[Frontiers in Bioscience 5, e124-152, November 1, 2000]

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Epilepsy, Seizure, Anti-Epileptic Drug, Drug Discovery , Development, Etiology, Review


Copyright © Frontiers in Bioscience, 1995


Simon P. Aiken1 and William M. Brown2

1 School of Biology, University of St. Andrews, St. Andrews, Fife KY16 9TS, UK, 2 Taro Pharmaceuticals, 5 Skyline Drive, Hawthorne, NY 10532, US

1. Abstract
2. Introduction to epilepsy and related disorders
2.1. Incidence and prevalence
2.2. Causes of epilepsy
2.3. Types of seizure
2.4. Types of epilepsy
2.5. Related disorders
2.5.1. Severe myoclonic epilepsy of infancy
2.5.2. West syndrome
2.5.3. Lennox-Gastaut syndrome
2.5.4. Landau-Kleffner syndrome
2.5.5. Hemifacial spasm
2.5.6. Trigeminal neuralgia
2.6. Diagnosis
2.7. Medical management of epilepsy: general principles
2.8. Non-pharmacological treatment of epilepsy
2.8.1. Surgery
2.8.2. Vagus nerve stimulator
2.8.3. Ketogenic diet
3. The challenge of developing anti-epileptic drugs
3.1. Discovery and development of AEDs
3.2. Rational drug discovery in a perfect world
3.3. Etiology of epilepsy
3.3.1. Genes implicated in epilepsy
3.3.2. Therapeutic strategies suggested by these mechanisms
3.4. Animal models of epilepsy
3.5. Known reference compounds
3.6. Objective, reliable clinical outcomes
3.7. Other challenges in clinical development
3.8. Toxicity issues
3.9. Conclusion
4. Pharmacotherapy of epilepsy
4.1. First generation drugs
4.1.1. Bromide salts
4.1.2. Barbiturates
4.1.3. Primidone
4.1.4. Phenytoin
4.1.5. Fosphenytoin
4.1.6. Ethosuximide
4.1.7. Acetazolamide
4.1.8. Sodium valproate/valproic acid
4.1.9. Benzodiazepines
4.1.10. Carbamazepine
4.1.11. Oxcarbazepine
4.2. New generation drugs
4.2.1. Felbamate
4.2.2. Gabapentin
4.2.3. Lamotrigine
4.2.4. Topiramate
4.2.5. Tiagabine
4.2.6. Vigabatrin
4.2.7. Zonisamide
4.2.8. Levetiracetam
4.2.9. Flunarizine
4.3. The "next generation"
4.3.1. Remacemide
4.3.2. Ganaxolone
4.3.3. Losigamone
4.3.4. Stiripentol
4.3.5. Pregabalin
4.3.6. Harkoseride
4.3.7. Rufinamide
5. Conclusions
6. Acknowledgements
7. References


Epilepsy is a major public health issue, not least because of the aging population in many developed nations and the known increase in the frequency of epilepsy and seizures in later life. Despite the massive scale of the problem and much research, epilepsy remains poorly understood. Despite more than 20 approved drugs in the developed nations and several non-pharmacological options, up to 30% of patients are still refractory to treatment. Despite over a century of pharmacotherapy and neuroscience research, rational design of anti-epileptic drugs (AEDs) is only now starting to yield results, because of the heterogeneity of the disease and our still limited understanding of it. Discovery and development of AEDs has been especially difficult, because of the regulatory issues of satisfactorily proving safety and efficacy, ethical constraints on placebo-controlled trial designs, the fact that seizures are typically widely spaced in time, and the fact that the person undergoing the seizure is typically in no state to remember, letalone assess, what happened. Several non-pharmacological therapies have been developed: brain surgery was first used more than a century ago; the ketogenic diet was first developed 80 years ago; and the vagus nerve stimulator was introduced recently. Pharmacotherapy remains the mainstay of treatment and is effective in most patients. AEDs can be roughly divided according to their time on the market. The first generation extends from the bromides and the barbiturates (the first of which was phenobarbital), to sodium valproate and carbamazepine. The second generation begins with felbamate and includes drugs approved from 1993 to 2000. "Next generation" drugs are still in clinical development and may reach the marketplace in the near future. Intensive research is being conducted both by pharmaceutical and biotech companies and by academic scientists and clinicians; our understanding of the condition is advancing rapidly but many challenges remain in discovering and developing better AEDs.


2.1. Incidence and prevalence

Epilepsy is a chronic brain disorder characterized by recurrent seizures that affects 1-3% of the U.S. and Canadian populations (1-3). Epilepsy occurs with a prevalence of about 0.5% and a cumulative lifetime incidence of 3% (4-6). Consequently, as many as one person in 20 will experience a seizure during his or her lifetime (2,6). Epilepsy is thus the second leading neurological disorder, exceeded only by stroke. Approximately 50 million people worldwide suffer from the condition (3), and more than 5 five million experience at least one seizure per month; almost three-quarters of those receive no treatment for their seizures (7).

'Seizures' and 'epilepsy' are often used as if they are synonymous, and yet they are not; seizures are a symptom of epilepsy. While all epilepsies are characterized by seizures, not all seizures are epileptic. Epilepsy is the underlying neurological condition that can lead to brief disturbances in the brain's electrical functions.

Worldwide, there are considerable differences in the epidemiology of epilepsies and seizures. In Latin America, for example, two incidence studies have shown that in Chile and Ecuador, incidence rates approach double those of the industrialized nations (see 4,5,8-10). Clearly, this raises the question as to whether epilepsies and/or seizures could represent a marker of some endemic disease or socioeconomic condition. A high prevalence of epilepsy in several African countries is believed to be associated with parasitic infections, particularly neurocysticercosis (11-15). Other possible etiological factors include intracranial infections, perinatal brain damage, head injuries, toxic agents, and hereditary factors (see 16-20).

Many studies have concluded that the onset of epilepsy occurs at the extremes of life; children under 10 and seniors over 60 years are represented disproportionately in patients with epilepsy (see 4,6,21-34). This is a particularly important observation given the aging of the post second world war "Baby Boomers," especially in the U.S. The boomers are a cohort of approximately 75 million Americans born between 1946 and 1964; they will reach the age of 65 in 2010 and beyond (35-38). As a result, a large increase in the number of patients with epilepsy can be expected in the first few decades of this century. Similar demographic patterns are evident throughout the developed and even much of the developing world.

While few people die during seizures, the large number of people suffering them, high costs associated with the condition, and lifestyle limitations make epilepsy a major medical problem (39-43). Patients with epilepsy do have a mortality rate higher than that of the general population (see 44). This is partly due to what is referred to as "sudden unexpected death in epilepsy" (SUDEP; 45-51). Furthermore, patients are subject to considerable risk of physical injury during seizures (52-61).

In addition to the medical condition itself, the psychosocial consequences of poorly controlled seizures can be severe (62-65). Patients with epilepsy are generally undereducated and underemployed in relation to their level of ability (66-70). Additionally, some people still consider the condition to be associated with mental illness, and even demonic possession (71-74). Thus, many epilepsy sufferers feel stigmatized by their condition (73,74).

2.2. Causes of epilepsy

There are believed to be over 100 underlying causes of epilepsy; however, in as many as 70% of cases no cause is ever found. Some of the known causes include brain injuries, infections that lead to brain damage (e.g. cerebral malaria, cysticercosis), tumors and abscesses, disturbances in blood circulation to the brain (such as stroke), certain metabolic disorders, high fevers, lead or other poisoning, and intrauterine injury (see 16-20,75).

2.3. Types of seizure

While there are more than 40 different types of epilepsy-related seizures, they fall into 3 broad categories. The distinction depends largely on the part of the brain affected (76-78). The 3 categories are:

  • generalized seizures (occurring in 46% of patients),
  • partial seizures (occurring in 32% of patients), and
  • partial seizures that secondarily generalize (occurring in 20% of patients) (76-78).

Generalized seizures cause loss or alteration of consciousness, involve the entire brain, and affect the whole body. They include grand mal (tonic-clonic) seizures, where typically the person falls down unconscious as the body stiffens (tonic) and then jerks (clonic), as the skeletal muscles alternate between relaxation and rigidity, and petit mal ('absence') seizures, where there is a momentary alteration of consciousness without abnormal movements. Such absence seizures are typically brief (3-30 seconds), only involve a short cessation of physical movement and/or loss of attention, and may even go unnoticed by others. Partial seizures occur when abnormal electrical activity involves only one area of the brain. There are also two kinds of partial seizure: simple seizures, where the person remains conscious; and complex seizures, in which consciousness is lost or altered. It is also possible for simple or complex partial seizures to evolve into generalized seizures. In fact, in some patients, the progression may be so quick that the partial stage is hardly noticeable. While the type and nature of seizures vary widely between individuals, they are typically stereotyped within individuals.

2.4. Types of epilepsy

Following this categorization of seizures, the International League Against Epilepsy (ILAE) classifies epilepsies as either local or generalized. Seizures from local epilepsies originate from a discrete cortical site; seizures from generalized epilepsies originate from both cerebral hemispheres (79). The ILAE also distinguishes between idiopathic and symptomatic epilepsies. Those associated with a known or suspected brain disease or lesion are referred to as symptomatic. Epilepsies that are inherited without identifiable pathology are labeled idiopathic. Idiopathic epilepsies often carry a better prognosis than symptomatic disorders.

Clinically, the distinction between partial (or secondarily generalized) seizures and primary generalized seizures is meaningful because the two types respond differently to anti-epileptic drugs (AEDs). For example, partial seizures frequently respond to carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid. Similarly, valproic acid or ethosuximide control generalized seizures in many patients who experience absence attacks, and valproic acid also controls seizures in many patients with generalized seizures.

Most epileptic seizures last only a minute or two and are not life-threatening. However, repeated seizures (status epilepticus; 80,81) without regaining consciousness between attacks and prolonged seizures can lead to permanent brain damage (82,83). Status epilepticus is defined as a seizure that lasts at least 30 minutes or is repeated at sufficiently brief intervals to produce a continued epileptic condition lasting a total of 30 minutes without the patient fully regaining consciousness (80,83-86).

2.5. Related disorders

2.5.1. Severe myoclonic epilepsy of infancy

Severe myoclonic epilepsy of infancy (SMEI) is a recently recognized epileptic syndrome. It is characterized by multiple febrile seizures (often prolonged), subsequent development of uncontrollable mixed-myoclonic seizures, and, eventually, by psychomotor retardation (87-90).

2.5.2. West syndrome

West syndrome is a rare form of infantile spasm occurring early in neonatal development. It is associated with hypsarrhythmias (abnormal EEG recordings) and sometimes with mental retardation. The spasms vary from violent 'jackknife' movements of the body to no more than mild twitching of the nose or mouth. There may be more than one underlying cause of West syndrome (91-94).

2.5.3. Lennox-Gastaut syndrome

Lennox-Gastaut syndrome is a childhood disorder characterized by several kinds of seizures, mental retardation, resistance to most AEDs (95), and characteristic EEG features (96-100). Felbamate was the first drug shown to be effective in treating Lennox-Gastaut syndrome in controlled trials and remains the drug- of-choice for this condition (see 101).

2.5.4. Landau-Kleffner syndrome

Landau-Kleffner syndrome is another rare childhood epilepsy, usually beginning between the ages of 3 and 8. It is characterized by severe language difficulties, particularly involving comprehension. Patients may also be unable to recognize environmental sounds, such as a ringing telephone. Whilst all Landau-Kleffner patients have abnormal temporal lobe EEGs, only about two-thirds suffer seizures. The seizures are typically responsive to AEDs (102-104).

2.5.5. Hemifacial spasm

Hemifacial spasm is characterized by chronic involuntary twitching or spasm on one side of the face, usually starting around the eye and progressing down the face. The most common cause is a blood vessel pressing against the facial nerve. The condition is sometimes treated with a neuromuscular blocker, such as botulinum toxin, or by surgery (105-107).

2.5.6. Trigeminal neuralgia

Patients suffering from trigeminal neuralgia (or tic douloureux) experience sudden electric shock-like pains on one side of the jaw or chin. These acute pains generally last for a few seconds at a time, and may occur for days, weeks or months, followed by a longer period that is symptom-free. The cause involves damage to the trigeminal nerve that innervates the jaw and face, and may be traced to a blood vessel pressing against the nerve or a tumor. Treatment of trigeminal neuralgia is generally with AEDs, such as carbamazepine or phenytoin. Baclofen, clonazepam or valproic acid may also be used, and surgery may be an option in some cases (108-111).

2.6. Diagnosis

Diagnosis of the first seizure is still based largely on the patient's medical history (6). Many paroxysmal events may be confused with epileptic seizures, including syncope, movement disorders, parasomnias, and psychogenic seizures (112-116). Syncope is one of the conditions most commonly confused with epileptic seizures. Studies in which volunteers were videotaped during induced syncopal events illustrate the common occurrence of repetitive clonic, myoclonic or dystonic movements on fainting. Such movements rarely persist beyond 5-10 seconds, and do not exhibit the organized progression from tonic to clonic phase typically seen in true convulsive seizures (see 112, 114-116).

Most authorities recommend that patients who experience an unprovoked seizure undergo a brain imaging study in an effort to detect underlying cerebral lesions. Such a scan would likely uncover tumors, abscesses, vascular malformations, stroke, or traumatic injury (see 117-119).

Electroencephalography (EEG) is often helpful in evaluating patients presenting with a seizure (120). Uses of EEG include detection of epileptiform activity, strengthening the putative diagnosis, identification of focal electrocerebral abnormalities (suggesting a focal structural brain lesion), and documentation of specific epileptiform patterns associated with particular epilepsy syndromes (for example, generalized spike-and-wave discharges associated with a generalized epilepsy, or focal discharges associated with a localization-related epilepsy) (120).

While many physicians choose not to prescribe anti-epileptic therapy for patients after a single seizure, the decision to treat initial seizures with medication is controversial and widely debated (see 6,113,121-125). Factors of concern include the likelihood of recurrent seizures, the risks of the treatment itself, and the ability of the treatment to decrease the risk of recurrent seizures. In addition, the potential psychological, social, and vocational consequences of further seizures must be considered (62-65).

2.7. Medical management of epilepsy: general principles

The goal of treating epilepsy is to control the seizures completely without causing unacceptable side effects. Pharmacotherapy remains the mainstay of epilepsy treatment (126,127). In the last decade, several new anti-epileptic drugs have become available, and more are in development (128). The key step is the selection of an AED that is appropriate for the patient's particular type of epilepsy. A specific epilepsy syndrome diagnosis is based on the history of the patient's seizure types, neurological status, and EEG findings. In selecting an AED, the physician must also consider the patient's willingness to tolerate the adverse effects of certain treatments.

2.8. Non-pharmacological treatment of epilepsy

While pharmacotherapy remains the mainstay of epilepsy treatment (129), there are other options for some patients, including brain surgery (130-132), the recently introduced vagal nerve stimulator (133-135), and the much-debated ketogenic diet (136-138). These treatments and the uses of each will now be discussed.

2.8.1. Surgery

Brain surgery is an option in some epileptic patients, though those with progressive metabolic or neurodegenerative conditions are usually poor candidates (see 130,132). The most common surgical procedures include anterior temporal lobe resection (6,131,139) and hemispherectomies (132). Such surgery frequently results in complete seizure control, though the surgery is considered successful even if the patient requires AEDs to remain seizure-free.

2.8.2. Vagus nerve stimulator

The vagus nerve stimulator is a novel, non-pharmacological treatment for epileptic patients whose seizures are uncontrolled by AEDs (140-143). The FDA approved the device in 1997. The device is no panacea and is not appropriate for all patients, but controlled studies have demonstrated efficacy (140,144).

Effects of vagal nerve stimulation on brain activity have been known since the 1930s (see 145). In the 1950s, it was noted that vagal nerve stimulation caused desynchronization on EEGs (see 145,146). As seizures represent synchronized electrical activity, it is reasonable to suppose that vagal stimulation might inhibit seizures. Vagal nerve stimulation was indeed shown to decrease the frequency and duration of seizures in animal models (147).

In the currently approved product, a bipolar lead is wrapped around the left vagus nerve and tunneled to the infra-clavicular region, where it is connected to the signal generator. This signal generator delivers a precise pattern of stimulation to the vagus nerve. Typically, the device stimulates for 30 seconds every five minutes. In addition, the patient or a caregiver can manually activate the stimulator at the onset of a seizure, with the goal of terminating the seizure before it escalates (134,140-142).

2.8.3. Ketogenic diet

A hotly debated non-pharmacological treatment for epilepsy is the so-called ketogenic diet, a special high-fat, low-carbohydrate diet that induces ketosis, a condition in which abnormally large amounts of ketones are produced, with a resulting anti-epileptic effect (136,148-153). Although the diet was developed in the 1920s, it remains unknown how or why ketosis affects seizure activity, so the principles behind the therapy have been developed from years of clinical experience and assumptions, rather than from a mechanistic understanding (154). It seems to work in some animal models of epilepsy (155), but not in others (156).


3.1. Discovery and development of AEDs

Because epilepsy covers a range of disease states and there are many underlying causes, coupled with the difficulty in identifying the cause in many patients and the general lack of understanding of the disease, success with target-based strategies for drug discovery has been limited. This section discusses some aspects of research and development strategy.

In addition to scientific and clinical problems, regulatory issues have been important in the history of AED discovery and development. In the U.S., the 1938 Food Drug & Cosmetic Act (157) (enacted following the Elixir Sulfanilamide tragedy; 158) required proof of safety before a drug could be approved for marketing. The subsequent 1962 Kefauver-Harris amendments to the Act (enacted after the thalidomide tragedy; 159,160) required proof of efficacy (161-164). These two pieces of legislation effectively stopped the introduction of new AEDs in the U.S., because of the difficulties in proving the safety and efficacy of an AED (165,166). The regulatory requirements were rather less stringent in Europe, carbamazepine and valproate being introduced as first-line AEDs in 1963 and 1974, respectively (167). They were subsequently introduced in the U.S. in 1974 and 1978, respectively (128).

No new AED was introduced in the U.S. between 1978 and 1993. Despite that, a greater understanding of pharmacokinetics lead to a more efficient use of existing drugs and, more importantly, it was recognized that the development of drugs on an empirical basis was no longer sensible. As a result, more effort was devoted to understanding the molecular and chemical bases of epilepsy and the rational development of new AEDs (see 168).

3.2. Rational drug discovery in a perfect world

In a perfect world, four areas of knowledge are required for the effective and efficient discovery and development of new drugs. In this perfect world, drug discovery scientists would:

  • know the mechanism(s) of the disease
  • possess reliable preclinical animal models of the disease that are representative - or at least indicative - of human results
  • have reference compounds, even clinically unusable compounds, after which new drugs can be modeled and against which new drugs can be assessed
  • have objective, reliable clinical outcome measures.

Armed with this knowledge, the scientist identifies drug targets (169-171), develops in vitro screening assays to be used prior to animal models, designs compounds, perhaps conducts random screening using the in vitro assay (172,173), identifies lead compounds with activity, makes variants and analogs of the lead compounds, and identifies those compounds that are worth carrying forward to animal studies. Promising compounds are then tested in animal models of the disease.

Efficacy is, of course, only half the story. In vitro and animal studies to assess safety (toxicity, mutagenicity), pharmacokinetics (adsorption, distribution, metabolism, and excretion), and pharmacodynamics (therapeutic profile) are also required. If the drug passes all these tests and is still considered safe and efficacious, applications are made to the appropriate regulatory authorities to begin human studies.

3.3. Etiology of epilepsy

Most forms of epilepsy are associated with synchronous firing by large numbers (hundreds of thousands) of neurons, a phenomenon that is readily detected by EEG in the form of a large 'interictal' spike (see 174-177). Such synchronous firing is thought to result from burst firing of pyramidal cells, which generate synchronous activity in post-synaptic neurons by the process of temporal summation (see 178,179). The large-scale firing is terminated by the opening of voltage-dependent and calcium-dependent potassium channels, preventing further spread of the seizure (180).

