Faculty Bibliography

Over the last two decades a total of 11 antiepileptic drugs (AEDs) have been introduced to the US market. Randomized, placebo-controlled trials have yielded information about each drug's efficacy, tolerability, and safety profile; however, few studies have compared the newer generation AEDs directly with the older generation. Comparative studies are not always straightforward in their interpretation, as many characteristics of drugs, both favorable and unfavorable, may not be highlighted by such studies. In general, findings from the literature suggest that the newer generation AEDs (including vigabatrin, felbamate, gabapentin, lamotrigine, tiagabine, topiramate, levetiracetam, oxcarbazepine, zonisamide, pregabalin, rufinamide, and lacosamide) enjoy both improved tolerability and safety compared with older agents such as phenobarbital, phenytoin, carbamazepine, and valproate. This is partially supported by some of the findings of the QSS and the TTA Committee of the American Academy of Neurology (AAN), whose review of four AEDs (gabapentin, lamotrigine, topiramate, and tiagabine) is discussed. Briefly, when compared with carbamazepine, lamotrigine was better tolerated; topiramate adverse events (AEs) were fairly comparable to carbamazepine and valproate; and tiagabine compared with placebo was associated with a higher discontinuation rate due to AEs. The findings of the SANAD trial are also presented; when administered to patients with partial epilepsy, carbamazepine was most likely to fail due to AEs, and lamotrigine and gabapentin were least likely to fail due to AEs. When administered to patients with idiopathic generalized epilepsy, topiramate was most frequently associated with AE-related discontinuation, followed by valproate; and while valproate was the most efficacious drug in this arm of the study, lamotrigine was more tolerable. What makes the SANAD study valuable and somewhat unique is its head-to-head comparison of one drug with another. Such comparative trials are overall lacking for new AEDs, although some conclusions can be drawn from the available data. In the end, however, AED selection must be based on individual patient and drug characteristics.

Experimental and clinical findings have shown in the past decade that specific proinflammatory mediators and their cognate receptors are upregulated in epileptic brain tissue. In particular, the IL-1 receptor (R)/Toll-like receptor (TLR) signaling pathways are activated in experimental models of seizures and in human epileptic tissue from drug-resistant patients. Pharmacological targeting of these proinflammatory pathways using selective receptor antagonists, or the use of transgenic mice with perturbed cell signaling, demostrated that the activation of IL-1R type 1 and TLR4 by their respective endogenous ligands, i.e., interleukin (IL)-1b and High Mobility Group Box 1, is implicated in the precipitation and recurrence of experimentally induced seizures in rodents. This evidence highlights a new target system for pharmacological intervention to inhibit seizures by interfering with mechanisms involved in their genesis and recurrence.

Rationale: To identify genetic influences on human epilepsy we performed a genome wide association study (GWAS) on DNA samples from unrelated patients with either idiopathic generalized (IGE) or cryptogenic focal (CFE) seizures compared to unrelated healthy controls. Methods: The Illumina HumanHap550 Bead Chip was used to genotype over 500,000 single nucleotide polymorphisms (SNPs) across the entire genome in a cohort of cryptogenic focal patients (n=295) and healthy controls (n=2,282). A second cohort of idiopathic generalized patients (n=412) and separate controls (n=3,876) was then genotyped on the same platform. Differences between SNP minor allele frequencies were compared between patients and controls using contingency analysis. Copy number variation (CNV) was identified using the Penn CNV software program. All subjects were of European ancestry and all studies approved by the local institutional review boards at each participating site. Results: SNP rs9572727 on Chr 13q22 near the 5' end of Dachshund 1 (DACH1) was the marker that exhibited the largest statistical difference between cases and controls: focal cohort p=0.001, OR 1.93; IGE cohort p= 3.46x10-13, OR 2.89; combined cohort p=1.71x10-14, OR 2.48. Other candidate genes include MYH11 and MMP8 for the combined cohort (p=1.3x10-9 and p=6.3x10-7 respectively) ZNF695 and VGLL3 for the focal cohort and C6orf103, ENPP2 and C7orf41 for the IGE cohort. In addition, preliminary CNV analysis identified two IGE patients that carry a 1.5 Mb deletion at 15q13.3 and two separate IGE patients that carry a 1.2 Mb deletion on 16p13.11, both CNV regions were previously associated with epilepsy. Conclusions: Our GWAS results identify several novel candidate genes for further analysis to identify potential epilepsy susceptibility alleles. These preliminary data await replication in an independent cohort and suggest that variations in genes related to developmental biology and control of gene expression may be associated with epilepsy susceptibility. In addition, we have identified CNVs on 15q13.3 and 16p13.11 in our cohort previously reported as a susceptibility factors for epilepsy. Future work will increase the size of the current cohorts and replicate these studies in independent cohorts

Summary: Clinical treatment trials for seizures disorders are usually consist of trying to enroll a patient population that has a high frequency of a specific seizure type, then blindly and randomly treating them with an antiseizure drug versus placebo and comparing seizure frequency before and after treatment. This study design is adequate to evaluate effectiveness to a limited extent for short-term oral medication treatment trials. However, epilepsy clinical investigators are often inspired by their patients to study other important outcomes including cognitive, behavioral and endocrine outcomes. Further, novel treatment approaches currently under development such as gamma-knife treatment for temporal lobe epilepsy and anti-inflammatory molecular interventions for intractable epilepsy require using different timelines and outcomes measures than standard antiseizure drug trials. Finally the influence of the basic science epilepsy researchers on clinical trials in humans is enormous yet the strategies of testing hypotheses derived in the lab to human clinical trials remains unsystematic and unsatisfying for investigators on both sides of the aisle. We will provide a forum for presenting several real and several proposed clinical trial designs that incorporate novel outcome measures and are informed by basic research. There will also be discussion and critique of the trials. Clinical investigators and especially basic science investigators are encourage to attend and to participate in the discussion The clinical trials under discussion will include a trial of cognitive preservation in temporal lobe epilepsy, testosterone levels and behavior alterations with antiseizure drugs, the trial design of using gamma-knife to treat temporal lobe epilepsy and a proposed approach to evaluating anti-inflammatory antiseizure treatments, incorporating such considerations as an appropriate study population and biomarkers for efficacy or toxicity. The presenters will be Drs. Quigg, Perucca and Harden. The discussion leaders will be Drs. Herman and French