This section addresses pharmacologic treatment of the epilepsies. Despite the availability of other treatments, including surgery, various devices, and behavioral/homeopathic treatments, antiepileptic drugs (AEDs) continue to be the mainstay of therapy for people with epilepsy. The overwhelming majority of individuals diagnosed with epilepsy will take AEDs for some period of time during the course of their illness, when they are available. Often, this treatment will last for decades and have a major impact on quality of life. There are currently over 20 drugs available for the treatment of epilepsy, and 10 were approved for use within the last 15 years. The availability of a large number of therapeutic options is advantageous for patients, but at the same time, this array increases the complexity of appropriate drug selection and management. The selection of antiepileptic drug is critical to the long-term well-being of the person with epilepsy, and this selection must be made with great care. In the absence of the “ideal” antiepileptic drug, it is optimal to have several reasonable choices in order to cover the great variability in types of epilepsy as well as individual patient characteristics. It is the intent of this section to provide important and useful information that will facilitate the selection of optimal treatment strategies.

Pharmacologic treatment of epilepsy has come a long way in the last century. Before the discovery in the mid-19th century that bromide could be used as a treatment for epilepsy, there was no useful treatment available for the disorder. Of interest, valproic acid existed as a solvent but was not identified as an antiepileptic drug for another 100 years.

Bromide was suggested as an AED in 1857, but for the wrong reasons. When Edward Sieveking presented 52 cases of epilepsy at the Royal Medical and Chirurgical Society in London, one physician, Charles Locock, mentioned that he had used potassium bromide to treat “hysterical” epilepsy, which usually occurred around menstruation (catamenial epilepsy today). It had also been reported that potassium bromide caused impotence in males, and the idea was that bromide would reduce sexual excitement in women and calm down epileptic activity, which, in fact, it did.⁷ In 1912 phenobarbital was discovered, and it remains a useful AED today. It is also the major anticonvulsant agent used in veterinary medicine.

The German chemist Adolph von Baeyer synthesized “malonylurea” from a reaction of urea with malonic acid, a chemical found in apples. This became known as “barbituric acid.” Its discovery led to various derivatives, and by 1903 Fischer and von Mering had synthesized a therapeutic barbiturate that induced sleep.

Further development focusing on barbituric acid led to the synthesis of phenobarbital. Hauptmann’s clinical studies in 1912 demonstrated both sedative action and anticonvulsant activity.⁷ Various alterations in the phenobarbital molecule led to the discovery of benzodiazepines.¹⁰

The idea that compounds could be tested for anticonvulsant activity now gained a foothold among neurologists and psychiatrists, and this eventually led to more new treatments for epilepsy. After phenobarbital, the next drug to appear was phenytoin. Phenytoin (diphenylhydantoin) was first synthesized in 1908 by a German physician named Heinrich Biltz. He sold his discovery to Parke-Davis, which did not find an immediate use for it. In 1936, H. Houston Merritt and Tracy Putnam discovered phenytoin’s usefulness for controlling seizures. Using an animal model of maximal electroshock (MES), Merritt and Putnam found that phenytoin could control seizures without the sedation of phenobarbital, and by 1938 it was marketed as a new antiepileptic drug in the form of Dilantin sodium. Nearly 75 years later, phenyt-oin remains one of the most effective AEDs for partial-onset seizures and is used as a main agent in the treatment of status epilepticus.

After the development of phenytoin, other drugs entered the market, with primidone being introduced in 1952.¹¹ It was synthesized by making a minor alteration in the phenobarbital molecule. Primidone’s efficacy, like that of phenytoin, was established in the MES test developed by Merritt and Putnam. It appeared to have anticonvulsant activity that was independent of phenobarbital and also more effective.

Ethosuximide appeared in 1960, and carbamazepine in 1974. Valproate was accidentally recognized as an AED in the 1960s. As already noted, it had been available as a solvent for other AEDs for some time, but during testing in animal models it was found to be more effective alone than the experimental drugs thought to be of interest. Today, valproic acid is still among the most effective broad-spectrum AEDs available.

In 1969, the National Institutes of Neurological Disorders and Stroke (NINDS) initiated the Anticonvulsant Drug Development (ADD) Program under the leadership of J. Kiffen Penry. In 1975, as a response to the dearth of new compounds being identified for use in epilepsy, the Epilepsy Branch of the NINDS established the Anticonvulsant Screening Project (ASP) in collaboration with investigators at the University of Utah.^12,13 The problem at the time was that the pharmaceutical industry had almost no interest in developing AEDs, and the NINDS believed it had the responsibility of trying to stimulate corporate interest by identifying promising compounds through the drug screening program. The ASP’s role was and still is to identify possible drug candidates and evaluate their antiepileptic potential in animal models. Subsequently, the ADD program would (and, to some extent, still does) take these candidate drugs forward into clinical testing. This collaboration was the first attempt to screen organic compounds systematically on a large scale in animal models as a means of discovering and then developing new therapies for epilepsy. To date, the ASP has
screened more than 24,000 compounds. The fact that we have a new generation of antiepileptic drugs available is in large part due to the direct influence and inspiration of the ADD program and the ASP.