What causes this neuronal discharge in epileptic patients? It is clear that an epileptic seizure is associated with a shift in the balance between excitation and inhibition in the brain, manifested as a large, prolonged depolarization of the neurons. The generation of dendritic potentials may be an underlying cause of this, especially the generation of calcium spikes in the dendrites.

3.3.1. Genes implicated in epilepsy

Genetic research into epilepsy is a very active area; the picture so far is that the inheritance of epilepsy is complex and polygenic, like that of diabetes and cancer (see 181-191). Given the heterogeneity of the clinical condition, it is hardly surprising that more than one gene is involved.

Despite this, some autosomal dominant idiopathic epilepsies with simple inheritance patterns have been identified and genetically characterized (24, 188, 189, 192, 193). An understanding of these epilepsies will aid in understanding the much larger number of epilepsy conditions with complex inheritance. These idiopathic conditions point to single gene defects that can cause epilepsy.

Autosomal dominant nocturnal frontal lobe epilepsy, a rare idiopathic partial epilepsy syndrome, is caused in some families by mutations in the gene encoding the alpha-4-subunit of the neuronal nicotinic acetylcholine receptor (194-204). In vitro studies suggest that the mutations lead to impaired function of the acetylcholine receptor, raising the possibility of cholinergic therapy for this condition (see 188,189,195,201).

Benign familial neonatal convulsions is an idiopathic generalized epilepsy in newborns that follows autosomal dominant inheritance. Defects in the genes encoding two homologous voltage-gated potassium channels appear to be the cause of the condition (186,205).

Generalized epilepsy with febrile seizures appears to result from mutations in a voltage-sensitive sodium channel (206,207). At least in the family studied, there was a linkage to 19q13.1 and a mutation was identified in the gene encoding the voltage-gated sodium channel beta-1-subunit. The mutation lead to a change in a conserved cysteine residue that disrupted a disulfide bridge, apparently leading to loss of function (206). Other research has suggested an additional locus on chromosome 2 (208).

In several other conditions, genetic linkages have been established, again suggesting single gene defects, though the specific genes have yet to be characterized. Familial partial epilepsy syndrome with variable foci (FPEVF) has been linked to a 3.8cM region on chromosome 22q11-q12, between markers D22S1144 and D22S685. The syndrome is inherited in an autosomal dominant manner with incomplete penetrance (209). In juvenile myoclonic epilepsy, there is evidence that a locus is located on chromosome 15, in addition to a previously characterized one on chromosome 6 (see 181,210-212). Interestingly, the GABAB receptor gene is located near the chromosome 6 locus (213-215), and the gene encoding the alpha-7-subunit of the acetylcholine receptor is near the chromosome 15 locus (210).

Thus, at least three autosomal-dominant idiopathic epilepsies are channelopathies and result from mutations in genes encoding ion channels. Benign familial neonatal convulsions result from mutations affecting voltage-sensitive potassium channels (216,217). Nocturnal frontal lobe epilepsy results from mutations affecting a central nicotinic acetylcholine receptor (216). Generalized epilepsy with febrile seizures result from mutations affecting a voltage-sensitive sodium channel (206,207). Recently published research suggests that idiopathic generalized epilepsy may result from mutations in gene encoding the calcium channel beta-4-subunit, CACNB4 (218).

At least one idiopathic epilepsy, however, is not a channelopathy. Unverricht-Lundborg disease - an autosomal recessive disorder - is caused by defects in the cystatin B gene (also known as stefin B), leading to the absence, or greatly reduced level, of the gene product. How the absence of this gene product leads to epilepsy is much less clear. The cystatins are a family of cysteine protease inhibitors (219). Unverricht-Lundborg disease is a clinically recognizable form of progressive myoclonic epilepsy. There was no biochemical marker for the disease, but a positional cloning strategy lead to characterization of the gene responsible. In a seminal paper on the condition, two mutations in the cystatin B gene were found in patients with Unverricht-Lundborg disease (220). Since then, an unstable expansion of a 12-base-pair mini-satellite repeat sequence in the promoter region of the gene has been found to be the most common defect (221-223). A series of other mutations has since been characterized (224-228).

3.3.2. Therapeutic strategies suggested by these mechanisms

The most important inhibitory neurotransmitter in the brain is gamma-aminobutyric acid (GABA) (229,230). It has long been known that downgrading the brain's GABAergic system (for example, with the GABAA antagonist bicuculline or with penicillin) causes epileptiform activity in humans and animals. Many currently available AEDs interfere with GABA neurotransmission in some way (231).

More recently, drugs have been used successful to treat epilepsy by interfering with the excitatory amino acid system. Agonists at all three subclasses of excitatory amino acid receptor (N-methyl-d-glutamic acid, NMDA; alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA; and kainate) cause epileptiform activity. Felbamate is an example of an AED that appears to inhibit NMDA transmission, although it also interacts with the GABA system (101).

Direct or indirect actions of AEDs on ion channels may contribute to their anti-epileptic activity. Felbamate and zonisamide inhibit both calcium and sodium channels. NMDA toxicity in particular is associated with influx of calcium to reach potentially cytotoxic concentrations, and so blocking calcium channels also appears to be a rational approach to the therapy of epilepsy.

3.4. Animal models of epilepsy

The drug discovery scientist needs reliable preclinical animal models of the disease that are representative- or at least indicative - of human results. The availability of animal models has shaped the history of AED discovery and development.

The earliest AEDs resulted from what was hardly a model system of rational drug design! The use of bromide salts and phenobarbital to treat epilepsy was entirely empiric; neither was intended to treat the condition. Bromide salts were being used to inhibit masturbation and sexual behavior (see 128,216,232-234). Phenobarbital was a sedative. Both were given to epileptic patients and happened to show some degree of efficacy.

The development of animal models of epilepsy lead to a rather more systematic way of evaluating potential AEDs (235-237). It had been known since the 1880s that electrical stimulation of animals could produce replicable seizures. Later, it was found that certain chemicals, including picrotoxin, bicuculline, strychnine, and pentylenetetrazol, could induce experimental seizures.

Animal seizure models were first used successfully by Merritt and Putnam in the late 1930s. They screened compounds using electrically induced seizures in cats and discovered the anti-convulsant properties of phenytoin (diphenylhydantoin; 238-243).

Better models were to follow. Swinyard and colleagues differentiated between threshold and spread in seizures (see 244). Some AEDs raise the seizure threshold; drugs that operate in this way (such as ethosuximide) are typically effective against absence seizures. This can be assessed using pentylenetetrazol-induced seizures in animals (245). Other drugs limit seizure spread. Drugs that operate in this way (such as phenytoin) are typically effective against partial and generalized tonic-clonic seizures. This can be assessed using the maximal electroshock (MES) animal model (245).

The kindling model of epilepsy in animals resembles psychomotor epilepsy in humans, in which patients experience both illusory phenomena and complex motor actions. The test animal is 'kindled' by repeated high-frequency electrical stimulation to a part of the limbic system (e.g. the amygdala) (246-248). Sensitivity of the neuronal circuits increases during the kindling process, until seizures can be produced in response to relatively small stimulation. This phenomenon suggests that epilepsy in humans may be caused by relatively brief electrical events that chronically alter the properties of the neuronal circuits. Treatment with the non-specific central nervous system (CNS) convulsant pentylenetetrazol (PTZ) can also be used to produce a kindling model of epilepsy, as can treatment with picrotoxin (249).

However, while animal models did advance AED research and essentially lead to the all of the first generation drugs except bromides and phenobarbital, they also created a problem in that they were used so extensively - in fact, almost exclusively. If your screen is the same animal model, it is likely that you will select only closely related drugs, or at least drugs that act in the same way (inhibiting the same seizures in the same way in the same animal model).

Even with the "new generation" of AEDs, despite the benefit of 30 years of neuroscience research, most AEDs were found by screening (i.e., chance, as opposed to rational design), or else they were variations of existing drugs. In fact, to date the only truly rationally designed AEDs are the GABA analogs vigabatrin, tiagabine, gabapentin, and pregabalin, which followed from the "GABA hypothesis" of epilepsy (229,230).

Today, several animal models of epilepsy are used in drug discovery (247,250-257). However, these animal models do not necessarily correlate with epilepsy in humans. More than 25 genes have now been identified in mice that lead to epileptic seizures when mutated (258,259). Many of these genes have been characterized, and they encode voltage- and ligand-gated ion channels. For example, the "tottering" mouse has mutations in the gene encoding the high voltage-activated alpha-1a-calcium channel subunit, and the lethargic mouse has mutations in the beta-4-calcium channel subunit gene (218,258,260,261). Together with results from the human idiopathic epilepsies discussed above, these animal models and the ability to make transgenic animals bearing the human mutations (262) should enable better models to be developed in the near future.

3.5. Known reference compounds

The drug discovery scientist also needs known reference compounds, even those that are clinically unusable, after which new drugs can be modeled and against which new drugs can be tested. As outlined in this review, this is no longer a problem; there is a long history of AEDs, going back to the bromides. There are, of course, many more molecules that have failed at some stage in development. Successes and failures can provide the scientist with insights.

3.6. Objective, reliable clinical outcomes

The drug discovery scientist also needs objective, reliable clinical outcomes to assess drugs. This is a particular problem with epilepsy. What is needed - ideally - is a clinical measure that does not depend on the seizure patient (or their caregiver) remembering or recording what happened.

There is currently no such measure in epilepsy; to assess efficacy, typically careful documentation of changes in ictal activity is used, determined by seizure counts based on patient recall, ideally direct clinical observation, and (at least for absence seizures) EEG monitoring. Assessment of seizure severity is another measure. The choice depends on the design of the trial. In short-term trials, parameters such as time to the nth seizure after randomization have been used as an index of anti-epileptic efficacy, but the clinical relevance of such measures is debatable. In add-on trials, changes in seizure counts and the proportion of patients achieving 50%, 75%, and 100% reduction in seizure frequency can be used. For long-term monotherapy trials in newly diagnosed patients, the proportion of patients achieving prolonged remission (1 year or longer) usually represents the most clinically meaningful efficacy outcome (263). Retention of patients on a treatment can also be a useful measure, although it is a composite endpoint, dependent on both efficacy and tolerability.

3.7. Other challenges in clinical development

Ethical considerations are a challenge in any clinical trial of a putative AED, especially because of the placebo control (264,265). The use of placebo-only treatment in epileptic patients is discouraged, not just because of the distress associated with seizures, but because severe seizures can result in injury, permanent brain damage, and, in the case of status epilepticus, even death (266-270). There is a further problem in that seizures and status epilepticus can be induced by withdrawing or altering the dose of an existing AED (271-275), making it difficult to wean a patient from his or her existing AED regimen in order to test a new drug. Quite separately, the placebo effect is well known in epilepsy studies, especially where parents or guardians monitor and report on the patients' seizures, as is typically the case (they are well-meaning, but not very objective) (276).

The now conventional approach to clinical trials of new AEDs is to use concomitant treatment with an established drug and the experimental drug, compared with established drug plus placebo (264,269,277-279). While this solves the ethical problem, it creates inevitable difficulties in interpreting results, because of possible drug interactions. Plasma levels of all drugs need to be closely monitored, as different classes of AED can alter each other's metabolism and drastically affect plasma levels (280-282). Despite these obvious problems, most of the current AEDs were tested in this way, beginning with the pioneering work of Rodin and colleagues on carbamazepine (283).

Testing a new drug in this way is not necessarily a bad thing. Polytherapy, the concomitant use of two or more drugs to treat one disease, is indeed common practice in epilepsy (284-288). Many AEDs are developed with the intention of being used in conjunction with existing drugs, and thus clinical trials taking this into account are quite appropriate.

The idea of ethically acceptable monotherapy trial design has not been forgotten (279,289-294). In recent years, some monotherapy trials have been conducted, in restricted circumstances (264). For example, felbamate was studied in placebo-controlled monotherapy trials in patients following pre-surgical electroencephalographic and video monitoring (295-297). In these trials, the patients underwent intensive neurodiagnostic monitoring after partial or complete withdrawal from their prior AEDs. In the hospital setting, a true placebo-controlled study is possible; seizures are closely monitored and not allowed to continue or progress to a potentially brain-damaging situation. Additionally, the monitoring of seizures is likely to be more objective than it typically is when parents, guardians, or others are involved (266).

AED trials are associated with relatively high drop-out rates (264). One reason for this is the rarity of seizures; dosing has to continue for several weeks, which then leads to poor compliance and inaccurate reporting of events by patients and caregivers. Additionally, the disturbance of a patient's established drug regime may result in seizures serious enough to force discontinuation of the test drug (or placebo) (271,298). In the treatment of most epileptics, care must be taken to achieve a suitable dose (balancing toxic effects against seizure prevention), and this individual approach to treatment further complicates a clinical trial.

One final problem is that a large proportion of patients entering a clinical trial represent 'atypical' epileptics who have responded poorly to existing drugs. In some cases then, a clinical trial may underestimate the true efficacy of a new AED.

3.8. Toxicity issues

Toxicity data for AEDs are often difficult to interpret, because many patients will be taking more than one drug. Plasma levels of one drug may be affected by the presence of another (280-282), and so toxicity should be correlated with plasma level and not dose. Some investigators have queried whether even that is valuable (299).

Neurological adverse effects of AEDs present a particular problem. Not surprisingly with CNS-acting drugs, serious neurological problems may occur. In many of the patients, however, the underlying epilepsy is itself a very serious neurological condition, and ascribing a particular neurological adverse effect to the AED may be unwise or impossible.

Several studies have shown that different classes of AED seem to be associated with teratological effects when taken during pregnancy (300-303). The individual drugs with the highest incidences were primidone, valproate, phenytoin, carbamazepine, and phenobarbital. Why these distinct classes of drug should all be associated with teratological effects is both intriguing and worrying. The incidence of malformations increased in polytherapy, and certain combinations (e.g. valproate plus carbamazepine, or primidone plus phenytoin plus phenobarbital) were associated with significantly greater susceptibility.

Another problem is that some AEDs may exacerbate seizures in certain patients (304-307). This phenomenon is poorly understood (305).

3.9. Conclusion

Discovery and development of new AEDs presents special challenges to the pharmaceutical industry; the researcher does not live in the perfect world outlined above. Rational, target-based research is hampered by our still limited understanding and the heterogeneity of epilepsy. While animal models are now available and have been important in the development of AEDs, they are only models and may not correlate well with the many forms of human epilepsy. Additionally, clinical trials are inevitably more complex than with most drugs, and have to be conducted with extreme care. Again, because of the heterogeneity of the condition, patient selection criteria add another variable into any clinical trial.


Epilepsy has been recognized for at least 3000 years; the earliest recorded account is in an Akkadian (Babylonian) text known as the Sakikku, dating from around 1050 BC (71,308,309). Since then, there have been many attempts to control epilepsy. The evolution of effective drug treatment for epilepsy has been a gradual and erratic process. There have been both scientific and regulatory reasons for this over the last decades.

Modern pharmacotherapy of epilepsy goes back as far as the introduction of phenobarbital in 1912 in the U.S. (see 310), and back to the 1860s if the use of bromide salts is included (128,216,234). Phenytoin (Dilantin) was introduced in 1938, and is still widely used (240). Despite this long history, successful pharmacotherapy remains a major challenge to this day, the disease being chronic and often life-long.

There are now more than 20 different drugs approved for the treatment of epilepsy in the developed nations, but the currently available drugs are far from perfect. Up to 30% of patients with epilepsy remain refractory to medical management with current AEDs (6,311-316). Seizure control in many of these patients is achieved by polytherapy, and at the expense of serious side effects, complications from drug interactions (317), and a resulting decrease in quality of life.

The AED market can be crudely categorized according to the length of time drugs have been on the market: first-generation AEDs, new-generation AEDs, and what we will term the "next generation" (i.e. those drugs in development but not yet approved or marketed). We will now discuss the currently marketed AEDs and those likely to be approved soon.

4.1. First generation drugs

4.1.1. Bromide salts

The introduction of bromide in 1857 by Sir Charles Locock for the treatment of seizures can be considered the start of modern anti-epileptic pharmacotherapy (see 128,216,234). Despite its use for well over a century, the mechanism of action is still poorly understood, but presumably involves blockade of chloride transport. Bromide is also an inhibitor of carbonic anhydrase, a key enzyme in active chloride transport. The main problem with bromide therapy was always the very narrow therapeutic index (232-234). CNS side effects are the most common and most severe, including dizziness, emotional changes, and frequently psychosis. The very long half-life of elimination (approximately 12 days) contributes to the danger of chronic toxicity. Bromides also cause dermatological side effects (232-234).

4.1.2. Barbiturates Phenobarbital

Several barbiturates are effective in treating epileptic disorders (318,319). Phenobarbital (5-ethyl-5-phenyl barbituric acid; Figure1) was the first AED of real clinical value. It was introduced in 1911 as a sedative and hypnotic, but was soon found to be useful as an anti-convulsant, though it was - at the time - erroneously believed that the anti-epileptic effect was simply a consequence of sedation. It has been in continuous use as a sedative and anticonvulsant ever since; it remains one of the best available drugs for the treatment of certain seizure types, especially grand mal and focal seizures (310). Following its development, more than 50 other barbituric acid analogs and derivatives have been and are still being developed and tested (see 318-324; Figure1).

Figure 1. AEDs structurally related to phenobarbital. Mephobarbital

Mephobarbital (methylphenobarbital; Figure1) was introduced in the U.S. in 1935; it is less sedating than phenobarbital. Its anticonvulsant action is due to its slow conversion in the liver to phenobarbital; it remains unclear whether mephobarbital itself contributes to the pharmacological effect. Some neurologists suggested that

mephobarbital caused fewer behavioral side effects than phenobarbital in children, although this has been disputed (see 325). Eterobarb

Eterobarb (N,N' dimethoxymethyl phenobarbital (DMMP); 5-ethyl-1,3-bis(methoxymethyl)-5-phenyl-barbituric acid; Zipnotic; Figure1) is also structurally related to phenobarbital; it is an alkoxymethyl derivative. Eterobarb is reportedly equipotent with phenobarbital in preventing seizures, and causes less sedation. It shows efficacy in treating grand mal, psychomotor, or focal epilepsy (326-330), and is approved in some countries, but other clinical trials were abandoned and development was stopped.

4.1.3. Primidone

Primidone (5-ethyldihydro-5-phenyl-4,6(1H,5H)-pyrimidinedione; 2-deoxyphenobarbital; Figure1) is also a structural analog of phenobarbital, in which the carbonyl group at the 2 position is replaced with a methylene group. This drug seems better tolerated in some patients than phenobarbital. Primidone is slowly metabolized in the liver and is excreted in urine as phenylethylmalonamide (PEMA), phenobarbital, and p-hydroxyphenobarbital (331). Primidone's pattern of activity is similar to that of phenytoin, though its action is at least partly due to its metabolic conversion to phenobarbital and PEMA, both of which have anticonvulsant activity (332-334).

4.1.4. Phenytoin

Phenytoin (5,5-diphenylhydantoin; Figure1) is also structurally related to phenobarbital (243,335,336). Phenytoin was one of the first AEDs to be tested in animal models of epilepsy (238,240-243). It was first introduced for the treatment of epilepsy in the U.S. in 1938 (128,239,337), and remains one of the most commonly prescribed anti-epileptics in the U.S. It is believed to act by blocking voltage-sensitive sodium channels (336). Its anti-convulsant effect is approximately equal to that of phenobarbital, but it does not cause sedation. It is effective in treating grand mal, focal sensory and motor, and psychomotor seizures. In parenteral form, the drug is also used to treat status epilepticus.

4.1.5. Fosphenytoin

Fosphenytoin (Cerebyx) is a water-soluble parenteral phenytoin prodrug (a disodium phosphate ester; Figure1), and has several advantages over phenytoin. It is better tolerated, and can be administered intravenously or intramuscularly (338-345). Uses for fosphenytoin include intravenous administration for the treatment of status epilepticus (341), and treatment of patients who are unable to take oral medication or in whom a more rapid attainment of a therapeutic drug level is required. Fosphenytoin has a short half-life (8-15 minutes) and is converted to phenytoin. Being water-soluble, it does not require a propylene glycol solvent and, as a result, causes less hypotension, bradycardia, thrombophlebitis, and fewer local skin reactions than does intravenous phenytoin (340,341,343). Fosphenytoin has been used for some years in the U.S. and has recently been licensed in the U.K. (341).

