Newer GABAergic agents for pharmacotherapy of infantile spasms

Infantile spasms is an age-specific epileptic syndrome in infants and young children. Although the exact mechanism is unknown, adrenocorticotrophic hormone (ACTH) has been the mainstay for the therapeutic management of infantile spasms and other developmental epilepsies. Clinical benefits of ACTH in infantile spasms could partially relate to its stimulatory effects on the release of adrenocorticosteroids and neurosteroids. Glucocorticoids, pyridoxine and ketogenic diet therapy have all been used for the treatment of refractory infantile spasms. Recent studies indicate that several newer anticonvulsant agents, which are positive allosteric modulators of GABA(A) receptors, are as effective as ACTH in acutely controlling infantile spasms. The efficacy of agents that enhance GABA-mediated inhibition (such as vigabatrin and benzodiazepines) for rapid and complete abolition of infantile spasms has been demonstrated in several clinical studies. Ganaxolone, a novel neuroactive steroid has, however, demonstrated outstanding efficacy and better tolerability in children with intractable infantile spasms. Zonisamide, topiramate, deoxycorticosterone and neurosteroids are emerging as effective treatment approaches. These new antiepileptic drugs represent a potential nonhormonal approach for infantile spasms, but additional studies are needed to verify their efficacy and tolerability. Future studies will hopefully identify rational antiseizure drugs that not only control infantile spasms but also abrogate its risk on the development of the brain.