Historical trend toward improved long-term outcome in childhood absence epilepsy.

We retrospectively analyzed published studies to investigate historical trends in outcome of childhood absence epilepsy (CAE). We included patients based on onset of absence seizures in childhood, 3 Hz bilateral spike-wave discharges on EEG, and availability of seizure-free outcome data. The primary endpoint was seizure-freedom off medications by study publication year. We also analyzed relationships between seizure-freedom and 1. treatment medication, and 2. CAE diagnostic criteria. We included 29 studies published 1945-2013, encompassing 2416 patients. Seizure-freedom off medications was higher for studies after 1985 versus before 1975 (82% versus 35%; p < 0.001). Ethosuximide and valproate were used more commonly after 1985, and patients previously treated with ethosuximide or valproate had higher seizure-freedom off medications than those treated only with other medications (64% versus 32%; χ2>10; p < 0.001). Although differences in diagnostic criteria for early vs. later studies did not reach statistical significance, later studies tended to use normal EEG background (p = 0.09) and absence of comorbid disorders (p = 0.09) as criteria more commonly. These findings demonstrate that seizure-freedom off medications has improved in published CAE studies after 1985. Our results are limited due to retrospective analysis. Further work is needed with prospective, controlled trials to establish factors leading to improved long-term prognosis in CAE.

How did phenobarbital's chemical structure affect the development of subsequent antiepileptic drugs (AEDs)?

Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of which resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures that are diverse and completely different from that of phenobarbital. Sixteen AEDs were introduced between 1990 and 2012. Most of these AEDs were developed empirically, using mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their multiple mechanisms of action, explains their diverse chemical structures. The antiepileptic market is therefore crowded. Future design of new AEDs must have a potential for treating nonepileptic central nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis, or restless legs syndrome). The barbiturates were once used as sedative-hypnotic drugs, but have been largely replaced in this role by the much safer benzodiazepines. In contrast, phenobarbital is still used worldwide in epilepsy. Nevertheless, the development of nonsedating phenobarbital derivatives will answer a clinical unmet need and might make this old AED more attractive.