4.1.6. Ethosuximide

Subsequently, further derivatives and analogs of phenytoin and phenobarbital were synthesized by manipulating the cyclic ureide moiety from which both are derived. These include the hydantoins and diones, as well as the succinimides methsuximide (346; Figure1) and phensuximide (Figure1). Ethosuximide (2-ethyl-2-methylsuccinimide; Figure1) is a T-type calcium channel blocker, used in treating absence seizures. It was introduced in 1958. It is absorbed from the gastrointestinal tract and extensively hydroxylated in the liver to an inactive metabolite (347). Ethosuximide is generally free of serious adverse effects, and continues to be used to this day.

4.1.7. Acetazolamide

Acetazolamide (Diamox; Figure2) is an unsubstituted sulfonamide that inhibits carbonic anhydrase. It was approved for the treatment of epilepsy in 1953 (348). It non-competitively inhibits brain carbonic anhydrase, leading to accumulation of carbon dioxide that seems to decrease the spread of seizure activity and increase the seizure threshold (348). In recent years it has fallen from favor somewhat, but does have a broad spectrum of anti-epileptic activity and a long track record of generally safe and successful use, especially in patients with refractory seizures.

Figure 2. Structure of acetazolamide.

4.1.8. Sodium valproate / valproic acid

Although valproic acid (dipropyl acetic acid or 2-propylvaleric acid; VPA; Figure3) was first prepared by Burton in 1882 (349), its anti-epileptic properties were not appreciated until 80 years later by Meunier (see 350). Valproic acid is chemically distinct from other AEDs. It was developed as an anti-epileptic drug in Europe during the 1960s and was subsequently introduced in the U.S. Valproate is a major broad-spectrum anti-epileptic drug effective against many different types of epileptic seizures, especially in simple and complex absence seizures.

Figure 3. Structure of A: valproic acid and B: sodium valproate.

The incidence of toxicity associated with the clinical use of valproate is generally low, but two rare side effects, idiosyncratic fatal hepatotoxicity and teratogenicity (351,352), necessitate caution. Pancreatitis is also a rare though serious adverse effect (353). Animal studies indicate that the mechanisms leading to hepatotoxicity and teratogenicity are distinct and differ from the mechanisms of the anticonvulsant action of valproate.

As a result of its wide spectrum of anticonvulsant activity against different seizure types, it is believed that valproate acts through several mechanisms. There is evidence that valproate up-regulates GABA synthesis and release, potentiating GABAergic function in some brain regions. Valproate also appears to alter dopaminergic and serotonergic function. One disadvantage of valproate is its short half-life, making steady plasma levels of the drug difficult to achieve, although the recent introduction of sustained release formulations has reduced this problem. More recently, divalproex sodium, a stable coordination compound of valproic acid and sodium valproate in a 1:1 molar ratio, has been developed. It is believed to act essentially as a prodrug, dissociating into valproate in the GI tract.

4.1.9. Benzodiazepines

Benzodiazepines have long been used to treat convulsive seizures, though some are not suitable for routine use because tolerance develops rapidly; they are also typically sedatives (354,355). They are very useful in emergencies: diazepam (Figure4) and lorazepam (Figure4) remain first-line drugs for the control of status epilepticus (85,356,357). Other benzodiazepines in use as AEDs include clonazepam (358; Figure4), clobazam (359; Figure4), nitrazepam (360; Figure4), and midazolam (361-364; Figure4). It is believed that the benzodiazepines act as enhancers of GABA receptor binding, which causes increased stability of the cell membrane and a reduction in the synaptic response to excitatory stimulation (354). Thus, benzodiazepines facilitate the actions of GABA in the brain.

Figure 4. Benzodiazepines used as AEDs.

4.1.10. Carbamazepine

Carbamazepine (5H-dibenz[b,f]azepine carboxamide) is an iminostilbene derivative (Figure5), structurally related to the tricyclic antidepressants, such as amitriptyline and imipramine. The anticonvulsant activity of carbamazepine appears to involve limitation of seizure propagation, by reducing post-tetanic potentiation of synaptic transmission. Carbamazepine was first synthesized in 1960 by Schindler, who had a decade earlier patented the structurally closely related imipramine. Carbamazepine was later found to have anti-epileptic properties (365). It was introduced in 1962 for the treatment of trigeminal neuralgia. It has some structural similarity to phenytoin; its anticonvulsant activity has been associated with the carbamoyl group.

Figure 5. Structures of carbamazepine and oxcarbazepine.

In recent years, extended release carbamazepine formulations have been developed, allowing twice daily dosing. These formulations provide increased convenience, better patient compliance, and more constant serum levels of the drug, reducing peak level toxicity problems and trough level seizures.

The most frequently observed adverse reactions are CNS-related and dose-dependent, including dizziness, drowsiness, ataxia, nystagmus, blurred vision, slurred speech, confusion, headache, and nausea and vomiting. Carbamazepine can also produce more serious adverse effects, including bone marrow suppression (leading to aplastic anemia), granulocytopenia and/or thrombocytopenia, and liver damage (366-372). Carbamazepine is metabolized in the liver to form carbamazepine-10,11-epoxide, which also has anti-convulsant properties. However, the epoxide is reactive and is believed to be responsible for the blood dyscrasias.

Unlike phenytoin, there is a linear relationship between the dose of the drug and its plasma concentration, so carbamazepine has a wider margin of safety, and measurement of the plasma levels is a useful guide to optimum dosage. The anticonvulsant action of the drug appears to be mediated by a selective binding to voltage-dependent sodium channels. After such binding the sodium channels become stabilized and inactive, so further sodium movement is inhibited. However, how such modulation of sodium channels affects epileptic seizures remains unclear.

4.1.11. Oxcarbazepine

Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz(b,f)azepine-5-carboxamide; Figure5) reportedly has equivalent efficacy to its structural analog carbamazepine, its tolerability is at least equal to that of other AEDs (373,374), and it is less toxic than carbamazepine (375). It can be considered a prodrug, being rapidly metabolized to a hydroxyl derivative. Although it may cause fewer interactions with other AEDs, it may induce metabolism of oral contraceptives and hence reduce their effectiveness (376,377). It is thought to act as a sodium channel antagonist (373).Oxcarbazepine has been marketed in many countries since 1990, and has more than 125,000 patient years of experience. A new formulation (Trileptal) has recently been approved by the FDA for monotherapy or for use in conjunctive therapy of partial seizures (with or without secondary generalization).

4.2. New generation drugs

Until the introduction of felbamate in 1993, no new AED had been launched in the U.S. for 15 years. The "new generation" includes felbamate (Felbatol) and gabapentin (Neurontin), both approved in 1993, lamotrigine (Lamictal), approved in 1994, topiramate (Topamax), approved in 1996, and tiagabine (Gabitril), approved in 1997 (378).

4.2.1. Felbamate

Felbamate (2-phenyl-1,3-propanediol dicarbamate; Felbatol; Figure6) was first synthesized in 1954 (379), although it did not enter serious clinical development until 1982 (380). Felbamate is chemically related to meprobamate (381,382), an anxiolytic drug (383), both being propanediol dicarbamates (Figure6). Meprobamate also has anti-epileptic properties in animal models, and in light of the drug's long history of safe use it has been suggested that it be reconsidered as a potential AED (384). The exact details of felbamate's mechanisms of action remain unclear. The drug appears to have two actions in that it enhances the GABAergic system and inhibits excitatory amino acid responses.

Figure 7. Structures of GABA and of AEDs intended to affect GABA neurotransmission.

Rho and coworkers studied the effect of meprobamate and felbamate at the GABAA receptor using whole-cell voltage-clamp recordings from cultured rat hippocampal neurons (383). Meprobamate increased GABA-evoked responses and, at higher concentrations, had an independent channel-blocking effect. In fact, meprobamate caused greater potentiation than felbamate at the same concentration. Both drugs prolonged the mean burst duration of GABA-activated currents in excised outside-out membrane patches. Rho and coworkers concluded that both drugs had barbiturate-like actions at GABAA receptors, and that meprobamate had greater activity and could directly activate the receptor, whereas felbamate could not (383).

In animal models, felbamate blocks PTZ-, MES-, and picrotoxin-induced seizures, but has little effect on strychnine- or bicuculline-induced seizures (383,385, 386). This spectrum of action is consistent with felbamate acting in a barbiturate-like manner to potentiate GABAA receptor responses (383,385, 386).

Felbamate was widely proclaimed as the first new AED in many years when it received FDA approval in 1993 for monotherapy in adults with partial seizures and as an adjunctive therapy in children suffering from Lennox-Gastaut syndrome (383,385,387,388). Within the first year on the U.S. market, as many as 120,000 patients took the drug, and it was judged efficacious in many patients whose epilepsy had been refractory to other AEDs (383,387,389). Felbamate has also been used to treat infantile spasms or West syndrome (390-392), hemifacial spasm (393), acquired epileptic aphasia (394), and trigeminal neuralgia (395).

However, because of potentially fatal adverse effects of hepatic failure (396), aplastic anemia (397-401), and other blood dyscrasias (402) associated with the use of felbamate during early 1994, a "black-box" warning was added to the drug's package insert. As a result, use of felbamate is now restricted to patients with severe epilepsy refractory to other therapies (403,404). Felbamate continues to be used in many patients, though not as a first-line treatment.

Felbamate was the first drug shown to be effective in controlled studies in Lennox-Gastaut syndrome. The Felbamate Study Group reported a double-blind, placebo-controlled add-on trial of felbamate in 73 patients suffering from Lennox-Gastaut syndrome (278). Patients receiving felbamate experienced a 34% decrease in the frequency of atonic seizures and a 19% decrease in total seizure frequency. Additionally, a trial by Avanzini and coworkers included 80 patients suffering from Lennox-Gastaut syndrome, of whom 60% experienced a >50% reduction in seizure frequency. Of these, 6% were seizure-free during treatment (405).

4.2.2. Gabapentin

Gabapentin (Neurontin) was approved in the U.S. in 1993, as an adjunctive therapy in patients 12 years of age or older with localization-related epilepsy. Gabapentin is a 3-alkylated (lipophilic) GABA analog (Figure7). Although structurally related to GABA (Figure7), gabapentin does not seem to interact with any known GABA recognition site, nor with a variety of other ligand-binding sites (including excitatory amino acid receptors) (406,407). Invivo autoradiographical studies suggest that there is a binding site for gabapentin in the brain, although its function is unclear.

The efficacy and safety of gabapentin as a monotherapy for treatment of partial onset seizures was evaluated in three large multicenter, double-blind, parallel-group, dose-controlled trials (408,409). These three trials provided good evidence for the efficacy and safety of gabapentin monotherapy for the treatment of partial-onset seizures. In one trial, outpatients with refractory partial epilepsy (n=275) maintained on stable doses of AEDs were switched to gabapentin monotherapy. Patients exited the study if their seizure frequency increased; only 3% of patients did withdraw because of this (see 408). In another trial, hospitalized patients (n=82) were weaned off their prior AEDs and were assigned to gabapentin monotherapy at 300 mg/day or 3600 mg/day. Patients remained in the trial for a maximum of 8 days, unless they satisfied various exit criteria. Time to exit was significantly longer in patients receiving 3600mg than those receiving 300mg gabapentin (see 408). In a further study, patients with recently diagnosed partial seizures (n=292) received gabapentin (300, 900, or 1800 mg/day) or carbamazepine (600 mg/day). Patients remained in the trial for up to 6 months or until they experienced an exit event. Mean time to exit was significantly longer for patients who received gabapentin at 900 mg/day or 1800 mg/day than those who received 300 mg/day (see 408).

<4.2.3. Lamotrigine

Lamotrigine (Lamictal) is a phenyltriazine anticonvulsant agent (Figure8); the drug is structurally unrelated to any currently available AED. Lamotrigine was approved in 1994 as an adjunctive treatment for localization-related epilepsy in adults. It exhibits a broad spectrum of anti-epileptic activity (410,411); in animal models, its spectrum is similar to those of phenytoin and carbamazepine. The agent is useful in treating patients with localization-related or generalized epilepsies (412). Its mechanism of action remains unclear, but it appears that the drug may stabilize neuronal membranes by blocking voltage-sensitive sodium channels, thereby inhibiting release of excitatory amino acid neurotransmitters (412).

Figure 8. Structure of lamotrigine.

4.2.4. Topiramate

Topiramate (Topamax), a sulfamate-substituted derivative of d-fructose (Figure9), is structurally unrelated to any other currently available anticonvulsant. It was approved in the U.S. in 1997, and is indicated for use as an adjunctive therapy in adults with localization-related epilepsy. It also has efficacy in some generalized epilepsies. Topiramate is quickly absorbed, has linear pharmacokinetics, minimal protein binding, and a long half-life (413-415). Some analyses of data from randomized controlled studies suggest topiramate may be the most potent of the new generation of AEDs (416). Its mechanism of action remains unclear, but seems to involve blockade of voltage-sensitive sodium channels, increased GABA activity, and glutamate blockade via non-NMDA receptors. Preliminary clinical research has suggested that topiramate may also be useful in treating mania in patients with bipolar disorder, post-traumatic stress disorder, and frequent migraine and chronic daily headaches.

Figure 9. Structure of topiramate.

4.2.5. Tiagabine

Tiagabine is one of few rationally designed AEDs in that it was designed based on the GABAergic theory of epilepsy (Figure7). Tiagabine is a potent and selective inhibitor of the synaptosomal uptake of GABA, and it appears to lack benzodiazepine-like sedative effects. The drug is structurally related to nipecotic acid, but crosses the blood-brain barrier to a greater degree, being much more lipophilic. Tiagabine was approved in the U.S. in 1997 as an adjunctive therapy for patients 12 years of age or older with localization-related epilepsy. The inhibition of GABA reuptake allows increased binding of GABA to post-synaptic receptors, and the enhanced GABA activity may prevent propagation of seizure impulses (417). However, it is unclear whether inhibiting GABA reuptake is the drug's only effect (418,419).

4.2.6. Vigabatrin

Vigabatrin (gamma-vinyl-GABA; Figure7) is a close structural analog of GABA and operates as an enzyme-activated, irreversible inhibitor of GABA transaminase, an enzyme that degrades GABA (420). Vigabatrin crosses the blood-brain barrier. Once bound to GABA transaminase, the drug is converted into a reactive intermediate that irreversibly inhibits the enzyme, resulting in dose-dependently increased levels of GABA in the brain (420,421). The product is a racemate, but only the s(+)-enantiomer is pharmacologically active (422). Nuclear magnetic resonance spectroscopy has demonstrated 2-3 fold increases in GABA concentration in the brains of adult epileptic patients treated with standard doses of vigabatrin (423). Increased GABA concentrations are not only neuroprotective in theory, but extensive experimental evidence has shown that they do protect the brain against chemically and electrically induced convulsions (421).

The clinical development of vigabatrin was delayed in the U.S. by findings of microvacuolation in the white matter of brains in rodents and dogs. However, extensive monitoring in humans through autopsy, MRI, and cognitive function tests has confirmed that this does not occur in humans (424). The FDA's external advisory committee has recommended vigabatrin (Sabril) for approval as an adjunctive therapy, but final action is still pending. The drug has been extensively used in more than 45 countries.

4.2.7. Zonisamide

Zonisamide (1-(1,2-benzoxazol-3-yl) methane-sulfonamide; Zonegran; Excegran; Figure10) is a 1,2-benzisoxazole derivative and the first agent of this class to be developed as an AED. Zonisamide was launched in Japan as early as 1989. In various animal models, zonisamide has considerable activity. It appears to block the propagation/spread of seizure discharges and to suppress the epileptogenic focus (425).

Figure 10. Structure of zonisamide.

The marketing of zonisamide in the U.S. was delayed by reports of nephrolithiasis by European and American investigators (426). However, the drug has been used successfully in Japan for a range of epilepsy types, including infantile spasms (427) and myoclonic seizures (428). Efficacy as a neuroprotectant and in the treatment of mania has also been suggested. Zonisamide is active in a wide range of animal models of epilepsy (429), and is efficacious in the treatment of simple and complex partial seizures and (to a lesser extent) generalized seizures. The FDA approved zonisamide in 1999.

The mechanism of action of zonisamide has not been elucidated, but it is known to block sodium channels (429) and T-type calcium channels (430). Block of T-type channels would be expected to shift the channel population toward the inactivation state, thus allowing fewer channels to open upon depolarization. This in turn would inhibit the spread of epileptiform activity.

Zonisamide is generally well-tolerated. The most common side effects are drowsiness, loss of appetite, gastrointestinal problems and CNS toxicity, although the rare occurrence of nephrolithiasis suggests patients should be monitored carefully (426). Interestingly, the incidence of nephrolithiasis in Japanese patients appears to be much lower in than in the U.S. or Europe, and the causative link with the drug has been disputed. The drug was teratogenic in animal models (425).

4.2.8. Levetiracetam

Levetiracetam (Figure 11) is structurally related to piracetam (Nootropil; a cognitive enhancer and anti-myoclonic drug), but unrelated to other AEDs. Levetiracetam was approved in the U.S. in late 1999 for the adjunctive treatment of partial onset seizures with and without secondary generalization in adults. It was also assessed for the treatment of Alzheimer's disease, but development for this indication was discontinued.

Figure 11. Structure of levetiracetam.

Levetiracetam has been evaluated in double-blind, placebo-controlled, phase III clinical studies in the U.S. and in Europe. More patients receiving levetiracetam experienced a reduction in weekly seizure frequency when compared to placebo, and levetiracetam-treated patient groups had significantly more responders (incidence with at least a 50% reduction from baseline in partial onset seizure frequency). More than 900 patients participated in these studies, and over 3000 people received levetiracetam in various clinical studies. Levetiracetam was well tolerated, and most adverse experiences were mild or moderate (431).

<4.2.9. Flunarizine

Flunarizine (Figure12) is a calcium channel blocker with neuronal protective properties. It is effective against migraine, vertebrobasilar insufficiency, epilepsy (432-438), and alternating hemiplegia. Somewhat contradictory results have been obtained as to its efficacy in epilepsy; Durrheim et al. reported that as add-on therapy to sodium valproate it was effective in treating reading epilepsy (439), while Alving et al. concluded that it showed no statistical advantage over the placebo in reducing total seizure frequency in patients with complex partial seizures (440). Other studies have questioned its value in treating epilepsy (441-443).

Figure 12. Structure of flunarizine

4.3. The "next generation"

Other new AEDs in clinical development are summarized below.

4.3.1. Remacemide

Remacemide (Figure13) acts by blocking NMDA receptors and by prolonging inactivation of sodium channels. The desglycinated metabolite, ARL12495AA, is approximately twice as potent as the parent drug (444-447). It has been suggested that modulation of the metabolism of remacemide could be of therapeutic use (448).

Figure 13. Structure of remacemide hydrochloride.

In binding studies in cerebral cortical membranes (444), ARL12495AA was shown to have 150 times the affinity of remacemide for the NMDA receptor (displacement of [3H]MK801). ARL12495AA reduces NMDA-induced depolarizations in various invitro preparations, and the mechanism of NMDA block probably involves an action at the channel site on the NMDA receptor complex. Unlike MK801 and many other NMDA blockers however, remacemide exhibits low toxicity.

The anti-convulsant effect of remacemide has been demonstrated in the WAG/Rij rat, a genetic model for generalized absence epilepsy (449). Remacemide and its metabolite both decreased the number of spike-wave discharges, without causing major effects on behavior or the EEG spectral content. In the case of the metabolite, the mean duration of spike-wave discharges was prolonged, a unique combination of effects in an AED.

Invitro electrophysiological studies have demonstrated that remacemide and ARL12495AA increase spike duration and decrease or eliminate spike after-hyperpolarization, in rat CA1 hippocampal neurons (448). Thus, the drugs appear to modulate sodium and/or potassium channel activity. Such multiple mechanisms may contribute to remacemide's anti-epileptic activity.

Clinical trials have shown remacemide to be well tolerated and efficacious in patients with partial and secondary generalized seizures. Remacemide is currently undergoing phase III trials in Europe and the U.S. (450,451).

