All network activities, and therefore all forms of epilepsy, are ultimately based on the electrical behavior of individual neurons. At the cellular level, the last 25 years have seen enormous progress in the understanding of normal and abnormal electrical activity, and that progress is rooted in genetics. Genetic studies, correlated with electrophysiologic ones, have identified many mutations in ion channels that are responsible for various epilepsy syndromes. Examples of this are mutations in Na+ channels that lead to Dravet syndrome and mutations in GABA receptor subunits that are responsible for juvenile myoclonic epilepsy.
The mechanistic understanding of seizures and epilepsy has also been greatly enhanced in the last three decades by structural and developmental studies closely tied to genetics. Various forms of epilepsy are caused by aberrant neurogenesis and neuronal migration, leading to dysplastic cortex that has abnormal electrical activity and connectivity. The recent elucidation of the mTOR pathway, for example, has shown us how neuronal development and migration are controlled through several genetic steps, and mutations there can lead to tuberous sclerosis and related disorders that are accompanied by epilepsy.
Treatment
From the time that epilepsy was first recognized as a disease of the brain, treatment emphasized the control of seizures and not much else. A century after the introduction of bromide, there were, by 1967, perhaps half a dozen effective drugs available, including phenobarbital, phenytoin, and carbamazepine. Between 1967 and 1993, no new drugs for epilepsy were marketed in the USA, but the next 25 years saw a dramatic improvement. The years from 1993 to 2018 saw the introduction of perhaps 15 new drugs, most recently brivaracetam. However, in spite of this huge effort, at the expense of billions of dollars, each new drug makes less than 5% of previously refractory patients seizure-free.
Surgery
The idea of treating medically refractory epilepsy by surgical removal of the epileptic focus or network goes back more than a century, but advances in the last 25 years have been based on the revolution in imaging brought about by MRI. The easy and noninvasive identification of mesial temporal sclerosis and focal cortical dysplasias has enabled thousands of patients to become seizure-free. Complete control of seizures is obtained in only 50% to 75% of patients who undergo surgery, hardly better than a century ago, but advanced imaging and electrographic techniques have made surgery possible for many patients who previously would not have been candidates.
