synthesis in activated astrocytes. The same dose regimen of VX-765 also reduced acute seizures in mice and delayed their onset time. These results support a new target system for anticonvulsant pharmacological intervention to control epileptic activity that does not respond to some common anticonvulsant drugs

BACKGROUND: To evaluate the efficacy of highly-active antiretroviral therapy (HAART) in individuals taking cytochrome P450 enzyme-inducing antiepileptics (EI-EADs), we evaluated the virologic response to HAART with or without concurrent antiepileptic use. METHODS: Participants in the US Military HIV Natural History Study were included if taking HAART for >/=6 months with concurrent use of EI-AEDs phenytoin, carbamazepine, or phenobarbital for >/=28 days. Virologic outcomes were compared to HAART-treated participants taking AEDs that are not CYP450 enzyme-inducing (NEI-AED group) as well as to a matched group of individuals not taking AEDs (non-AED group). For participants with multiple HAART regimens with AED overlap, the first 3 overlaps were studied. RESULTS: EI-AED participants (n = 19) had greater virologic failure (62.5%) compared to NEI-AED participants (n = 85; 26.7%) for the first HAART/AED overlap period (OR 4.58 [1.47-14.25]; P = 0.009). Analysis of multiple overlap periods yielded consistent results (OR 4.29 [1.51-12.21]; P = 0.006). Virologic failure was also greater in the EI-AED versus NEI-AED group with multiple HAART/AED overlaps when adjusted for both year of and viral load at HAART initiation (OR 4.19 [1.54-11.44]; P = 0.005). Compared to the non-AED group (n = 190), EI-AED participants had greater virologic failure (62.5% vs. 42.5%; P = 0.134), however this result was only significant when adjusted for viral load at HAART initiation (OR 4.30 [1.02-18.07]; P = 0.046). CONCLUSIONS: Consistent with data from pharmacokinetic studies demonstrating that EI-AED use may result in subtherapeutic levels of HAART, EI-AED use is associated with greater risk of virologic failure compared to NEI-AEDs when co-administered with HAART. Concurrent use of EI-AEDs and HAART should be avoided when possible

PURPOSE: We investigated the cumulative probability of seizure remission and relapse in an adult population with drug-resistant epilepsy and frequent seizures. In addition, we determined clinical predictors of remission and relapse in this population. METHODS: IN 2003, we identified 246 patients at a single center with drug-resistant epilepsy defined as at least one seizure per month and failure of at least two antiepileptic drugs. These patients were followed prospectively (cohort design). We examined the cumulative probability of seizure remission and relapse in this population using Kaplan-Meier methodology. Clinical predictors of remission and relapse were also evaluated using Cox regression analysis. KEY FINDINGS: The estimated cumulative probability of 12-month seizure remission was 34.6% at 7 years in the entire population and 33.4% when limited to those without surgery. The risk for relapse after a 12-month period of seizure remission was 71.2% at 5 years. Negative predictors of seizure remission included developmental delay, symptomatic generalized epilepsy syndrome, duration of intractability, and number of antiepileptic drugs failed. Localization-related epilepsy was the only negative predictor of relapse. SIGNIFICANCE: Among patients with drug-resistant epilepsy, 5% per year enter seizure remission even with a follow-up of 6 years. However, a substantial proportion of these patients relapse after the first year following a remission. The large proportion of patients entering a significant remission gives these patients hope; however, caution should be advised when discussing the likelihood of future seizures

Blurring of the cortical gray and white matter border on MRI is associated with normal aging, pathological aging, and the presence of focal cortical dysplasia. However, it remains unclear whether normal variations in signal intensity contrast at the gray and white matter junction reflect the functional integrity of subjacent tissue. This study explores the relationship between verbal abilities and gray and white matter contrast (GWC) in healthy human adults. Participants were scanned at 3 T MRI and administered standardized measures of verbal expression and verbal working memory. GWC was estimated by calculating the non-normalized T1 image intensity contrast above and below the cortical gray/white matter interface. Spherical averaging and whole-brain correlational analyses were performed. Sulcal regions exhibited higher contrast compared to gyral regions. We found a strongly lateralized and regionally specific profile with reduced verbal expression abilities associated with blurring in left hemisphere inferior frontal cortex and temporal pole. Reduced verbal working memory was associated with blurring in widespread left frontal and temporal cortices. Such lateralized and focal results provide support for GWC as a measure of regional functional integrity and highlight its potential role in probing the neuroanatomical substrates of cognition in healthy and diseased populations