4.3.2. Ganaxolone

Ganaxolone (CCD 1042; 3-alpha-hydroxy-3-beta-methyl-5-alpha-pregnan-20-one; Figure14) is a member of a class of neuroactive steroids that have been termed "epalons" (452,453). Epalons modulate the GABAA receptor / chloride ionophore complex in the CNS via a specific steroid-sensitive site, and as a result have anti-epileptic, anxiolytic, sedative, and hypnotic properties. Epalons are structurally related to progesterone but have no hormonal activity; ganaxolone is a 3-beta-methyl-substituted analog of the endogenous neuroactive steroid 3-alpha-hydroxy-5-alpha-pregnan-20-one. It is under development as an AED for treating generalized absence seizures and simple or complex partial seizures.

Figure 14. Structure of ganaxalone.

Ganaxolone has been shown to inhibit binding to the GABAA receptor / chloride channel complex and also to enhance binding at the benzodiazepine and muscimol binding sites (454). These actions suggest that ganaxolone is a positive allosteric modulator of the GABAA receptor.

Ganaxolone is an efficacious anticonvulsant agent in a variety of acute seizure models, as well as in electrical and chemical kindling models (455). The drug attenuates seizures in animals resulting from PTZ, bicuculline or aminophylline treatment in rodents, and in the kindling model of epilepsy. Electroshock-induced seizures are attenuated only at doses that produce ataxia (454). In contrast to these results however, Snead (1998) found that PTZ- or gamma-hydroxybutyric acid-induced absence seizures in rats were exacerbated by ganaxolone (456).

In healthy volunteers, ganaxolone was well tolerated after single (up to 1500 mg) and multiple doses (up to 300 mg bid for 10 days). The drug was rapidly absorbed from the gastrointestinal tract after oral administration. Pharmacokinetics were linear and dose-proportional (457). Ganaxolone was in phase II trials in France and the U.S. in 1998, and early results suggest promising activity in patients with infantile spasms.

The difficulty in reaching bioactive concentrations of neurosteroids has caused problems in the pharmacological development of such drugs however. It may be possible to combine therapy with a drug to modify the metabolism of the neurosteroid.

4.3.3. Losigamone

Losigamone (5-(2-chlorophenylhydroxymethyl)-4-methoxy-2(5H)-furanone; Figure15) is a tetronic acid derivative in clinical trials as an AED (458). The drug is being developed as a racemate (459), though its enantiomers have somewhat different properties (56,460). Although the mechanism of action is unclear, losigamone probably acts via the NMDA system; it also affects the GABAA receptor-linked chloride channel. Currently, losigamone is in phase III clinical trials in Europe and the U.S. It is being promoted as an adjunct therapy for patients with refractory partial epilepsy, and as an alternative monotherapy for patients with partial epilepsy.

Figure 15. Structure of losigamone.

Losigamone significantly reduced NMDA-induced depolarizations in the mouse cortical wedge preparation, without affecting AMPA-induced depolarizations. Furthermore, release of glutamate stimulated by veratridine or potassium was reduced by losigamone in the same preparation (461). Gasior etal. (1999) demonstrated losigamone's efficacy at treating cocaine-induced seizures in the mouse (462).

The pharmacokinetics of losigamone were investigated in healthy volunteers, and were found to be linear (463). Losigamone was rapidly absorbed after oral administration, and is extensively metabolized, predominantly by hydroxylation and conjugation (464). The drug was well tolerated and no serious adverse effects occurred, although in some subjects there was a reversible increase in transaminases (463).

4.3.4. Stiripentol

Stiripentol (4,4-dimethyl-1-[3,4-(methylenedioxy)- phenyl]-1-penten-3-ol; Figure16) is an alpha-ethylene alcohol with multiple effects on GABAergic neurotransmission (465). The drug does not appear to be a GABA agonist, but inhibits GABA uptake (as demonstrated in a synaptosomal preparation) and also inhibits GABA transaminase (466,467). Stiripentol is an effective anti-convulsant in animal models, including electroshock, PTZ, bicuculline, and strychnine. Stiripentol has a chiral center; when the s-enantiomer was given orally to rats, only the s-enantiomer was found in blood, whereas following administration of the r-enantiomer, both the r and s forms were detected in the systemic circulation (468,469). Other studies have shown differences in potency and pharmacokinetics between the enantiomers (470,471).

Figure 16. Structure of stiripentol.

Stiripentol has shown promise as an adjunctive therapy in uncontrolled atypical absence seizures in children (472). Only one patient out of 10 reported an adverse effect (vomiting) that warranted withdrawal of the drug. Stiripentol has also shown efficacy in patients with partial seizures and refractory epilepsy (438), and in the treatment of cocaine-induced seizures (462).

The inhibition of cytochrome P-450 by stiripentol is worth noting; it results in marked drug interactions with other AEDs, such as phenytoin, carbamazepine, and phenobarbital (438). Finnell etal. (1994) demonstrated a significant reduction of the teratogenic effect of phenytoin in mice by the co-administration of stiripentol, an effect that could be explained in terms of reduced production of a teratogenic metabolite of phenytoin (473).

4.3.5. Pregabalin

Pregabalin (4-amino-3-isobutylbutyric acid; isobutyl GABA; Figure7) is an AED under development; it is currently in phase III trials. Its mechanism of action is unclear. It is chemically related to gabapentin and apparently interacts with the same binding site and has a similar pharmacological profile to gabapentin (474). Pregabalin is claimed to be more potent than gabapentin in preclinical trials of anticonvulsant activity (474,475). Results from early clinical trials have shown efficacy in treating patients with refractory complex partial seizures (with or without secondary generalization); pregabalin compared favorably to gabapentin. Pregabalin was well tolerated in healthy volunteers and is readily absorbed after oral administration (474,476).

4.3.6. Harkoseride

In early 1999, a new anti-convulsant agent, harkoseride (ADD 234037; Figure17), entered phase II clinical trials. Initial safety studies of intravenous harkoseride showed no serious adverse effects in healthy volunteers, and demonstrated a pharmacokinetic profile ideal for an AED following oral dosing. Animal studies of harkoseride have also suggested a wide margin of safety. The drug reduces seizures in mice and rats at oral doses from 0.5 to 5mg/kg.

Figure 17. Structure of harkoseride.

4.3.7. Rufinamide

Rufinamide (CGP 331010; Figure18) is a GABA uptake inhibitor in development. It is in phase III trials in Switzerland and the U.S. and shows promise as a therapy for patients with partial epilepsy and generalized tonic-clonic epilepsy. Rufinamide is orally absorbed and is generally well tolerated (477,478), although tremor and tiredness have been reported as adverse effects. In a double-blind trial of 50 patients with refractive epilepsy, rufinamide as an adjunct therapy reduced seizure frequency by 42%, compared with an increase of 52% in placebo recipients.

Figure 18. Structure of rufinamide.


The goal of treating epilepsy is to control seizures completely without causing unacceptable side effects. None of the currently available treatments accomplishes that; many of the drugs reviewed here have unwelcome side effects and complete seizure control is rare under any regimen. Given the heterogeneity of the disease, it is extremely unlikely that there will ever be a single ideal AED. However, as we understand more and more about the condition, patients will be classified into rational groups and will be treated accordingly.

Ideally, the drug discovery scientist knows the mechanism(s) of the disease, possesses reliable preclinical

animal models of the disease that are representative or indicative of human results, has reference compounds after which new drugs can be modeled and against which new drugs can be tested, and has objective, reliable clinical outcome measures. Even after more than a century of pharmacotherapy and research, the scientist really only has one of these, a set of existing AEDs, with varying qualities and properties.

Our understanding of the etiology of epilepsy is advancing rapidly and has entered the genetic age; single gene defects with simple inheritance patterns have been characterized and are providing some insight. Additionally, better animal models can be generated, using transgenic technology and our improving knowledge of these gene defects.

Animal models have lead to significant advances in AED discovery twice before: the work of Merritt & Putnam and then of Swinyard and colleagues. There is every reason to believe that better models, better screening technologies, and the advent of techniques such as combinatorial chemistry for generating lead compounds will similarly advance AED research again.

Even if the drug discovery scientist had all four ideal elements, there remain special problems unique to epilepsy. The use of placebo control in epileptic patients is generally considered unethical, not only because of the distress associated with seizures, but because severe seizures can lead to injury, brain damage, or even death. A further problem is that seizures and status epilepticus can be induced by withdrawing or altering the dose of an existing AED, making it difficult to wean a patient from his or her existing AED regimen in order to test a new drug. Even changes in the law have conspired against AED researchers, because of difficulties in satisfactorily proving safety and efficacy!

However, creative scientists and physicians have found ways around these problems. New drugs can be tested without placebo controls using a technique pioneered by Rodin and colleagues on carbamazepine: the new AED is used concomitantly with an established AED and the combination is compared with the established AED plus placebo. It is hardly the perfect solution, given drug-drug interactions, but most AEDs have been tested in this way. True monotherapy placebo-controlled studies have been conducted in special circumstances, specifically in patients undergoing intensive neurodiagnostic monitoring after partial or complete withdrawal from their prior AEDs. In the hospital setting, a true placebo-controlled study may be possible because seizures can be monitored and not allowed to progress to a potentially brain-damaging situation.

The recent introduction of new AEDs with new novel mechanisms of action has opened up the field of epilepsy research. With many new compounds currently in development and the vast amount of ongoing epilepsy and more general neuroscience research, the pharmacotherapy of epilepsy looks set to undergo radical changes in the next decade.


We thank Dr. Philip M. Brown for assistance with the figures.


1. Hauser W.A., J.F. Annegers & L.T. Kurland: Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia 34, 453-468 (1993)

2. Shorvon, S.D.: Epidemiology, classification, natural history and genetics of epilepsy. Lancet 336, 93-96 (1990)

3. Patsalos, P.N.: The new generation of anti-epileptic drugs. Emerg Drugs 4, 87-105 (1999)

4. Hauser, W.A., J.F. Annegers & W.A. Rocca: Descriptive epidemiology of epilepsy: contributions of population-based studies from Rochester, Minnesota. Mayo Clin Proc 71, 576-586 (1996)

5. Shorvon, S.D.: The epidemiology and treatment of chronic and refractory epilepsy. Epilepsia 37 Suppl 2, S1-S3 (1996)

6. Brodie, M.J. & J.A. French: Management of epilepsy in adolescents and adults. Lancet 356, 323-329 (2000)

7. Porter, R.J.: Therapy of epilepsy. Curr Opin Neurol Neurosurg 1, 206-211 (1988)

8. Jallon, P.: Epidemiology of epilepsies in Latin America. Epilepsies 10, 123-129 (1998)

9. Roman, G.C. & N. Senanayake: Epilepsy in Latin America. J Liga Bras Epilepsia 6, 47-52 (1993)

10. Senanayake, N. & G.C. Roman: Epidemiology of epilepsy in developing countries. Bull WHO 71, 247-258 (1993)

11. Jallon, P.: Epilepsy in developing countries. Epilepsia 38, 1143-1151 (1997)

12. De Bittencourt, P.R.M., B. Adamolekum, N. Bharucha, A. Carpio, O.H. Cossio, M.A. Danesi, M. Dumas, H. Meinardi, A. Ordinario, N. Senanayake, R. Shakir & J. Sotelo: Epilepsy in the tropics: I. Epidemiology, socioeconomic risk factors, and etiology. Epilepsia 37, 1121-1127 (1996)

13. Shorvon, S.D. & P.J. Farmer: Epilepsy in developing countries: a review of epidemiological, sociocultural, and treatment aspects. Epilepsia 29 Suppl 1, S36-S54 (1988)

14. Carpio, A., A. Escobar & W.A. Hauser: Cysticercosis and epilepsy: a critical review. Epilepsia 39, 1025-1040 (1998)

15. Pal, D.K., A. Carpio & J.W. Sander: Neurocysticercosis and epilepsy in developing countries. J Neurol Neurosurg Psychiatry 68, 137-143 (2000)

16. Annegers, J.F., W.A. Rocca & W.A. Hauser: Causes of epilepsy: contributions of the Rochester epidemiology project. Mayo Clin Proc 71, 570-575 (1996)

17. Temkin, N.R., M.M. Haglund & H.R. Winn: Causes, prevention, and treatment of post-traumatic epilepsy. New Horiz 3, 518-522 (1995)

18. Marks, D.A., J. Kim, D.D. Spencer & S.S. Spencer: Seizure localization and pathology following head injury in patients with uncontrolled epilepsy. Neurology 45, 2051-2057 (1995)

19. Chadwick, D.: Seizures and epilepsy after traumatic brain injury. Lancet 355, 334-336 (2000)

20. Angeleri, F., J. Majkowski, G. Cacchio, A. Sobieszek, S. D'Acunto, R. Gesuita, A. Bachleda, G. Polonara, L. Krolicki, M. Signorino & U. Salvolini: Posttraumatic epilepsy risk factors: one-year prospective study after head injury. Epilepsia 40, 1222-1230 (1999)

21. Hauser, W.A.: Seizure disorders: The changes with age. Epilepsia 33 Suppl 4, S6-S14 (1992)

22. Hauser, W.A.: The prevalence and incidence of convulsive disorders in children. Epilepsia 35 Suppl 2, S1-S6 (1994)

23. Murphy, C.C., E. Trevathan & M. Yeargin-Allsopp: Prevalence of epilepsy and epileptic seizures in 10-year-old children: results from the metropolitan Atlanta developmental disabilities study. Epilepsia 36, 866-872 (1995)

24. Minassian, B.A., J. Sainz & A.V. Delgado-Escueta: Genetics of myoclonic and myoclonus epilepsies. Clin Neurosci 3, 223-235 (1995)

25. Rowan, A.J.: Reflections on the treatment of seizures in the elderly population. Neurology 51, S28-S33 (1998)

26. Gareri, P., T. Gravina, G. Ferreri & G. De Sarro: Treatment of epilepsy in the elderly. Prog Neurobiol 58, 389-407 (1999)

27. Kramer, U., Y. Nevo, M.Y. Neufeld, A. Fatal, Y. Leitner & S. Harel: Epidemiology of epilepsy in childhood: a cohort of 440 consecutive patients. Pediatr Neurol 18, 46-50 (1998)

28. Kramer, U.: Epilepsy in the first year of life: a review. J Child Neurol 14, 485-489 (1999)

29. Hamer, H.M., E. Wyllie, H.O. Lüders, P. Kotagal & J. Acharya: Symptomatology of epileptic seizures in the first three years of life. Epilepsia 40, 837-844 (1999)

30. Kurtz, Z., P. Tookey & E. Ross: Epilepsy in young people: 23-year follow up of the British national child development study. Brit Med J 316, 339-342 (1998)

31. Faught, E.: Epidemiology and drug treatment of epilepsy in elderly people. Drugs Aging 15, 255-269 (1999)

32. Eisenschenk, S. & R. Gilmore: Strategies for successful management of older patients with seizures. Geriatrics 54, 31-40 (1999)

33. De Toledo, J.C.: Changing presentation of seizures with aging: clinical and etiological factors. Gerontology 45, 329-335 (1999)

34. Stephen, L.J. & M.J. Brodie: Epilepsy in elderly people. Lancet 355, 1441-1446 (2000)

35. Cornman, J.M. & E.R. Kingson: Trends, issues, perspectives, and values for the aging of the baby boom cohorts. Gerontologist 36, 15-26 (1996)

36. Frank-Stromborg M.: Changing demographics in the United States. Implications for health professionals. Cancer 67 Suppl 6, 1772-1778 (1991)

37. Hodes, R.J., V. Cahan & M. Pruzan: The National Institute on Aging at its twentieth anniversary: achievements and promise of research on aging. J Am Geriatr Soc 44, 204-206 (1996)

38. Kennedy, M.: Baby Boomers likely to go out with a bang. West Med J 97, 24-27 (1998)

39. Murray, M.I., M.T. Haopern & I.E. Leppik: Cost of refractory epilepsy in adults in the USA. Epilepsy Res 23, 139-148 (1996)

40. Begley, C.E., J.F. Annegers, D.R. Lairson, T.F. Reynolds & W.A. Hauser: Cost of epilepsy in the United States: A model based on incidence and prognosis. Epilepsia 35, 1230-1243 (1994)

41. Begley, C.E., M. Famulari, J.F. Annegers, D.R. Lairson, T.F. Reynolds, S. Coan, S. Dubinsky, M.E. Newmark, C. Leibson, E.L. So & W.A. Rocca: The cost of epilepsy in the United States: an estimate from population-based clinical and survey data. Epilepsia 41, 342-351 (2000)

42. Langfitt, J.T.: Cost evaluations in epilepsy: an update. Epilepsia 41 Suppl 2, S62-8 (2000)

43. O'Callaghan, F.J., C. Osmond & C.N. Martyn: Trends in epilepsy mortality in England and Wales and the United States, 1950-1994. Am J Epidemiol 151, 182-189 (2000)

44. Langan, Y., N. Nolan & M. Hutchinson: The incidence of sudden unexpected death in epilepsy (SUDEP) in South Dublin and Wicklow. Seizure 7, 355-358 (1998)

45. Nashef, L., D.R. Fish, S. Garner, J.W. Sander & S.D. Shorvon: Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 36, 1187-1194 (1995)

46. Nilsson, L., B.Y. Farahmand, P.G. Persson, I. Thiblin & T. Tomson: Risk factors for sudden unexpected death in epilepsy: a case-control study. Lancet 353, 888-893 (1999)

47. Appleton, R.E.: Sudden, unexpected death in epilepsy in children. Seizure 6, 175-177 (1997)

48. McGugan, E.A.: Sudden unexpected deaths in epileptics-a literature review. Scot Med J 44, 137-139 (1999)

49. Langan, Y., L. Nashef & J.W. Sander: Sudden unexpected death in epilepsy: a series of witnessed deaths. J Neurol Neurosurg Psychiatry 68, 211-213 (2000)

50. Annegers, J.F. & S.P. Coan: SUDEP: overview of definitions and review of incidence data. Seizure 8, 347-352 (1999)

51. Opeskin, K., A.S. Harvey, S.M. Cordner & S.F. Berkovic: Sudden unexpected death in epilepsy in Victoria. J Clin Neurosci 7, 34-37 (2000)

52. Zwimpfer, T.J., J. Brown, I. Sullivan & R.J. Moulton: Head injuries due to falls caused by seizures: a group at high risk for traumatic intracranial hematomas. J Neurosurg 86, 433-437 (1997)

53. Spitz, M.C., J.A. Towbin, D. Shantz & L.E. Adler: Risk factors for burns as a consequence of seizures in persons with epilepsy. Epilepsia 35, 764-767 (1994)

54. Neufeld, M.Y., T. Vishne, V. Chistik & A.D. Korczyn: Life-long history of injuries related to seizures. Epilepsy Res 34, 123-127 (1999)

55. Buck, D., G.A. Baker, A. Jacoby, D.F. Smith & D.W. Chadwick: Patients' experiences of injury as a result of epilepsy. Epilepsia 38, 439-444 (1997)

56. Jones, F.A. & J.A. Davies: The anticonvulsant effects of the enantiomers of losigamone. Br J Pharmacol 128, 1223-1228 (1999)

57. Desai, K.B., W.J. Ribbans & G.J. Taylor: Incidence of five common fracture types in an institutional epileptic population. Injury 27, 97-100 (1996)

58. Wirrell, E.C., P.R. Camfield, C.S. Camfield, J.M. Dooley & K.E. Gordon: Accidental injury is a serious risk in children with typical absence epilepsy. Arch Neurol 53, 929-932 (1996)

59. Spitz, M.C.: Injuries and death as a consequence of seizures in people with epilepsy. Epilepsia 39, 904-907 (1998)

60. Josty, I.C., V. Narayanan & W.A. Dickson: Burns in patients with epilepsy: changes in epidemiology and implications for burn treatment and prevention. Epilepsia 41, 453-456 (2000)

61. Ficker, D.M.: Sudden unexplained death and injury in epilepsy. Epilepsia 41 Suppl 2, S7-12 (2000)

62. O'Donoghue, M.F., D.M. Goodridge, K. Redhead, J.W. Sander & J.S. Duncan: Assessing the psychosocial consequences of epilepsy: a community-based study. Br J Gen Pract 49, 211-214 (1999)

