Proof of principle trials: EEG surrogate endpoints

Pivotal studies in man require prolonged administration to demonstrate effi cacy for most seizure types. Earlier evidence of human efficacy can be of v alue for decision making, and EEG surrogate endpoints can be of value in th is respect. Studies of spontaneous EEG discharges under standard recording conditions can demonstrate meaningful acute EEG effects of antiepileptic dr ugs (AEDs). These require a rapidly effective formulation of the product, p referably intravenous. The EEG recording conditions are standardised and th e subject is required to perform a task to maintain a constant level of vig ilance. The outcome measure of efficacy is spike count per minute or, if th e discharges are more protracted (as generalised no spike and wave), the pe rcentage of recording time occupied by discharges. Sub-acute experiments ar e conducted under less rigorously standardised conditions, but over longer periods, using ambulatory monitoring or telemetry to record the EEG. The ph otoparoxysmal responses (PPRs) of photosensitive subjects, evoked using a s tandardised stimulation protocol, are subject to less variability than spon taneous epileptiform activity. The PPR is elicited over a range of flash ra tes that can be used as a measure of sensitivity, and an effective treatmen t will reduce the range or abolish the PPR. Reduction in photosensitivity i s demonstrable after a single dose of various AEDs, at clinically relevant plasma concentrations, even using drugs that are not generally effective fo r long-term treatment of photosensitive epilepsy. Evoked potential and nerv e conduction studies and electronystagmography can be used to assess possib le neurotoxicity, and quantitative EEG analysis can be employed to assess s edative effects. (C) 2001 Elsevier Science B.V. All rights reserved.