Faculty Bibliography

Focal cortical dysplasia (FCD) is characterized by disorganized cerebral cortical cytoarchitecture. Increased expression of several intermediate filament (IF) proteins such as neurofilament, vimentin, alpha-internexin, and nestin observed in dysplastic 'balloon' neurons (DN) may contribute to disrupted cortical lamination. We hypothesized that increased IF protein expression results from enhanced IF gene transcription within dysplastic neurons. We used a novel strategy to evaluate IF mRNA expression in three FCD specimens from medically intractable epilepsy patients. Poly(A) mRNA was amplified (aRNA) from single microdissected DN, morphologically normal neurons at the margin of the FCD resection, morphologically normal neurons in non-FCD cortex from epilepsy patients, and normal control neurons. Radiolabeled aRNA from single neurons was used to probe cDNA arrays containing the low (NFL), medium (NFM) and high (NFH) molecular weight neurofilament isoform, alpha-internexin, desmin, vimentin, peripherin (PRPH), nestin, and glial fibrillary acidic protein (GFAP) cDNAs. Hybridization intensity of aRNA-cDNA hybrids was used to quantify relative IF abundance. Increased expression of nestin, alpha-internexin, PRPH, vimentin, NFL, NFM, and NFH mRNAs was found in DN when compared with the three control neuronal subtypes. Desmin and GFAP mRNAs were not detected in any cell types. Expression of PRPH mRNA and protein in select DN was confirmed by reverse transcription-polymerase chain reaction and immunohistochemistry. We conclude that aberrant expression of IF proteins in FCD likely results from enhanced transcription of IF genes in dysplastic neurons and propose that future analysis of transcriptional elements that regulate IF expression be evaluated in FCD

Seizure frequency data are difficult to work with because they are so variable both between and within patients. Seizures can come in clusters, thereby adding to the variation in seizure frequency. Also, seizure frequency data are non-parametric in nature, making them difficult to analyze by some statistical techniques without transforming them. Therefore, to improve data analysis in proof of efficacy studies, manipulations of seizure frequency are commonly used, such as the proportion of responders above an arbitrary threshold, or the response ratio. Other useful endpoints are time to nth seizure, number of seizure-free days, proportion of seizure-free patients, and assessment of seizure severity using rating scales. The choice of endpoint(s) will depend upon the design of the study

A subset of the 27 safety and pharmacokinetic studies of levetiracetam has been conducted in selected special populations: children, the elderly, and people with renal or hepatic impairment. The results of these studies indicate that higher doses need to be used for children (on a per-weight basis), and individuals with renal dysfunction require dosage modifications related to creatinine clearance. Individuals with hepatic impairment do not require modifications from standard doses. Little information is available on the effect of levetiracetam on the developing fetus, so cautious use during pregnancy is recommended until more information is available. Additional studies will refine the recommendations for use of levetiracetam in these special populations

Status epilepticus (SE) is a common, serious, potentially life-threatening, neurologic emergency characterized by prolonged seizure activity. Generalized convulsive status epilepticus (GCSE) is the most widely recognized form of SE. Direct consequences of convulsive movements from SE can result in injury to the body and brain. Nonconvulsive status epilepticus (NCSE) is underrecognized, with controversy surrounding the consequences and treatment. High mortality rates with GCSE have been noted in the past. New treatments for SE are emerging with new parenteral drug formulations as well as new agents for refractory SE, offering an opportunity to improve outcome. Special drug delivery systems, drug combinations, and neuroprotective agents that prevent the subsequent development of epilepsy may soon emerge as future options for treating SE

For many years, epileptologists had few choices for treating seizures. Within the past 20 years several 'new generation' antiepileptic drugs (AEDs) were introduced. The most recent additions include oxcarbazepine, levetiracetam, and zonisamide. New agents have been shown in clinical trials to offer similar efficacy compared with older, more established AEDs, but the new agents offer important improvements in safety. Although clinical trials to specifically measure the efficacy of the new AEDs in treating idiopathic generalized epilepsy are rare, the new agents have demonstrated efficacy in treating generalized tonic-clonic convulsions. Data for treatment of Lennox-Gastaut syndrome indicate a clear effect with lamotrigine or topiramate and possibly some effect with zonisamide and levetiracetam. Studies of juvenile myoclonic epilepsy and absence seizures suggest that zonisamide, lamotrigine, topiramate, and levetiracetam may be effective. Each of the new AEDs is effective in controlling partial seizures. These agents may also be appropriate choices for newly diagnosed patients or those whose conditions are refractory to treatment. In clinical trials, patients who are refractory to treatment are often given escalated doses to gain effect, but higher doses also result in more adverse events and higher withdrawal rates. Generally, the higher the dose, the greater the odds of withdrawal, with the exception of levetiracetam, which is not associated with increased withdrawal rates at high doses. Newly diagnosed patients are likely to be controlled with the first therapy given to them. It is therefore important to select an agent with the best safety, efficacy, and tolerability profile possible