63. Jones, M.W.: Consequences of epilepsy: why do we treat seizures? Can J Neurol Sci 25, S24-S26 (1998)

64. Hoare, P. & S. Kerley: Psychosocial adjustment of children with chronic epilepsy and their families. Dev Med Child Neurol 33, 201-215 (1991)

65. Smith, D.F., G.A. Baker, M. Dewey, A. Jacoby & D.W. Chadwick: Seizure frequency, patient-perceived seizure severity and the psychosocial consequences of intractable epilepsy. Epilepsy Res 9, 231-241 (1991)

66. Edwards, V.E.: Social problems confronting a person with epilepsy in modern society. Proc Austr Assn Neurol 11, 239-243 (1974)

67. Jacoby, A.: Impact of epilepsy on employment status: Findings from a UK study of people with well-controlled epilepsy. Epilepsy Res 21, 125-132 (1995)

68. Yagi, K.: Factors preventing people with epilepsy from employment. Acta Orthop Scand Suppl 165-172 (1989)

69. Elwes, R.D., J. Marshall, A. Beattie & P.K. Newman: Epilepsy and employment. A community based survey in an area of high unemployment. J Neurol Neurosurg Psychiatr 54, 200-203 (1991)

70. Collings, J.A. & B. Chappell: Correlates of employment history and employability in a British epilepsy sample. Seizure 3, 255-262 (1994)

71. Eadie, M.J.: The understanding of epilepsy across three millennia. Clin Exp Neurol 31, 1-12 (1994)

72. De Villiers, J.C.: A few thoughts on the history of epilepsy. S Afr Med J 83, 212-215 (1993)

73. Krauss, G.L., S. Gondek, A. Krumholz, S. Paul & F. Shen: "The scarlet E:" the presentation of epilepsy in the English language print media. Neurology 54, 1894-1898 (2000)

74. Baker, G.A., J. Brooks, D. Buck & A. Jacoby: The stigma of epilepsy: a European perspective. Epilepsia 41, 98-104 (2000)

75. Meldrum, B.S.: Epileptic brain damage: a consequence and a cause of seizures. Neuropathol Appl Neurobiol 23, 185-201 (1997)

76. Mosewich, R.K. & E.L. So: A clinical approach to the classification of seizures and epileptic syndromes. Mayo Clin. Proc 71, 405-414 (1996)

77. So, E.L.: Classifications and epidemiologic considerations of epileptic seizures and epilepsy. Neuroimaging Clin N Am 5, 513-526 (1995)

78. Bauer, G.: Seizure types and epileptic syndromes in adults. Eur Neurol 34 Suppl 1, 13-17 (1994)

79. Everitt, A.D. & J.W. Sander: Classification of the epilepsies: time for a change? A critical review of the International Classification of the Epilepsies and Epileptic Syndromes (ICEES) and its usefulness in clinical practice and epidemiological studies of epilepsy. Eur Neurol 42, 1-10 (1999)

80. Treiman, D.M.: Status epilepticus. Baillieres Clin Neurol 5, 821-839 (1996)

81. Haafiz, A. & N. Kissoon: Status epilepticus: current concepts. Pediatr Emerg Care 15, 119-129 (1999)

82. Berg, A.T., S. Shinnar, S.R. Levy & F.M. Testa: Status epilepticus in children with newly diagnosed epilepsy. Ann Neurol 45, 618-623 (1999)

83. Lowenstein, D.H.: Status epilepticus: an overview of the clinical problem. Epilepsia 40 Suppl 1, S3-S8 (1999)

84. Lowenstein, D.H., T. Bleck & R.L. Macdonald: It's time to revise the definition of status epilepticus. Epilepsia 40, 120-122 (1999)

85. Bleck, T.P.: Management approaches to prolonged seizures and status epilepticus. Epilepsia 40 Suppl 1, S59-S66 (1999)

86. Kapur, J.: Status epilepticus in epileptogenesis. Curr Opin Neurol 12, 191-195 (1999)

87. Ohki, T., K. Watanabe, T. Negoro, K. Aso, Y. Haga, K. Kasai, M. Kito & N. Maeda: Severe myoclonic epilepsy in infancy: evolution of seizures. Seizure 6, 219-224 (1997)

88. Hurst, D.L.: Severe myoclonic epilepsy of infancy. Pediatr Neurol 3, 269-272 (1987)

89. Hurst, D.L.: Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia 31, 397-400 (1990)

90. Yakoub, M., O. Dulac, I. Jambaque, C. Chiron & P. Plouin: Early diagnosis of severe myoclonic epilepsy in infancy. Brain Dev 14, 299-303 (1992)

91. Pinard, J.M., O. Delalande, C. Chiron, C. Soufflet, P. Plouin, Y. Kim & O. Dulac: Callosotomy for epilepsy after West syndrome. Epilepsia 40, 1727-1734 (1999)

92. Haginoya, K., K. Kon, S. Tanaka, M. Munakata, R. Kato, M. Nagai, H. Yokoyama, S. Maruoka, T. Yamazaki & K. Iinuma: The origin of hypsarrhythmia and tonic spasms in West syndrome: evidence from a case of porencephaly and hydrocephalus with focal hypsarrhythmia. Brain Dev 21, 129-131 (1999)

93. Watanabe, K.: West syndrome: etiological and prognostic aspects. Brain Dev 20, 1-8 (1998)

94. Ito, M.: Anti-epileptic drug treatment of West syndrome. Epilepsia 39 Suppl 5, 38-41 (1998)

95. Holmes, G.L.: Diagnosis and management of seizures in children. In: Major Problems in Clinical Pediatrics, volume 30, W.B. Saunders, Philadelphia (1987)

96. Trevathan, E., C.C. Murphy & M. Yeargin-Allsopp: Prevalence and descriptive epidemiology of Lennox-Gastaut syndrome among Atlanta children. Epilepsia 38, 1283-1288 (1997)

97. Wheless, J.W. & J.E. Constantinou: Lennox-Gastaut syndrome. Pediatr Neurol 17, 203-211 (1997)

98. Heiskala, H.: Community-based study of Lennox-Gastaut syndrome. Epilepsia 38, 526-531 (1997)

99. Ohtahara, S., Y. Ohtsuka & K. Kobayashi: Lennox-Gastaut syndrome: a new vista. Psychiatry Clin Neurosci 49, S179-S183 (1995)

100. Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30, 389-399 (1989)

101. Brown, W.M. & S.P. Aiken: Felbamate: clinical and molecular aspects of a unique anti-epileptic drug. Crit Rev Neurobiol 12, 205-222 (1998)

102. Sayit, E., E. Dirik, H. Durak, N. Uzuner, O. Anal & N.T. Cevik: Landau-Kleffner syndrome: relation of clinical, EEG and Tc-99m-HMPAO brain SPECT findings and improvement in EEG after treatment. Ann Nucl Med 13, 415-418 (1999)

103. Gordon, N.: The Landau-Kleffner syndrome: increased understanding. Brain Dev 19, 311-316 (1997)

104. Eslava-Cobos, J. & L. Mejia: Landau-Kleffner syndrome: much more than aphasia and epilepsy. Brain Lang 57, 215-224 (1997)

105. Bandini, F. & L. Mazzella: Gabapentin as treatment for hemifacial spasm. Eur Neurol 42, 49-51 (1999)

106. Pego Reigosa, R. & J.R. Pulpeiro Rios: Hemifacial spasm. J Neurol Neurosurg Psychiatry 64, 687 (1998)

107. Evidente, V.G. & C.H. Adler: Hemifacial spasm and other craniofacial movement disorders. Mayo Clin Proc 73, 67-71 (1998)

108. Kitt, C.A.: Trigeminal neuralgia: opportunities for research and treatment. Pain 85, 3-7 (2000)

109. Burchiel, K.J. & K.V. Slavin: On the natural history of trigeminal neuralgia. Neurosurgery 46, 152-155 (2000)

110. Jackson, E.M., G.M. Bussard, M.A. Hoard & R.F. Edlich: Trigeminal neuralgia: a diagnostic challenge. Am J Emerg Med 17, 597-600 (1999)

111. Rose, F.C.: Trigeminal neuralgia. Arch Neurol 56, 1163-1164 (1999)

112. Krumholz, A.: Nonepileptic seizures: diagnosis and management. Neurology 53 Suppl 2, S76-S83 (1999)

113. Van Rijckevorsel, K.: Medical treatment of newly diagnosed epilepsy. Acta Neurol Belg 99, 226-230 (1999)

114. Roberts, R.: Differential diagnosis of sleep disorders, non-epileptic attacks and epileptic seizures. Curr Opin Neurol 11, 135-139 (1998)

115. Bye, A., D. Kok, F. Ferenschild & J. Vles: Paroxysmal non-epileptic events in children: A retrospective study over a period of 10 years. J Paediatr Child Health 36, 244-248 (2000)

116. Bowman, E.S. & P.M. Coons: The differential diagnosis of epilepsy, pseudoseizures, dissociative identity disorder, and dissociative disorder not otherwise specified. Bull Menninger Clin 64, 164-80 (2000)

117. Cascino, G.D.: How has neuroimaging improved patient care? Epilepsia 35 Suppl 6, S103-S107 (1994)

118. Chugani, H.T.: The role of PET in childhood epilepsy. J Child Neurol 9 Suppl 1, S82-S88 (1994)

119. Kuzniecky, R.I.: MRI in cerebral developmental malformations and epilepsy. Magn Reson Imaging 13, 1137-1145 (1995)

120. Sundaram, M., R.M. Sadler, G.B. Young & N. Pillay: EEG in epilepsy: current perspectives. Can J Neurol Sci 26, 255-262 (1999)

121. Van Donselaar, C.A., A.T. Geerts & R.J. Schimsheimer: Idiopathic first seizure in adult life: who should be treated? Brit Med J 302, 620-623 (1991)

122. Beghi, E., M. Musicco, F. Viani, B. Bordo, W.A. Hauser & A. Nicolosi: A randomized trial on the treatment of the first epileptic seizure. Scientific background, rationale, study design and protocol. First Seizure Trial Group (FIR.S.T. Group). Ital J Neurol Sci 14, 295-301 (1993)

123. Wyllie, E.: Children with seizures: when can treatment be deferred? J Child Neurol 9 Suppl 2, 8-13 (1994)

124. Appleton, R.E.: Treatment of childhood epilepsy. Pharmacol Ther 67, 419-431 (1995)

125. Willmore, L.J.: Epilepsy emergencies: the first seizure and status epilepticus. Neurology 51 Suppl 4, S34-S38 (1998)

126. Emilien, G. & J.M. Maloteaux: Pharmacological management of epilepsy. Mechanism of action, pharmacokinetic drug interactions, and new drug discovery possibilities. Intl J Clin Pharmacol Ther 36, 181-194 (1998)

127. Privitera, M.D.: Evidence-based medicine and anti-epileptic drugs. Epilepsia 40 Suppl 5, S47-S56 (1999)

128. Bazil, C.W. & T.A. Pedley: Advances in the medical treatment of epilepsy. Annu Rev Med 49, 135-162 (1998)

129. Chapman, D.P. & W.H. Giles: Pharmacologic and dietary therapies in epilepsy: conventional treatments and recent advances. South Med J 90, 471-480 (1997)

130. Dam, M.: Epilepsy surgery. Acta Neurol Scand 94, 81-87 (1996)

131. Wieser, H.G.: Epilepsy surgery. Baillieres Clin Neurol 5, 849-875 (1996)

132. Sugimoto, T., H. Otsubo, P.A. Hwang, H.J. Hoffman, V. Jay & O.C. Snead III: Outcome of epilepsy surgery in the first three years of life. Epilepsia 40, 560-565 (1999)

133. McLachlan, R.S.: Vagus nerve stimulation for intractable epilepsy: a review. J Clin Neurophysiol 14, 358-368 (1997)

134. Amar, A.P., C.N. Heck, C.M. DeGiorgio & M.L. Apuzzo: Experience with vagus nerve stimulation for intractable epilepsy: some questions and answers. Neurol Med Chir (Tokyo) 39, 489-495 (1999)

135. FineSmith, R.B., E. Zampella & O. Devinsky: Vagal nerve stimulator: a new approach to medically refractory epilepsy. N J Med 96, 37-40 (1999)

136. Hassan, A.M., D.L. Keene, S.E. Whiting, P.J. Jacob, J.R. Champagne & P. Humphreys: Ketogenic diet in the treatment of refractory epilepsy in childhood. Pediatr Neurol 21, 548-552 (1999)

137. Tallian, K.B., M.C. Nahata & C.Y. Tsao: Role of the ketogenic diet in children with intractable seizures. Ann Pharmacother 32, 349-361 (1998)

138. Howrie, D.L., M. Kraisinger, H.W. McGhee, P.K. Crumrine & N. Katyal: The ketogenic diet: the need for a multidisciplinary approach. Ann Pharmacother 32, 384-385 (1998)

139. Jeong, S.W., S.K. Lee, K.K. Kim, H. Kim, J.Y. Kim & C.K. Chung: Prognostic factors in anterior temporal lobe resections for mesial temporal lobe epilepsy: multivariate analysis. Epilepsia 40, 1735-1739 (1999)

140. Handforth, A., C.M. De Giorgio, S.C. Schachter, B.M. Uthman, D.K. Naritoku, E.S. Tecoma, T.R. Henry, S.D. Collins, B.V. Vaughn, R.C. Gilmartin, D.R. Labar, G.L. Morris, M.C. Salinsky III, I. Osorio, R.K. Ristanovic, D.M. Labiner, J.C. Jones, J.V. Murphy, G.C. Ney & J.W. Wheless: Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology 51, 48-55 (1998)

141. Binnie, C.D.: Vagus nerve stimulation for epilepsy: a review. Seizure 9, 161-169 (2000)

142. Ben-Menachem, E.: Modern management of epilepsy: Vagus nerve stimulation. Baillieres Clin Neurol 5, 841-848 (1996)

143. Sirven, J.I., M. Sperling, D. Naritoku, S. Schachter, D. Labar, M. Holmes, A. Wilensky, J. Cibula, D.M. Labiner, D. Bergen, R. Ristanovic, J. Harvey, R. Dasheiff, G.L. Morris, C.A. O'Donovan, L. Ojemann, D. Scales, M. Nadkarni, B. Richards & J.D. Sanchez: Vagus nerve stimulation therapy for epilepsy in older adults. Neurology 54, 1179-1182 (2000)

144. Vagus Nerve Stimulation Study Group: A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 45, 224-230 (1995)

145. Chase, M.H., Y. Nakamura, C.D. Clemente & M.B. Sterman: Afferent vagal stimulation: neurographic correlates of induced EEG synchronization and desynchronization. Brain Res 5, 236-249 (1967)

146. Chase, M.H. & Y. Nakamura: EEG response to afferent abdominal vagal stimulation. Electroencephalogr Clin Neurophysiol 24, 396-400 (1968)

147. Zabara, J.: Inhibition of experimental seizures in canines by repetitive vagal stimulation. Epilepsia 33, 1005-1012 (1992)

148. MacCracken, K.A. & J.C. Scalisi: Development and evaluation of a ketogenic diet program. J Am Diet Assoc 99, 1554-1558 (1999)

149. Kinsman, S.L., E.P. Vining, S.A. Quaskey, D. Mellits & J.M. Freeman: Efficacy of the ketogenic diet for intractable seizure disorders: review of 58 cases. Epilepsia 33, 1132-1136 (1992)

150. Magrath, G., A. MacDonald & W. Whitehouse: Dietary practices and use of the ketogenic diet in the UK. Seizure 9, 128-130 (2000)

151. Katyal, N.G., A.N. Koehler, B. McGhee, C.M. Foley & P.K. Crumrine: The ketogenic diet in refractory epilepsy: the experience of Children's Hospital of Pittsburgh. Clin Pediat 39, 153-159 (2000)

152. Stafstrom, C.E. & S. Spencer: The ketogenic diet: a therapy in search of an explanation. Neurology 54, 282-283 (2000)

153. Lefevre, F. & N. Aronson: Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy. Pediatrics 105, E4-E6 (2000)

154. Berryman, M.S.: The ketogenic diet revisited. J Am Diet Assoc 97 Suppl 2, S192-S194 (1997)

155. Bough, K.J., P.J. Matthews & D.A. Eagles: A ketogenic diet has different effects upon seizures induced by maximal electroshock and by pentylenetetrazole infusion. Epilepsy Res 38, 105-114 (2000)

156. Thavendiranathan, P.: The MCT ketogenic diet: effects on animal seizure models. Exp Neurol 161, 696-703 (2000)

157. Wax, P.M.: Elixirs, diluents, and the passage of the 1938 Federal Food, Drug & Cosmetic Act. Ann Intern Med 122, 456-461 (1995)

158. Wax, P.M.: Elixir Sulfanilamide-Massengill revisited. Vet Human Toxicol 36, 561-562 (1994)

159. McFayden, R.E.: Thalidomide in America: A brush with tragedy. Clio Medica 11, 79-93 (1976)

160. Sherman, M. & S. Strauss: Thalidomide: A twenty-five year perspective. Food Drug Cosm Law J 41, 458-466 (1986)

161. Hollister, L.E., I.H. Page, C.C. Pfeiffer & M.B. Visscher: The Kefauver-Harris amendments of 1962: a critical appraisal of the first five years. J Clin Pharmacol J New Drugs 8, 69-73 (1968)

162. Hollister, L.E.: The FDA ten years after the Kefauver-Harris amendments. Perspect Biol Med 17, 243-249 (1974)

163. Simmons, H.E.: The drug regulatory system of the United States Food & Drug Administration: a defense of current requirements for safety and efficacy. Intl J Health Serv 4, 95-107 (1974)

164. Wardell, W.M.: History and application of drug safety and efficacy requirements in the United States. Agents Actions 8, 420-421 (1978)

165. Kramer, L.D., G.W. Pledger & M. Kamin: Prototype anti-epileptic drug clinical development plan. Epilepsia 34, 1075-1084 (1993)

166. Goyan, J.E.: Science: part of the problem, most of the answer. Drug Intell Clin Pharm 17, 566-569 (1983)

167. Patsalos, P.N. & J.W.A.S. Sander: Newer anti-epileptic drugs. Towards an improved risk-benefit ratio. Drug Safety 11, 37-67 (1994)

168. Spence, P.: From genome to drug-optimising the drug discovery process. Prog Drug Res 53, 157-191 (1999)

169. Rho, J.M. & R. Sankar: The pharmacologic basis of anti-epileptic drug action. Epilepsia 40, 1471-1483 (1999)

170. Patsalos, P.N.: Anti-epileptic drug pharmacogenetics. Ther Drug Monit 22, 127-130 (2000)

171. Dichter, M.A.: Emerging insights into mechanisms of epilepsy: implications for new anti-epileptic drug development. Epilepsia 35 Suppl 4, S51-S57 (1994)

172. Taylor, C.P. & J.L. Marks: Pharmaceutical industry screening for new anti-epileptic drugs. Adv Neurol 76, 41-47 (1998)

173. Meldrum, B.S.: Identification and preclinical testing of novel anti-epileptic compounds. Epilepsia 38 Suppl 9, S7-S15 (1997)

174. Traub, R.D., C. Borck, S.B. Colling & J.G. Jefferys: On the structure of ictal events in vitro. Epilepsia 37, 879-891 (1996)

175. Dorn, T. & O.W. Witte: Refractory periods following interictal spikes in acute experimentally induced epileptic foci. Electroencephalogr Clin Neurophysiol 94, 80-85 (1995)

176. Velluti, J.C., J. Costa da Costa & R.E. Russo: The cerebral hemisphere of the turtle in vitro. An experimental model with spontaneous interictal-like spikes for the study of epilepsy. Epilepsy Res 28, 29-37 (1997)

177. Schulz, R., H.O. Luders, M. Hoppe, I. Tuxhorn, T. May & A. Ebner: Interictal EEG and ictal scalp EEG propagation are highly predictive of surgical outcome in mesial temporal lobe epilepsy. Epilepsia 41, 564-570 (2000)

