A Randomized, Double-Blind, Cross-over Study of the Cognitive and Mood Effects of KEPPRA (Levetiracetam) Tablets in Healthy Older Adults.

III. INTRODUCTION:

Background Antiepileptic Drugs And Cognitive Dysfunction Epilepsy is the most common debilitating neurologic disorder, with a prevalence of about 6/1000 in the general population (Hauser and Hesdorffer, 1990). Along with the disabling psychosocial and physical disadvantages that accompany epilepsy, medication concerns are frequently reported (Gilliam F et al. 1997). The majority of adverse events related to medications pertain to cognition (Baker GA et al. 1997).

A variety of factors contribute to cognitive dysfunction in persons with epilepsy, one of which is treatment with antiepileptic drugs (AEDs). The effects of AEDs appear to display a dose dependent relationship to cognitive functioning. Even more striking adverse effects on cognition are found as a result of AED polytherapy. Evaluation of the cognitive effects of AEDs in patients with epilepsy can easily be confounded by seizure effects, underlying cerebral injury, genetic, factors, and chronic impact of living with seizures. To limit the confounding cognitive effects of epilepsy, investigators have examined the cognitive effects of AEDs in healthy volunteers. Meador et al. (1995) have presented data demonstrating mild untoward effects of three common first line AEDs in a group of young healthy adults employing a randomized, double-blind, incomplete block crossover design. More than one-half of the neurocognitive dependent variables exhibited AED effects when compared with non-drug baselines. Studies of newer drugs have shown variable impairment with gabapentin and lamotrigine showing less impairment compared to the older, first-line drugs and to topiramate.

Epilepsy In The Elderly The incidence of epilepsy increases as age advances beyond 50. Indeed there is a two- to three-fold increase above the age of 75 years compared with any other age group (Ramsay et al. 2004). This special population is at increased risk for development of adverse events related to AED treatment as they are likely to have multiple medical conditions, take numerous concomitant medications, have different metabolic characteristics, and are more likely to suffer from neurologic conditions such as stroke and dementia. The elderly are more susceptible to cognitive impairment by AEDs. However, little is known of factors affecting health-related quality of life in senior adults with epilepsy (Martin et al., 2003)6. All older AEDs have clear pharmacokinetic disadvantages as they are liver metabolized with many known drug interactions.

Levetiractam Levetiracetam was approved by the FDA in 1999 for the treatment of epilepsy. Levetiracetam was shown to be an effective pharmacologic treatment for refractory partial seizures in a number of large multicenter clinical trials (French, et al., 2001; Cramer et al., 2003; Morrell et al., 2003). The pharmacokinetic profile of levetiracetam has particular advantages over other anti-epileptic drugs. Pharmacologic advantages include low protein binding, renal clearance, and an absence of drug interactions (Perucca and Johannessen, 2003.).