The human photosensitive epilepsy model for clinical proof-of-principle trials of novel antiseizure medications. 1. Use of the EEG in drug development and characteristics of the model

Clinical development of novel antiseizure medications (ASMs) would benefit from an early proof-of-principle (POP) model. The photosensitivity model, which uses the photoparoxysmal electroencephalography (EEG) response (PPR) as a surrogate for seizures, is currently the only human model that allows POP trials of investigational compounds after a single drug administration. Typically, trials in this model are performed as single-blinded, placebo-controlled Phase IIa POP studies, evaluating a range of doses in small groups of patients with epilepsy. Although most patients in such trials exhibit generalized epilepsies, photosensitivity also occurs in focal-onset epilepsies. In the first part of this review, we describe the use of epileptiform discharges in drug testing, historical development of the photosensitivity model, the genetics and pathophysiology underlying the photosensitive response in patients with epilepsy, clinical characteristics of the patients, and details on drug testing. In the second part of this review, the outcome of numerous drug trials will be described in detail, including a critical discussion of the limitations of the model. In the past 50 years, the original and later standardized photosensitivity model has shown to be an unbiased, accurate, inexpensive method determining the potential efficacy of a novel ASM before entering large add-on trials with chronic drug administration, irrespective of the type of epilepsy.