178. Jensen, M.S. & Y. Yaari: Role of intrinsic burst firing, potassium accumulation, and electrical coupling in the elevated potassium model of hippocampal epilepsy. J Neurophysiol 77, 1224-1233 (1997)

179. Schwindt, P. & W. Crill: Mechanisms underlying burst and regular spiking evoked by dendritic depolarization in layer 5 cortical pyramidal neurons. J Neurophysiol 81, 1341-1354 (1999)

180. McBain, C.J.: Hippocampal inhibitory neuron activity in the elevated potassium model of epilepsy. J Neurophysiol 73, 2853-2863 (1995)

181. Serratosa, J.M.: Idiopathic epilepsies with a complex mode of inheritance. Epilepsia 40 Suppl 3, 12-16 (1999)

182. McNamara, J.O.: Emerging insights into the genesis of epilepsy. Nature 399 Suppl, A15-A22 (1999)

183. Berkovic, S.F. & I.E. Scheffer: Epilepsies with single gene inheritance. Brain Dev 19, 13-18 (1997)

184. Berkovic, S.F. & I.E. Scheffer: Genetics of human partial epilepsy. Curr Opin Neurol 10, 110-114 (1997)

185. Berkovic, S.F. & I.E. Scheffer: Genetics of the epilepsies. Curr Opin Neurol 12, 177-182 (1999)

186. Leppert, M. & N. Singh: Benign familial neonatal epilepsy with mutations in two potassium channel genes. Curr Opin Neurol 12, 143-147 (1999)

187. Allen, K.M. & C. Walsh: Shaking down new epilepsy genes. Nat Med 5, 516-518 (1996)

188. Steinlein, O.K.: Gene defects in idiopathic epilepsy. Rev Neurol (Paris) 155, 450-453 (1999)

189. Steinlein, O.K.: Idiopathic epilepsies with a monogenic mode of inheritance. Epilepsia 40 Suppl 3, 9-11 (1999)

190. Lander, E.S. & N.J. Schork: Genetic dissection of complex traits. Science 265, 2037-2048 (1994)

191. Robinson, R. & M. Gardiner: Genetics of childhood epilepsy. Arch Dis Child 82, 121-125 (2000)

192. Berkovic, S.F.: Epilepsy genes and the genetics of epilepsy syndromes: the promise of new therapies based on genetic knowledge. Epilepsia 38 Suppl 9, S32-S36 (1997)

193. Steinlein, O.K. & J.L. Noebels: Ion channels and epilepsy in man and mouse. Curr Opin Genet Dev 10, 286-291 (2000)

194. Steinlein, O.K., A. Magnusson, J. Stoodt, S. Bertrand, S. Weiland, S.F. Berkovic, K.O. Nakken, P. Propping & D. Bertrand: An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Hum Mol Genet 6, 943-947 (1997)

195. Steinlein, O.K., J.C. Mulley, P. Propping, R.H. Wallace, H.A. Phillips, G.R. Sutherland, I.E. Scheffer & S.F. Berkovic: A missense mutation in the neuronal nicotinic acetylcholine receptor alpha4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 11, 201-203 (1995)

196. Tenchini, M.L., S. Duga, M.T. Bonati, R. Asselta, A. Oldani, M. Zucconi, M. Malcovati, L. Dalpra & L. Ferini-Strambi: SER252PHE and 776INS3 mutations in the CHRNA4 gene are rare in the Italian ADNFLE population. Sleep 22, 637-639 (1999)

197. Oldani, A., M. Zucconi, R. Asselta, M. Modugno, M.T. Bonati, L. Dalpra, M. Malcovati, M.L. Tenchini, S. Smirne & L. Ferini-Strambi: Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome. Brain 121, 205-223 (1998)

198. Phillips, H.A., I.E. Scheffer, K.M. Crossland, K.P. Bhatia, D.R. Fish, C.D. Marsden, S.J. Howell, J.B. Stephenson, J. Tolmie, G. Plazzi, O. Eeg-Olofsson, R. Singh, I. Lopes-Cendes, E. Andermann, F. Andermann, S.F. Berkovic & J.C. Mulley: Autosomal dominant nocturnal frontal-lobe epilepsy: genetic heterogeneity and evidence for a second locus at 15q24. Am J Hum Genet 63, 1108-1116 (1998)

199. Bertrand, D.: Neuronal nicotinic acetylcholine receptors: their properties and alterations in autosomal dominant nocturnal frontal lobe epilepsy. Rev Neurol (Paris) 155, 457-462 (1999)

200. Kuryatov, A., V. Gerzanich, M. Nelson, F. Olale & J. Lindstrom: Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca2+ permeability, conductance, and gating of human alpha4beta2 nicotinic acetylcholine receptors. J Neurosci 17, 9035-9047 (1997)

201. Phillips, H.A., I.E. Scheffer, S.F. Berkovic, G.E. Hollway, G.R. Sutherland & J.C. Mulley: Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2. Nat Genet 10, 117-118 (1995)

202. Ito, M., K. Kobayashi, T. Fujii, T. Okuno, S. Hirose, H. Iwata, A. Mitsudome & S. Kaneko: Electroclinical picture of autosomal dominant nocturnal frontal lobe epilepsy in a Japanese family. Epilepsia 41, 52-58 (2000)

203. Hirose, S., H. Iwata, H. Akiyoshi, K. Kobayashi, M. Ito, K. Wada, S. Kaneko & A. Mitsudome: A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology 53, 1749-1753 (1999)

204. Steinlein, O.K., J. Stoodt, J. Mulley, S. Berkovic, I.E. Scheffer & E. Brodtkorb: Independent occurrence of the CHRNA4 Ser248Phe mutation in a Norwegian family with nocturnal frontal lobe epilepsy. Epilepsia 41, 529-535 (2000)

205. Yang, W.P., P.C. Levesque, W.A. Little, M.L. Conder, P. Ramakrishnan, M.G. Neubauer & M.A. Blanar: Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy. J Biol Chem 273, 19419-19423 (1998)

206. Wallace, R.H., D.W. Wang, R. Singh, I.E. Scheffer, A.L. George Jr., H.A. Phillips, K. Saar, A. Reis, E.W. Johnson, G.R. Sutherland, S.F. Berkovic & J.C. Mulley: Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet 19, 366-370 (1998)

207. Ryan, S.G.: Ion channels and the genetic contribution to epilepsy. J Child Neurol 14, 58-66 (1999)

208. Lopes-Cendes, I., I.E. Scheffer, S.F. Berkovic, M. Rousseau, E. Andermann & G.A. Rouleau: A new locus for generalized epilepsy with febrile seizures plus maps to chromosome 2. Am J Hum Genet 66, 698-701 (2000)

209. Xiong, L., M. Labuda, D.S. Li, T.J. Hudson, R. Desbiens, G. Patry, S. Verret, P. Langevin, S. Mercho, M.H. Seni, I. Scheffer, F. Dubeau, S.F. Berkovic, F. Andermann, E. Andermann & M. Pandolfo: Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12. Am J Hum Genet 65, 1698-1710 (1999)

210. Elmslie, F.V., M. Rees, M.P. Williamson, M. Kerr, M.J. Kjeldsen, K.A. Pang, A. Sundqvist, M.I. Friis, D. Chadwick, A. Richens, A. Covanis, M. Santos, A. Arzimanoglou, C.P. Panayiotopoulos, D. Curtis, W.P. Whitehouse & R.M. Gardiner: Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q. Hum Mol Genet 8, 1329-1334 (1997)

211. Durner, M.D., T. Sander, D.A. Greenberg, K. Johnson, G. Beck-Mannagetta & D. Janz: Localization of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients. Neurology 41, 1651-1655 (1991)

212. Durner, M., D. Janz, J. Zingsem & D.A. Greenberg: Possible association of juvenile myoclonic epilepsy with HLA-DRw6. Epilepsia 33, 814-816 (1992)

213. Grifa, A., A. Totaro, J.M. Rommens, M. Carella, A. Roetto, L. Borgato, L. Zelante & P. Gasparini: GABA (gamma-amino-butyric acid) neurotransmission: identification and fine mapping of the human GABAB receptor gene. Biochem Biophys Res Commun 250, 240-245 (1998)

214. Goei, V.L., J. Choi, J. Ahn, C.L. Bowlus, R. Raha-Chowdhury & J.R. Gruen: Human gamma-aminobutyric acid B receptor gene: complementary DNA cloning, expression, chromosomal location, and genomic organization. Biol Psychiatry 44, 659-666 (1998)

215. Elmslie, F.V., M.P. Williamson, M. Rees, M. Kerr, M.J. Kjeldsen, K.A. Pang, A. Sundqvist, M.L. Friis, A. Richens, D. Chadwick, W.P. Whitehouse & R.M. Gardiner: Linkage analysis of juvenile myoclonic epilepsy and microsatellite loci spanning 61 cM of human chromosome 6p in 19 nuclear pedigrees provides no evidence for a susceptibility locus in this region. Am J Hum Genet 59, 653-663 (1996)

216. Ryan, M. & R.J. Baumann: Use and monitoring of bromides in epilepsy treatment. Pediatr Neurol 21, 523-528 (1999)

217. Stoffel, M. & L.Y. Jan: Epilepsy genes: excitement traced to potassium channels. Nat Genet 18, 6-8 (1998)

218. Escayg, A., M. De Waard, D.D. Lee, D. Bichet, P. Wolf, T. Mayer, J. Johnston, R. Baloh, T. Sander & M.H. Meisler: Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet 66, 1531-1539 (2000)

219. Brown, W.M. & K.M. Dziegielewska: Friends and relations of the cystatin superfamily-new members and their evolution. Prot Sci 6, 5-12 (1997)

220. Pennacchio, L.A., A.E. Lehesjoki, N.E. Stone, V.L. Willour, K. Virtaneva, J. Miao, E. D'Amato, L. Ramirez, M. Faham, M. Koskiniemi, J.A. Warrington, R. Norio, A. de la Chapelle, D.R. Cox & R.M. Myers: Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science 271, 1731-1734 (1996)

221. Lalioti, M.D., M. Mirotsou, C. Buresi, M.C. Peitsch, C. Rossier, R. Ouazzani, M. Baldy-Moulinier, A. Bottani, A. Malafosse & S.E. Antonarakis: Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1). Am J Hum Genet 60, 342-351 (1997)

222. Lalioti, M.D., H.S. Scott, C. Buresi, C. Rossier, A. Bottani, M.A. Morris, A. Malafosse & S.E. Antonarakis: Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy. Nature 386, 847-851 (1997)

223. Virtaneva, K., E. D'Amato, J. Miao, M. Koskiniemi, R. Norio, G. Avanzini, S. Franceschetti, R. Michelucci, C.A. Tassinari, S. Omer, L.A. Pennacchio, R.M. Myers, J.L. Dieguez-Lucena, R. Krahe, A. de la Chapelle & A.E. Lehesjoki: Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1. Nat Genet 15, 393-396 (1997)

224. Lehesjoki, A.E. & M. Koskiniemi: Clinical features and genetics of progressive myoclonus epilepsy of the Univerricht-Lundborg type. Ann Med 30, 474-480 (1998)

225. Lehesjoki, A.E. & M. Koskiniemi: Progressive myoclonus epilepsy of Unverricht-Lundborg type. Epilepsia 40 Suppl 3, 23-28 (1999)

226. Bespalova, I.N., S. Adkins, M. Pranzatelli & M. Burmeister: Novel cystatin B mutation and diagnostic PCR assay in an Unverricht-Lundborg progressive myoclonus epilepsy patient. Am J Med Genet 74, 467-471 (1997)

227. Bespalova, I.N., M. Pranzatelli & M. Burmeister: G to C transversion at a splice acceptor site causes exon skipping in the cystatin B gene. Mutat Res 382, 67-74 (1997)

228. Lafrenière, R.G., D.L. Rochefort, N. Chrétien, J.M. Rommens, J.I. Cochius, R. Kälviäinen, U. Nousiainen, G. Patry, K. Farrell, B. Söderfeldt, A. Federico, B.R. Hale, O.H. Cossio, T. Sørensen, M.A. Pouliot, T. Kmiec, P. Uldall, J. Janszky, M.R. Pranzatelli, F. Andermann, E. Andermann & G.A. Rouleau: Unstable insertion in the 5'-flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1. Nat Genet 15, 298-302 (1997)

229. Bradford, H.F.: Glutamate, GABA and epilepsy. Prog Neurobiol 47, 477-511 (1995)

230. Chapman, A.G.: Glutamate and epilepsy. J Nutr 130 Suppl 4S, 1043S-1045S (2000)

231. Holland, K.D., A.C. McKeon, D.J. Canney, D.F. Covey & J.A. Ferrendelli: Relative anticonvulsant effects of GABAmimetic and GABA modulatory agents. Epilepsia 33, 981-986 (1992)

232. Balme, R.H.: Early medicinal use of bromides (Sir Charles Locock). J R Coll Physicians Lond 10, 205-208 (1976)

233. Joynt, R.J.: The use of bromides for epilepsy. Am J Dis Child 128, 362-363 (1974)

234. Friedlander, W.J.: Who was "the father of bromide treatment of epilepsy?" Arch Neurol 43, 505-507 (1986)

235. White, H.S.: Clinical significance of animal seizure models and mechanism of action studies of potential anti-epileptic drugs. Epilepsia 38 Suppl 1, S9-S17 (1997)

236. Avanzini, G.: Animal models relevant to human epilepsies. Ital J Neurol Sci 16, 5-8 (1995)

237. Deyn, P.P.: Animal models of focal epilepsy. Acta Neurol Belg 99, 222-225 (1999)

238. Merritt, H.H. & T.J. Putnam: Sodium diphenyl hydantoinate in the treatment of convulsive disorders. JAMA 111, 1068-1073 (1938)

239. Merritt, H.H. & T.J. Putnam: A new series of anticonvulsant drugs tested by experiments on animals. Arch Neurol Psych 39, 1003-1015 (1938)

240. Merritt, H.H. & T.J. Putnam: Landmark article Sept 17, 1938: Sodium diphenyl hydantoinate in the treatment of convulsive disorders. By H. Houston Merritt & Tracy J. Putnam. JAMA 251, 1062-1067 (1984)

241. Friedlander, W.J.: Putnam, Merritt, and the discovery of Dilantin. Epilepsia 27 Suppl 3, S1-S20 (1986)

242. Goldensohn, E.S.: Merritt-Putnam: the legacy. Epilepsia 33 Suppl 4, S3-S5 (1992)

243. Glazko, A.J.: Discovery of phenytoin. Ther Drug Monit 8, 490-497 (1986)

244. Swinyard, E.A.: Experimental models of epilepsy. A manual for the laboratory worker. Raven Press, New York, NY (1972)

245. White, H.S., M. Johnson, H.H. Wolf & H.J. Kupferberg: The early identification of anticonvulsant activity: role of the maximal electroshock and subcutaneous pentylenetetrazol seizure models. Ital J Neurol Sci 16, 73-77 (1995)

246. Matagne, A. & H. Klitgaard: Validation of corneally kindled mice: a sensitive screening model for partial epilepsy in man. Epilepsy Res 31, 59-71 (1998)

247. Löscher, W.: Animal models of intractable epilepsy. Prog Neurobiol 53, 239-258 (1997)

248. Della Paschoa, O.E., M.R. Kruk, R. Hamstra, R.A. Voskuyl & M. Danhof: Seizure patterns in kindling and cortical stimulation models of experimental epilepsy. Brain Res 770, 221-227 (1997)

249. Shandra, A.A., A.M. Mazarati, L.S. Godlevsky & R.S. Vastyanov: Chemical kindling: implications for anti-epileptic drugs-sensitive and resistant epilepsy models. Epilepsia 37, 269-274 (1996)

250. Velisek, L., J. Veliskova & S.L. Moshe: Developmental seizure models. Ital J Neurol Sci 16, 127-133 (1995)

251. Fariello, R.G.: Critical review of the animal models of generalized epilepsies. Ital J Neurol Sci 16, 69-72 (1995)

252. Kubova, H. & S.L. Moshe: Experimental models of epilepsy in young animals. J Child Neurol 9 Suppl 1, S3-S11 (1994)

253. Ullal, G.R., P. Satishchandra & S.K. Shankar: Effect of anti-epileptic drugs and calcium channel blocker on hyperthermic seizures in rats: animal model for hot water epilepsy. Indian J Physiol Pharmacol 40, 303-308 (1996)

254. Seyfried, T.N., M.T. Todorova & M.J. Poderycki: Experimental models of multifactorial epilepsies: the EL mouse and mice susceptible to audiogenic seizures. Adv Neurol 79, 279-290 (1999)

255. Nissinen, J., T. Halonen, E. Koivisto & A. Pitkanen: A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdala in rat. Epilepsy Res 38, 177-205 (2000)

256. Dailey, J.W., Q.S. Yan, L.E. Adams-Curtis, J.R. Ryu, K.H. Ko, P.K. Mishra & P.C. Jobe: Neurochemical correlates of anti-epileptic drugs in the genetically epilepsy-prone rat (GEPR). Life Sci 58, 259-266 (1996)

257. Marescaux, C. & M. Vergnes: Genetic Absence Epilepsy in Rats from Strasbourg (GAERS). Ital J Neurol Sci 16, 113-118 (1995)

258. Puranam, R.S. & J.O. McNamara: Seizure disorders in mutant mice: relevance to human epilepsies. Curr Opin Neurobiol 9, 281-287 (1999)

259. Frankel, W.N.: Detecting genes in new and old mouse models for epilepsy: a prospectus through the magnifying glass. Epilepsy Res 36, 97-110 (1999)

260. Barclay, J. & M. Rees: Mouse models of spike-wave epilepsy. Epilepsia 40 Suppl 3, 17-22 (1999)

261. McNamara, J.O. & R.S. Puranam: Epilepsy genetics: an abundance of riches for biologists. Curr Biol 8, R168-R170 (1998)

262. Toth, M. & L. Tecott: Transgenic approaches to epilepsy. Adv Neurol 79, 291-296 (1999)

263. Perucca, E.: Evaluation of drug treatment outcome in epilepsy: a clinical perspective. Pharm World Sci 19, 217-222 (1997)

264. Binnie, C.D.: Design of clinical anti-epileptic drug trials. Seizure 4, 187-192 (1995)

265. Cramer, J.A.: Ethical issues in the planning and conduct of clinical trials of anti-epileptic drugs. Med Law 16, 209-214 (1997)

266. Pledger, G.W. & D. Schmidt: Evaluation of anti-epileptic drug efficacy. A review of clinical trial design. Drugs 48, 498-509 (1994)

267. Delgado-Escueta A.V., C. Wasterlain, D.M. Treiman & R.J. Porter: Status epilepticus. Adv Neurol 34, 537-541 (1983)

268. Mattson, R.H., J.A. Cramer, A.V. Delgado-Escueta, D.B. Smith & J.F. Collins: A design for the prospective evaluation of the efficacy and toxicity of anti-epileptic drugs in adults. Neurology 33 Suppl 1, 14-25 (1983)

269. Mignot, G.: Drug trials in epilepsy. Brit Med J 313, 1158 (1996)

270. De Lorenzo, R.J., J.M. Pellock, A.R. Towne & J.G. Boggs: Epidemiology of status epilepticus. J Clin Neurophysiol 12, 316-325 (1995)

271. DeGiorgio, C.M., J.E. Lopez, Z.N. Lekht & A.L. Rabinowicz: Status epilepticus induced by Felbatol withdrawal. Neurology 45, 1021-1022 (1995)

272. Shinnar, S. & A.T. Berg: Withdrawal of anti-epileptic drugs. Curr Opin Neurol 8, 103-106 (1995)

273. Schmidt, D. & L. Gram: A practical guide to when (and how) to withdraw anti-epileptic drugs in seizure-free patients. Drugs 52, 870-874 (1996)

274. Chadwick, D.: Does withdrawal of different anti-epileptic drugs have different effects on seizure recurrence? Further results from the MRC Anti-epileptic Drug Withdrawal Study. Brain 122, 441-448 (1999)

275. Lhatoo, S.D. & J.W. Sander: Stopping drug therapy in epilepsy. Curr Pharm Des 6, 861-863 (2000)

276. Group for the Evaluation of Cinromide in the Lennox-Gastaut Syndrome: Double-blind, placebo-controlled evaluation of cinromide in patients with the Lennox-Gastaut Syndrome. Epilepsia 30, 422-429 (1989)

277. Leppik, I.E., F.E. Dreifuss, G.W. Pledger, N.M. Graves, N. Santilli, I. Drury, J.Y. Tsay, M.P. Jacobs, E. Bertram, J.J. Cereghino, G. Cooper, J.T. Sahlroot, P. Sheridan, M. Ashworth, S.I. Lee & T.L. Sierzant: Felbamate for partial seizures: results of a controlled clinical trial. Neurology 41, 1785-1789 (1991)

278. Felbamate Study Group in Lennox-Gastaut Syndrome: Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med 328, 29-33 (1993)

279. Perucca, E. & T. Tomson: Monotherapy trials with the new anti-epileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Res 33, 247-262 (1999)

280. Patsalos, P.N.: Phenobarbitone to gabapentin: a guide to 82 years of anti-epileptic drug pharmacokinetic interactions. Seizure 3, 163-170 (1984)

281. Riva, R., F. Albani, M. Contin & A. Baruzzi: Pharmacokinetic interactions between anti-epileptic drugs. Clinical considerations. Clin Pharmacokinet 31, 470-493 (1996)

282. Rambeck, B., U. Specht & P. Wolf: Pharmacokinetic interactions of the new anti-epileptic drugs. Clin Pharmacokinet 31, 309-324 (1996)

283. Rodin, E.A., C.S. Rim & P.M. Rennick: The effect of carbamazepine on patients with psychomotor epilepsy; results of a double-blind trial. Epilepsia 15, 547-561 (1974)

284. Guberman, A.: Monotherapy or polytherapy for epilepsy? Can J Neurol Sci 25, S3-S8 (1998)

285. Deckers, C.L., Y.A. Hekster, A. Keyser, H. Meinardi & W.O. Renier: Reappraisal of polytherapy in epilepsy: a critical review of drug load and adverse effects. Epilepsia 38, 570-575 (1997)

286. Schneiderman, J.H.: Monotherapy versus polytherapy in epilepsy: a framework for patient management. Can J Neurol Sci 25, S9-S13 (1998)

287. Macdonald, R.L.: Is there a mechanistic basis for rational polypharmacy? Epilepsy Res 11 Suppl, 79-93 (1996)

288. Goldsmith, P. & P.R. de Bittencourt: Rationalized polytherapy for epilepsy. Acta Neurol Scand Suppl 162, 35-39 (1995)

289. Shorvon, S.D., M.L. Espir, T.J. Steiner, C.I. Dellaportas & F.C. Rose: Is there a place for placebo controlled trials of anti-epileptic drugs? Brit Med J (Clin Res Ed) 291, 1328-1329 (1985)

290. Alarcon, G., C.D. Binnie, R.D.C. Elwes & C.E. Polkey: Monotherapy anti-epileptic drug trials in patients undergoing presurgical assessment: Methodological problems and possibilities. Seizure 4, 293-301 (1995)

291. Gram, L. & D. Schmidt: Innovative designs of controlled clinical trials in epilepsy. Epilepsia 34 Suppl 7, S1-S6 (1993)

292. Beydoun, A.: Monotherapy trials of new anti-epileptic drugs. Epilepsia 38 Suppl 9, S21-S31, (1997)

293. Chadwick, D.: Monotherapy clinical trials of new anti-epileptic drugs: design, indications, and controversies. Epilepsia 38 Suppl 9, S16-S20 (1997)

294. Perucca, E.: Innovative monotherapy trial designs for the assessment of anti-epileptic drugs: a critical appraisal. Eur J Clin Pharmacol 54, 1-5 (1998)

295. Devinsky, O., R.E. Faught, B.J. Wilder, A.M. Kanner, M. Kamin, L.D. Kramer & A. Rosenberg: Efficacy of felbamate monotherapy in patients undergoing presurgical evaluation of partial seizures. Epilepsy Res 20, 241-246 (1995)

296. Bourgeois, B.F., I.E. Leppik, J.C. Sackellares, K. Laxer, R. Lesser, J.A. Messenheimer, L.D. Kramer, M. Kamin & A. Rosenberg: Felbamate: a double-blind controlled trial in patients undergoing presurgical evaluation of partial seizures. Neurology 43, 693-696 (1993)

297. Theodore, W.H., P. Albert, B. Stertz, B. Malow, D. Ko, S. White, R. Flamini & T. Ketter: Felbamate monotherapy: implications for anti-epileptic drug development. Epilepsia 36, 1105-1110 (1995)

298. Welty, T.E., M. Privitera & R. Shukla: Increased seizure frequency associated with felbamate withdrawal in adults. Arch Neurol 55, 641-645 (1998)

299. Lammers, M.W., Y.A. Hekster, A. Keyser, H. van Lier, H. Meinardi & W.O. Renier: Neither dosage nor serum levels of anti-epileptic drugs are predictive for efficacy and adverse effects. Pharm World Sci 17, 201-206 (1995)

300. Koch, S., E. Jager-Roman, G. Losche, H. Nau, D. Rating & H. Helge: Anti-epileptic drug treatment in pregnancy: drug side effects in the neonate and neurological outcome. Acta Paediatr 85, 739-746 (1996)

301. Koch, S., K. Titze, R.B. Zimmermann, M. Schröder, U. Lehmkuhl & H. Rauh: Long-term neuropsychological consequences of maternal epilepsy and anticonvulsant treatment during pregnancy for school-age children and adolescents. Epilepsia 40, 1237-1243 (1999)

302. Samrén, E.B., C.M. van Duijn, S. Koch, V.K. Hiilesmaa, H. Klepel, A.H. Bardy, G.B. Mannagetta, A.W. Deichl, E. Gaily, M.L. Granström, H. Meinardi, D.E. Grobbee, A. Hofman, D. Janz & D. Lindhout: Maternal use of anti-epileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia 38, 981-990 (1997)

303. Holmes, L.B., E.A. Harvey, K.S. Brown, A.M. Hayes & S. Khoshbin: Anticonvulsant teratogenesis: I. A study design for newborn infants. Teratology 49, 202-207 (1994)

304. Guerrini, R., A. Belmonte & P. Genton: Anti-epileptic drug-induced worsening of seizures in children. Epilepsia 39 Suppl 3, S2-S10 (1998)

305. Genton, P.: When anti-epileptic drugs aggravate epilepsy. Brain Dev 22, 75-80 (2000)

306. Genton, P. & J. McMenamin: Aggravation of seizures by anti-epileptic drugs: what to do in clinical practice. Epilepsia 39 Suppl 3, S26-S29 (1998)

307. Elger, C.E., J. Bauer, J. Scherrmann & G. Widman: Aggravation of focal epileptic seizures by antiepileptic drugs. Epilepsia 39 Suppl 3, S15-S18 (1998)

308. Jankovi, S.M., D.V. Soki, Z.M. Levi, V. Sul, J. Drulovi, N. Stojsavljevi, R. Veskov & J. Ivanu: Eponyms and epilepsy (history of Eastern civilizations). Srp Arh Celok Lek 124, 217-221 (1996)

309. Gross, R.A.: A brief history of epilepsy and its therapy in the Western Hemisphere. Epilepsy Res 12, 65-74 (1992)

310. Lerman-Sagie, T. & P. Lerman: Phenobarbital still has a role in epilepsy treatment. J Child Neurol 14, 820-821 (1999)

311. Cockerell, O.C., I. Eckle, D.M. Goodridge, J.W. Sander & S.D. Shorvon: Epilepsy in a population of 6000 re-examined: secular trends in first attendance rates, prevalence, and prognosis. J Neurol Neurosurg Psychiatry 58, 570-576 (1995)

312. Cockerell, O.C., A.L. Johnson, J.W. Sander, Y.M. Hart & S.D. Shorvon: Remission of epilepsy: results from the National General Practice Study of Epilepsy. Lancet 346, 140-144 (1995)

313. Devinsky, O.: Patients with refractory seizures. N Engl J Med 340, 1565-1570 (1999)

314. Regesta, G. & P. Tanganelli: Clinical aspects and biological bases of drug-resistant epilepsies. Epilepsy Res 34, 109-122 (1999)

315. Datta, P.K. & P.M. Crawford: Refractory epilepsy: treatment with new anti-epileptic drugs. Seizure 9, 51-57 (2000)

316. Kwan, P. & M.J. Brodie: Early identification of refractory epilepsy. N Engl J Med 342, 314-319 (2000)

317. Tanaka, E.: Clinically significant pharmacokinetic drug interactions between anti-epileptic drugs. J Clin Pharm Ther 24, 87-92 (1999)

318. Vining, E.P.: Use of barbiturates and benzodiazepines in treatment of epilepsy. Neurol Clin 4, 617-632 (1986)

319. Willis, J., A. Nelson, F.W. Black, A. Borges, A. An & J. Rice: Barbiturate anticonvulsants: a neuropsychological and quantitative electroencephalographic study. J Child Neurol 12, 169-171 (1997)

320. Getova, D., S. Moyanova, V. Georgiev & V. Ivanova: Anticonvulsive activity of a barbiturate derivative HB-7 in a model of allylglycine-induced epilepsy in cats. Acta Physiol Pharmacol Bulg 16, 43-49 (1990)

321. King, S.B., E.S. Stratford, C.R. Craig & E.K. Fifer: Synthesis and pharmacological evaluation of spiro-analogues of 5-benzyl-5-ethyl barbituric acid. Pharm Res 12, 1240-1243 (1995)

322. Getova, D. & S. Moyanova: Anticonvulsive effect of 2-hydroxylamine-5-ethyl-5-sec-pentyl barbituric acid (HB-7) in two experimental models of epilepsy. Methods Find Exp Clin Pharmacol 10, 267-272 (1988)

323. Smith, M.C. & B.J. Riskin: The clinical use of barbiturates in neurological disorders. Drugs 42, 365-378 (1991)

324. Bikker, J.A., J. Kubanek & D.F. Weaver: Quantum pharmacologic studies applicable to the design of anticonvulsants: theoretical conformational analysis and structure-activity studies of barbiturates. Epilepsia 35, 411-425 (1994)

325. Young, R.S., P.M. Alger, L. Bauer & D. Lauderbaugh: A randomized, double-blind, crossover study of phenobarbital and mephobarbital. J Child Neurol 4, 361-363 (1986)

326. Gallagher, B.B., I.P. Baumel, S.G. Woodbury & J.A. Dimicco: Clinical evaluation of eterobarb, a new anticonvulsant drug. Neurology 25, 399-404 (1975)

327. Goldberg, M.A., J. Gal, A.K. Cho & D.J. Jenden: Metabolism of dimethoxymethyl phenobarbital (eterobarb) in patients with epilepsy. Ann Neurol 5, 121-126 (1979)

328. Mattson, R.H., P.D. Williamson & E. Hanahan: Eterobarb therapy in epilepsy. Neurology 11, 1014-1017 (1976)

329. Smith, D.B., S.G. Goldstein & A. Roomet: A comparison of the toxicity effects of the anticonvulsant eterobarb (antilon, DMMP) and phenobarbital in normal human volunteers. Epilepsia 27, 149-155 (1986)

330. Wolter, K.D.: Eterobarb. Epilepsy Res 3 Suppl, 99-102 (1991)

331. Sato, J., Y. Sekizawa, A. Yoshida, E. Owada, N. Sakuta, M. Yoshihara, T. Goto, Y. Kobayashi & K. Ito: Single-dose kinetics of primidone in human subjects: effect of phenytoin on formation and elimination of active metabolites of primidone, phenobarbital and phenylethylmalonamide. J Pharmacobiodyn 15, 467-72 (1992)

332. Nagaki, S., N. Ratnaraj & P.N. Patsalos: Blood and cerebrospinal fluid pharmacokinetics of primidone and its primary pharmacologically active metabolites, phenobarbital and phenylethylmalonamide in the rat. Eur J Drug Metab Pharmacokinet 24, 255-264 (1999)

333. Ferranti, V., C. Chabenat, S. Menager & O. Lafont: Simultaneous determination of primidone and its three major metabolites in rat urine by high-performance liquid chromatography using solid-phase extraction. J Chromatogr B Biomed Sci Appl 718, 199-204 (1998)

334. El-Masri, H.A. & C.J. Portier: Physiologically based pharmacokinetics model of primidone and its metabolites phenobarbital and phenylethylmalonamide in humans, rats, and mice. J Drug Metab Dispos 26, 585-594 (1998)

335. Iivanainen, M.: Phenytoin: effective but insidious therapy for epilepsy in people with intellectual disability. J Intellect Disabil Res 42 Suppl 1, 24-31 (1998)

336. Tunnicliff, G.: Basis of the antiseizure action of phenytoin. J Gen Pharmacol 27, 1091-1097 (1997)

337. Putnam, T.J. & H.H. Merritt: Experimental determination of the anticonvulsant properties of some phenyl derivatives. Science 85, 525-526 (1937)

338. Knapp, L.E. & A.R. Kugler: Clinical experience with fosphenytoin in adults: pharmacokinetics, safety, and efficacy. J Child Neurol 13 Suppl 1, S15-S18 (1998)

339. Ramsay, R.E. & J. DeToledo: Intravenous administration of fosphenytoin: options for the management of seizures. Neurology 46, S17-S19 (1996)

340. Uthman, B.M., B.J. Wilder & R.E. Ramsay: Intramuscular use of fosphenytoin: an overview. Neurology 46, S24-S28 (1996)

341. Heafield, M.T.E.: Managing status epilepticus. New drug offers real advantages. Brit Med J 320, 953-954 (2000)

342. Jamerson, B.D., G.E. Dukes, K.L. Brouwer, K.H. Donn, J.A. Messenheimer & J.R. Powell: Venous irritation related to intravenous administration of phenytoin versus fosphenytoin. Pharmacother 14, 47-52 (1994)

343. Boucher, B.A.: Fosphenytoin: a novel phenytoin prodrug. Pharmacother 16, 777-791 (1996)

344. Luer, M.S.: Fosphenytoin. Neurol Res 20, 178-182 (1998)

345. Browne, T.R.: Fosphenytoin (Cerebyx). Clin Neuropharmacol 20, 1-12 (1997)

346. Tennison, M.B., R.S. Greenwood & M.V. Miles: Methsuximide for intractable childhood seizures. J Pediatrics 87, 186-189 (1991)

347. Millership, J.S., J. Mifsud & P.S. Collier: The metabolism of ethosuximide. Eur J Drug Metab Pharmacokinet 18, 349-353 (1993)

348. Reiss, W.G. & K.S. Oles: Acetazolamide in the treatment of seizures. Ann Pharmacother 30, 514-519 (1996)

349. Burton Beverly, S.: On the propyl derivatives and decomposition products of ethyl acetoacetate. Am Chem J 3, 385-395 (1882)

350. McElroy, S.L. & P.E. Keck Jr.: Anti-epileptic Drugs. In Textbook of Psychopharmacology. Eds. Schatzberg A., Nemeroff C.B., American Psychiatric Press, Washington DC, 351-375 (1995)

351. Konig, S.A., M. Schenk, C. Sick, E. Holm, C. Heubner, A. Weiss, I. Konig & R. Hehlmann: Fatal liver failure associated with valproate therapy in a patient with Friedreich's disease: review of valproate hepatotoxicity in adults. Epilepsia 40, 1036-1040 (1999)

352. Löscher, W.: Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol 58, 31-59 (1999)

353. Moreiras Plaza, M., G. Rodriguez Goyanes, L. Cuina & R. Alonso: On the toxicity of valproic-acid. Clin Nephrol 51, 187-189 (1999)

354. Ashton, H.: Guidelines for the rational use of benzodiazepines. When and what to use. Drugs 48, 25-40 (1994)

355. Ramsey-Williams, V.A., Y. Wu & H.C. Rosenberg: Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam. Pharmacol Biochem Behav 48, 765-772 (1994)

356. Knudsen, F.U., A. Paerregaard, R. Andersen & J. Andresen: Long-term outcome of prophylaxis for febrile convulsions. Arch Dis Childhood 74, 13-18 (1996)

357. Treiman, D.M., P.D. Meyers, N.Y. Walton, J.F. Collins, C. Colling, A.J. Rowan, A. Handforth, E. Faught, V.P. Calabrese, B.M. Uthman, R.E. Ramsay & M.B. Mamdani: A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 339, 792-798 (1998)

358. Obeid, T., A. Awada, N. Sayes, Y. Mousali & C. Harris: A unique effect of clonazepam on frontal lobe seizure control. Seizure 7, 431-433 (1999)

359. Canadian Clobazam Cooperative Group: Clobazam in treatment of refractory epilepsy: the Canadian experience. A retrospective study. Epilepsia 32, 407-416 (1991)

360. Chamberlain, M.C.: Nitrazepam for refractory infantile spasms and the Lennox-Gastaut syndrome. J Child Neurol 11, 31-34 (1996)

361. Lahat, E., M. Aladjem, G. Eshel, T. Bistritzer & Y. Katz: Midazolam in treatment of epileptic seizures. Pediatr Neurol 8, 215-216 (1992)

362. Lahat, E., M. Goldman, J. Barr, T. Bistritzer & M. Berkovitch: Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study. Brit Med J 321, 83-86 (2000)

363. Towne, A.R. & R.J. De Lorenzo: Use of intramuscular midazolam for status epilepticus. J Emerg Med 17, 323-328 (1999)

364. Pieri, L., R. Schaffner, R. Scherschlicht, P. Polc, J. Sepinwall, A. Davidson, H. Möhler, R. Cumin, M. Da Prada, W.P. Burkard, H.H. Keller, R.K. Müller, M. Gerold, M. Pieri, L. Cook & W. Haefely: Pharmacology of midazolam. Arzneimittelforschung 31, 2180-2201 (1981)

365. Schindler, W.: 5H-Dibenz[b,f]azepines. US patent 2,948,718 (1960)

366. Ishikita, T., A. Ishiguro, K. Fujisawa, I. Tsukimoto & T. Shimbo: Carbamazepine-induced thrombocytopenia defined by a challenge test. Am J Hematol 62, 52-55 (1999)

367. Cates, M. & R. Powers: Concomitant rash and blood dyscrasias in geriatric psychiatry patients treated with carbamazepine. Ann Pharmacother 32, 884-887 (1998)

368. Pisciotta, A.V.: Hematologic toxicity of carbamazepine. Adv Neurol 11, 355-368 (1975)

369. Blackburn, S.C., A.D. Oliart, L.A. García Rodríguez & S. Pérez Gutthann: Anti-epileptics and blood dyscrasias: a cohort study. Pharmacother 18, 1277-1283 (1998)

370. Kaufman, D.W., J.P. Kelly, J.M. Jurgelon, T. Anderson, S. Issaragrisil, B.E. Wiholm, N.S. Young, P. Leaverton, M. Levy & S. Shapiro: Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol Suppl 60, 23-30 (1996)

371. Franceschi, M., G. Ciboddo, G. Truci, A. Borri & N. Canal: Fatal aplastic anemia in a patient treated with carbamazepine. Epilepsia 29, 582-583 (1988)

372. Gerson, W.T., D.G. Fine, S.P. Spielberg & L.L. Sensenbrenner: Anticonvulsant-induced aplastic anemia: increased susceptibility to toxic drug metabolites in vitro. Blood 61, 889-893 (1983)

373. Tecoma, E.S.: Oxcarbazepine. Epilepsia 40 Suppl 5, S37-S46 (1999)

374. Schwabe, S.: Clinical development outlook of oxcarbazepine. Epilepsia 35 Suppl 3, S2-S4 (1994)

375. Kaelviaeinen, R., T. Keraenen & P.J. Riekkinen Sr.: Place of newer anti-epileptic drugs in the treatment of epilepsy. Drugs 46, 1009-1024 (1993)

376. Elwes, R.D. & C.D. Binnie: Clinical pharmacokinetics of newer anti-epileptic drugs. Lamotrigine, vigabatrin, gabapentin and oxcarbazepine. Clin Pharmacokinet 30, 403-415 (1996)

377. Klosterskov Jensen, P., V. Saano, P. Haring, B. Svenstrup & G.P. Menge: Possible interaction between oxcarbazepine and an oral contraceptive. Epilepsia 33, 1149-1152 (1992)

378. Sabers, A. & L. Gram: Drug treatment of epilepsy in the 1990s. Achievements and new developments. Drugs 52, 483-493 (1996)

379. Leppik, I.E.: Felbamate. Epilepsia 36 Suppl. 2, S66-S72 (1995)

380. Swinyard, E.A., R.D. Sofia & H.J. Kupferberg: Comparative anticonvulsant activity and neurotoxicity of felbamate and four prototype anti-epileptic drugs in mice and rats. Epilepsia 27, 27-34 (1986)

381. Ludwig, B.J. & J.R. Potterfield: The pharmacology of propanediol carbamates. Adv Pharmacol Chemother 9, 173-240 (1971)

382. Ludwig, B.J., L.S. Powell & F.M. Berger: Carbamate derivatives related to meprobamate. J Med Chem 12, 462-472 (1969)

383. Rho, J.M., S.D. Donevan & M.A. Rogawski: Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate. J Pharmacol Exp Ther 280, 1383-1391 (1997)

384. Frey, H.H. & I. Bartels: Felbamate and meprobamate: a comparison of their anticonvulsant properties. Epilepsy Res 27, 151-164 (1997)

385. Pellock, J.M. & J.G. Boggs: Felbamate: a unique anticonvulsant. Drugs Today 31, 9-17 (1995)

386. Pugliese, A.M. & R. Corradetti: Effects of the anti-epileptic drug felbamate on long-term potentiation in the CA1 region of rat hippocampal slices. Neurosci Lett 215, 21-24 (1996)

387. Burdette, D.E. & J.C. Sackellares: Felbamate pharmacology and use in epilepsy. Clin Neuropharmacol 17, 389-402 (1994)

388. Leppik, I.E. & D.L. Wolff: The place of felbamate in the treatment of epilepsy. CNS Drugs 4, 294-301 (1995)

389. Brodie, M.J. & J.M. Pellock: Taming the brain storms: felbamate updated. Lancet 346, 918-919 (1995)

390. Stafstrom, C.E.: The use of felbamate to treat infantile spasms. J Child Neurol 11, 170-171 (1996)

391. Hurst, D.L. & T.D. Rolan: The use of felbamate to treat infantile spasms. J Child Neurol 10, 134-136 (1995)

392. Hosain, S., L. Nagarajan, D. Carson, G. Solomon, J. Mast & D. Labar: Felbamate for refractory infantile spasms. J Child Neurol 12, 466-468 (1997)

393. Mellick, G.A.: Hemifacial spasm: successful treatment with felbamate. J Pain Symptom Mgmt 10, 392-395 (1995)

394. Glauser, T.A., L.S. Olberding, M.K. Titanic & D.M. Piccirillo: Felbamate in the treatment of acquired epileptic aphasia. Epilepsy Res 20, 85-89 (1995)

395. Cheshire, W.P.: Felbamate relieved trigeminal neuralgia. Clin J Pain 2, 139-142 (1995)

396. O'Neil, M.G., C.S. Perdun, M.B. Wilson, S.T. McGown & S. Patel: Felbamate-associated fatal acute hepatic necrosis. Neurology 46, 1457-1459 (1996)

397. Nightingale, S.L.: From the Food and Drug Administration. JAMA 272, 995 (1994)

398. Anon: Aplastic anemia and felbamate withdrawal. Am Fam Physic 50, 700 (1994)

399. Pennell, P.B., M.S. Ogaily & R.L. Macdonald: Aplastic anemia in a patient receiving felbamate for complex partial seizures. Neurology 45, 456-460 (1995)

400. Kaufman, D.W., J.P. Kelly, T. Anderson, D.C. Harmon & S. Shapiro: Evaluation of case reports of aplastic anemia among patients treated with felbamate. Epilepsia 38, 1265-1269 (1997)

401. Pellock, J.M.: Felbamate. Epilepsia 40 Suppl 5, S57-S62 (1999)

402. Ney, G.C., N. Schaul, J. Loughlin, K. Rai & V. Chandra: Thrombocytopenia in association with adjunctive felbamate use. Neurology 44, 980-981 (1994)

403. Farrington, E.: Felbamate: restrictions on use. Pediatr Nurs 21, 188-200 (1995)

404. Heydorn, W.E.: Felbamate-rise and fall of a novel anti-epilepsy compound. Expert Opin Invest Drugs 3, 1205-1208 (1994)

405. Avanzini, G., R. Canger, B. Dalla Bernardina & F. Vigevano: Felbamate in therapy-resistant epilepsy: an Italian experience. Epilepsy Res 25, 249-255 (1996)

406. Taylor, C.P., N.S. Gee, T.Z. Su, J.D. Kocsis, D.F. Welty, J.P. Brown, D.J. Dooley, P. Boden & L. Singh: A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res 29, 233-249 (1998)

407. Morris, G.L.: Gabapentin. Epilepsia 40 Suppl 5, S63-S70 (1999)

408. Beydoun, A.: Monotherapy trials with gabapentin for partial epilepsy. Epilepsia 40 Suppl 6, S13-S16 (1999)

409. Beydoun, A., B.M. Uthman & J.C. Sackellares: Gabapentin: pharmacokinetics, efficacy, and safety. Clin Neuropharmacol 18, 469-481 (1995)

410. Marciani, M.G., F. Spanedda & D. Mattia: Neurophysiologic and neuropsychologic profiles of lamotrigine in epilepsy. Clin Neuropharmacol 22, 159-163 (1999)

411. Coulter, D.A.: Anti-epileptic drug cellular mechanisms of action: where does lamotrigine fit in? J Child Neurol 12 Suppl 1, S2-S9 (1997)

412. Messenheimer, J.A.: Lamotrigine. Epilepsia 36 Suppl 2, S87-S94 (1995)

413. Sachdeo, R.C.: Topiramate. Clinical profile in epilepsy. Clin Pharmacokinet 34, 335-346 (1998)

414. Privitera, M.D.: Topiramate: a new anti-epileptic drug. Ann Pharmacother 31, 1164-1173 (1997)

415. Perucca, E. & M. Bialer: The clinical pharmakokinetics of the newer anti-epileptic drugs. Focus on topiramate, zomisomide and tiagabine. Clin Pharmacokinet 31, 29-46 (1996)

416. Kellett, M.W., D.F. Smith, P.A. Stockton & D.W. Chadwick: Topiramate in clinical practice: first year's postlicensing experience in a specialist epilepsy clinic. J Neurol Neurosurg Psychiatry 66, 759-763 (1999)

417. Adkins, J.C. & S. Noble: Tiagabine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy. Drugs 55, 437-460 (1998)

418. Schachter, S.C.: A review of the anti-epileptic drug tiagabine. Clin Neuropharmacol 22, 312-317 (1999)

419. Loiseau, P.: Review of controlled trials of Gabitril (tiagabine): a clinician's viewpoint. Epilepsia 40 Suppl 9, S14-S19 (1999)

420. French, J.A.: Vigabatrin. Epilepsia 40 Suppl 5, S11-S16 (1999)

421. Perucca, E.: The clinical pharmacology of the new anti-epileptic drugs. Pharmacol Res 28, 89-106 (1993)

422. Walker, M.C. & P.N. Patsalos: Clinical pharmacokinetics of new anti-epileptic drugs. Pharmacol Ther 67, 351-384 (1995)

423. Petroff, O.A., D.L. Rothman, K.L. Behar, T.L. Collins & R.H. Mattson: Human brain GABA levels rise rapidly after initiation of vigabatrin therapy. Neurology 47, 1567-1571 (1996)

424. Mumford, J.P. & D.J. Cannon: Vigabatrin. Epilepsia 35 Suppl 5, S25-S28 (1994)

425. Leppik, I.E.: Zonisamide. Epilepsia 40 Suppl 5, S23-S29 (1999)

426. Oommen, K.J. & S. Mathews: Zonisamide: a new anti-epileptic drug. Clin Neuropharmacol 22, 192-200 (1999)

427. Yanai, S., T. Hanai & O. Narazaki: Treatment of infantile spasms with zonisamide. Brain Dev 21, 157-161 (1999)

428. Kyllerman, M. & E. Ben-Menachem: Zonisamide for progressive myoclonus epilepsy: long-term observations in seven patients. Epilepsy Res 29, 109-114 (1998)

429. Peters, D.H. & E.M. Sorkin: Zonisamide: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs 45, 760-787 (1993)

430. Kito, M., M. Maehara & K. Watanabe: Mechanisms of T-type calcium channel blockade by zonisamide. Seizure 5, 115-119 (1996)

431. Kasteleijn-Nolst Trenité D.G.A., C. Marescaux, S. Stodieck, P.M. Edelbroek & J. Oosting: Photosensitive epilepsy: a model to study the effects of anti-epileptic drugs. Evaluation of the piracetam analogue, levetiracetam. Epilepsy Res 25, 225-230 (1996)

432. Agarwal, V.K., S. Jain, M. Vaswani, M.V. Padma & M.C. Maheshwari: Flunarizine as add-on therapy in refractory epilepsy: an open trial. J Epilepsy 9, 20-22 (1996)

433. Mahmood, I., V.K. Tammara & R.K. Baweja: Does percent reduction in seizure frequency correlate with plasma concentration of anticonvulsant drugs? Experience with four anticonvulsant drugs. Clin Pharmacol Ther 64, 547-552 (1998)

434. Fraser, A.D.: New drugs for the treatment of epilepsy. Clin Biochem 29, 97-110 (1996)

435. Straub, H., R. Kohling, A. Luke, J.D. Fautech, E.J. Speckmann, D. Moskopp, H. Wassmann, I. Tuxhorn, P. Wolf, H. Pannek & F. Oppel: The effects of verapamil and flunarizine on epileptiform activity induced by bicuculline and low Mg2+ in neocortical tissue of epileptic and primary non-epileptic patients. Brain Res 733, 307-311 (1996)

436. Binnie, C.D., F. de Beukelaar, J.W. Meijer, H. Meinardi, J. Overweg, A. Wauquier & A. van Wieringen: Open dose-ranging trial of flunarizine as add-on therapy in epilepsy. Epilepsia 26, 424-428 (1985)

437. Todd, P.A. & P. Benfield: Flunarizine. A reappraisal of its pharmacological properties and therapeutic use in neurological disorders. Drugs 38, 481-499 (1989)

438. Bebin, M. & T.P. Bleck: New anticonvulsant drugs. Focus on flunarizine, fosphenytoin, midazolam and stiripentol. Drugs 48, 153-171 (1994)

439. Durrheim, D.N. J. Joubert & R.D. Griesel: Flunarizine-effective add-on therapy in reading epilepsy. S Afr Med J 82, 21-23 (1992)

440. Alving, J., O. Kristensen, I. Tsiropoulos & K. Mondrup: Double-blind placebo-controlled evaluation of flunarizine as adjuct therapy in epilepsy with complex partial seizures. Acta Neurol Scand 79, 128-132 (1989)

441. Battaglia, A., A.R. Ferrari & R. Guerrini: Double-blind placebo-controlled trial of flunarizine as add-on therapy in refractory childhood epilepsy. Brain Dev 13, 217-222 (1991)

442. Hoppu, K., A.R. Nergardh, A.S. Eriksson, O. Beck, E. Forssblad & L.O. Boreus: Flunarizine of limited value in children with intractable epilepsy. Pediatr Neurol 13, 143-147 (1995)

443. Nakane, Y., M. Seino, K. Yagi, S. Kaji & T. Yamauchi: Effects of flunarizine therapy on intractable epilepsy. Arzneimittelforschung 39, 793-798 (1989)

444. Davies, J.A.: Remacemide hydrochloride: a novel anti-epileptic agent. Gen Pharmacol 28, 499-502 (1997)

445. Leach, J.P., J. Girvan, V. Jamieson, T. Jones, A. Richens & M.J. Brodie: Lack of pharmacokinetic interaction between remacemide hydrochloride and sodium valproate in epileptic patients. Seizure 6, 179-184 (1997)

446. Palmer, G.C., M.L. Stagnitto, J.M. Ordy, R.C. Griffith, J.J. Napier, R.J. Gentile, J.H. Woodhead, H.S. White & E.A. Swinyard: Preclinical profile of stereoisomers of the anticonvulsant remacemide in mice. Epilepsy Res 8, 36-48 (1991)

447. Hu, R.Q. & J.A. Davies: The effect of the desglycinyl metabolite of remacemide on cortical wedges prepared from DBA/2 mice. Eur J Pharmacol 287, 251-256 (1995)

448. Norris, S.K. & A.E. King: Electrophysiological effects of the anticonvulsant remacemide hydrochloride and its metabolite ARL 12495AA on rat CA1 hippocampal neurons in vitro. Neuropharmacol 36, 951-959 (1997)

449. Van Luijtelaar, E.L. & A.M. Coenen: Effects of remacemide and its metabolite FPL 12495 on spike-wave discharges, electroencephalogram and behaviour in rats with absence epilepsy. Neuropharmacol 34, 419-425 (1995)

450. Schachter, S.C. & D. Tarsy: Remacemide: Current status and clinical applications. Expert Opin Invest Drugs 9, 871-883 (2000)

451. Mawer, G.E., V. Jamieson, S.B. Lucas & J.M. Wild: Adjustment of carbamazepine dose to offset the effects of the interaction with remacemide hydrochloride in a double-blind, multicentre, add-on drug trial (CR2237) in refractory epilepsy. Epilepsia 40, 190-196 (1999)

452. Gasior, M., R.B. Carter, S.R. Goldberg & J.M. Witkin: Anticonvulsant and behavioral effects of neuroactive steroids alone and in conjunction with diazepam. J Pharmacol Exp Ther 282, 543-553 (1997)

453. Gee, K.W.: Epalons as anticonvulsants: actions mediated by the GABAA receptor complex. Proc West Pharmacol Soc 39, 55-60 (1996)

454. Carter, R.B., P.L. Wood, S. Wieland, J.E. Hawkinson, D. Belelli, J.J. Lambert, H.S. White, H.H. Wolf, S. Mirsadeghi, S.H. Tahir, M.B. Bolger, N.C. Lan & K.W. Gee: Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3-alpha-hydroxy-3-beta-methyl-5-alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid (A) receptor. J Pharmacol Exp Ther 280, 1284-1295 (1997)

455. Beekman, M., J.T. Ungard, M. Gasior, R.B. Carter, D. Dijkstra, S.R. Goldberg & J.M. Witkin: Reversal of behavioral effects of pentylenetetrazol by the neuroactive steroid ganaxolone. J Pharmacol Exp Ther 284, 868-877 (1998)

456. Snead, O.C.: Ganaxolone, a selective, high-affinity steroid modulator of the gamma-aminobutyric acid-A receptor, exacerbates seizures in animal models of absence. Ann Neurol 44, 688-691 (1998)

457. Monaghan, E.P., L.A. Navalta, L. Shum, D.W. Ashbrook & D.A. Lee: Initial human experience with ganaxolone, a neuroactive steroid with anti-epileptic activity. Epilepsia 38, 1026-1031 (1997)

458. Stein, U., K. Klessing & S.S. Chatterjee: Losigamone. Epilepsy Res 3 Suppl, 129-133 (1991)

459. Zhang, C.L., S.S. Chatterjee, U. Stein & U. Heinemann: Comparison of the effects of losigamone and its isomers on maximal electroshock induced convulsions in mice and on three different patterns of low magnesium induced epileptiform activity in slices of the rat temporal cortex. Naunyn Schmiedebergs Arch Pharmacol 345, 85-92 (1992)

460. Dimpfel, W., S.S. Chatterjee, M. Nöldner & M.K. Ticku: Effects of the anticonvulsant losigamone and its isomers on the GABAA receptor system. Epilepsia 36, 983-989 (1995)

461. Srinivasan, J., A. Richens & J.A. Davies: The effect of losigamone (AO-33) on electrical activity and excitatory amino acid release in mouse cortical slices. Br J Pharmacol 122, 1490-1494 (1997)

462. Gasior, M., J.T. Ungard & J.M. Witkin: Preclinical evaluation of newly approved and potential anti-epileptic drugs against cocaine induced seizures. J Pharmacol Exp Ther 290, 1148-1156 (1999)

463. Biber, A. & A. Dienel: Pharmacokinetics of losigamone, a new anti-epileptic drug, in healthy male volunteers. Intl J Clin Pharmacol Ther 34, 6-11 (1996)

464. Peeters, P.A., J.J. Van Lier, N. Van De Merbel, B. Oosterhuis, J. Wieling, J.H. Jonkman, K. Klessing & A. Biber: Pharmacokinetics of [14C]-labelled losigamone and enantiomers after oral administration to healthy subjects. Eur J Drug Metab Pharmacokinet 23, 45-53 (1998)

465. Lisgarten, J.N. & R.A. Palmer: The structure of stiripentol: 4,4 dimethyl-1-(3,4-methylenedioxyphenyl)-1-penten-3-ol-a novel anti-epileptic drug. Acta Crystallogr 44, 1992-1994 (1988)

466. Poisson, M., F. Huguet, A. Savattier, F. Bakri-Logeais & G. Narcisse: A new type of anticonvulsant, stiripentol. Pharmacological profile and neurochemical study. Arzneimittelforschung 34, 199-204 (1994)

467. Perez J, C. Chiron, C. Musial, E. Rey, H. Blehaut, P. d'Athis, J. Vincent & O. Dulac: Stiripentol: efficacy and tolerability in children with epilepsy. Epilepsia 40, 1618-1626 (1999)

468. Tang, C., K. Zhang, F. Lepage, R.H. Levy & T.A. Baillie: Metabolic chiral inversion of stiripentol in the rat. II. Influence of route of administration. Drug Metab Dispos 22, 554-560 (1994)

469. Zhang, K., C. Tang, M. Rashed, D. Cui, F. Tombret, H. Botte, F. Lepage, R.H. Levy & T.A. Baillie: Metabolic chiral inversion of stiripentol in the rat. I. Mechanistic studies. Drug Metab Dispos 22, 544-553 (1994)

470. Shen, D.D., R.H. Levy, J.L. Savitch, A.V. Boddy, F. Tombret & F. Lepage: Comparative anticonvulsant potency and pharmacokinetics of (+)-and (-)-enantiomers of stiripentol. Epilepsy Res 12, 29-36 (1992)

471. Arends, R.H., K. Zhang, R.H. Levy, T.A. Baillie & D.D. Shen: Stereoselective pharmacokinetics of stiripentol: an explanation for the development of tolerance to anticonvulsant effect. Epilepsy Res 18, 91-96 (1994)

472. Farwell, J.R., G.D. Anderson, B.M. Kerr, J.A. Tor & R.H. Levy: Stiripentol in atypical absence seizures in children: an open trial. Epilepsia 34, 305-311 (1993)

473. Finnell, R.H., B.M. Kerr, M. van Waes, R.L. Steward & R.H. Levy: Protection from phenytoin-induced congenital malformations by coadministration of the anti-epileptic drug stiripentol in a mouse model. Epilepsia 35, 141-148 (1994)

474. Bryans, J.S. & D.J. Wustrow: 3-substituted GABA analogs with central nervous system activity: a review. Med Res Rev 19, 149-177 (1999)

475. Taylor, C.P. & M.G. Vartanian: Profile of the anticonvulsant activity of CI-1008 (pregabalin) in animal models. Epilepsia 38 Suppl 8, 35 (1997)

476. Martin, L., X. Rabasseda, P. Leeson & J. Castaner: Pregabalin. Anti-epileptic. Drugs Future 24, 862-870 (1999)

477. Cardot, J.M., J.B. Lecaillon, C. Czendlik & J. Godbillon: The influence of food on the disposition of the anti-epileptic rufinamide in healthy volunteers. Biopharm Drug Dispos 4, 259-262 (1998)

478. Cheung, W.K., F. Kianifard, A. Wong, J. Mathieu, T. Cook, V. John, E. Redalieu & K. Chan: Intra- and inter-subject variabilities of CGP 33101 after replicate single oral doses of two 200-mg tablets and 400-mg suspension. Pharm Res 12, 1878-1882 (1995)