Drug treatment of epilepsy: Options and limitations

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Abstract

The modern antiepileptic drug (AED) era—spanning a period of more than 150 years from the first use of bromide in 1857 to 2008—has seen the introduction into clinical practice of a diverse group of effective and safe drugs. These AEDs have provided considerable benefits for those afflicted with epilepsy of all kinds. In as many as 60–70% of newly treated patients, current AEDs lead to satisfactory control of seizures and a favorable risk–benefit balance for the great majority of patients, albeit with considerable differences in response depending on the type of seizure and epilepsy syndrome and rare serious adverse events. Unfortunately, in 20–30% of patients, epilepsy cannot be controlled. Patients with drug-resistant epilepsy often have serious comorbidity, including injury, depression, anxiety, and increased mortality. The aim of antiepileptic treatment should be to control seizures as quickly as possible with no or minimal side effects and with no negative impact on the quality of life. Improved seizure control is likely to reduce the morbidity and increased mortality associated with uncontrolled epilepsy. In this short overview, the options and the limitations of treating patients with epilepsy are briefly summarized.

Introduction

Antiepileptic drugs provide satisfactory control of seizures for most patients with epilepsy. Seizures in about 65% of patients with new-onset epilepsy respond, seizure recurrence occurs in 5%, and 35% have uncontrolled epilepsy. Seizure precipitation can be avoided by lifestyle changes, particularly in adolescents with idiopathic generalized epilepsy. If two or three drug regimens have not brought complete seizure control, the diagnosis of epilepsy and of the epilepsy syndrome should be reevaluated, and if refractory epilepsy is confirmed, surgical options should be considered in suitable candidates. In this short overview, the options and the limitations of treating patients with epilepsy are briefly summarized. For extensive discussion and detailed references, see textbooks and monographs [1], [2], [3].

Section snippets

Currently used antiepileptic drugs

The following antiepileptic drugs (AEDs) have been approved by regulatory agencies in the United States and Europe: acetazolamide, carbamazepine, clonazepam, clorazepate, ethosuximide, ethotoin, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, mephenytoin, methsuximide, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, tiagabine, topiramate, trimethadione, valproate, vigabatrin, and zonisamide. The following additional agents are used mainly for the acute therapy of

Starting treatment

The decision to start drug treatment in a patient with unquestionable epilepsy requires a careful individual risk–benefit assessment. Although AEDs are able to prevent further seizures and reduce the severity of seizures, and treatment is recommended in all persons with a high risk of seizure recurrence, the side effects of AEDs need to be considered. High-risk features for seizure recurrence are symptomatic epilepsy with generalized tonic–clonic seizures (GCTS), complex or simple partial

Pharmacokinetics of antiepileptic drugs

From a clinical perspective, the ideal AED does not require monitoring of plasma concentrations, is metabolically inert and is not involved in adverse drug interactions, and can be conveniently given once or twice a day [5]. Unfortunately, a number of currently used classic AEDs induce or, less commonly, inhibit the cytochrome p450 system, such as carbamazepine (CBZ), phenobarbital (PHB), and phenytoin (PHT), or inhibit enzymes involved in glucuronidation, such as valproate (VPA) [6].

Adverse effects of antiepileptic drugs

Possible adverse effects of AEDs are listed in Table 2[7], [8], [9]. The main advantages of some of the modern AEDs include absence of hypersensitivity reactions, weight problems, and drug interactions that cause central nervous system toxicity. There is no need for routine laboratory monitoring and safety is improved with absence of life-threatening organ damage. Patients receiving carbamazepine should have a CBC once a month for the first year of therapy. If the white or red blood cell count

Choice of antiepileptic drug

Pragmatically, the choice of AED among first-line agents needs to be individualized, mainly on the basis of the patient profile, including efficacy for the seizure or epilepsy syndrome, tolerability, safety, ease of use, pharmacokinetics (including current or likely future need for concomitant medication for comorbidity), and finally cost (Table 3).

Finding the optimal dose of an antiepileptic drug

The drug of choice for a particular type of epilepsy is titrated to the lowest effective dose. If seizures continue, the daily dose is increased by small increments to the average effective dose [9], [10], [11]. Except in an emergency, there is no need for rapid titration. Most modern AEDs work within several days to a week of starting treatment. Rapid titration is not only unnecessary, but may even be harmful. It increases the risk of cutaneous hypersensitivity reactions, for example, with

Single-drug versus add-on therapy

Once single-drug therapy is not able to control seizures, addition of a second drug and substitution monotherapy are common options. When the initially prescribed AED fails to produce seizure freedom, transfer to monotherapy with an alternative agent (substitution) will lead to seizure control in as many as 15–30% of cases [15], [16].Two randomized controlled trials with mostly old, enzyme-inducing AEDs have compared substitution with combination therapy and obtained a rather similar outcome

Monitoring treatment with antiepileptic drugs

Target plasma AED concentrations are available for a number of drugs [see 9]. However, plasma AED concentrations are less useful to follow than the clinical course. Some patients have toxic symptoms at low concentrations, whereas others tolerate higher concentrations without apparent clinical symptoms. Some patients respond at very low concentrations; others do not respond even to very high concentrations. If treatment is ineffective, monitoring of concentration may unmask irregular drug

Management of drug-resistant epilepsy

The definition of drug resistance is elusive. In the broadest sense, all epilepsy is drug resistant, because drugs are a palliative treatment preventing the clinical expression of seizures but cannot affect the underlying pathological state. In a large study of patients evaluated and treated in Glasgow, Scotland, Kwan and Brodie [16] found that of 470 patients who had never before received an AED, 301 (64%) became seizure free for at least 12 months during treatment. Of the 248 patients

Prophylactic treatment

Head injuries with skull fractures, intracranial hemorrhages, focal neurological deficits, and amnesia cause posttraumatic epilepsy in 25 to 75% of cases. Prophylactic treatment with anticonvulsant drugs after the head injury reduces the probability of early posttraumatic seizures during the first few weeks after the injury, but does not prevent the development of permanent posttraumatic epilepsy months or years later. Early treatment after a second tonic–clonic seizure does not improve the

Overtreatment

The most common avoidable treatment errors stem from misdiagnosis and inadvertent overtreatment. Common forms of misdiagnosis occur early in the management of a patient who is thought to have epilepsy, but in fact has syncope with myoclonia or psychogenic nonepileptic seizures. Subsequent AED use provides no benefit, even at higher doses, which invariably result in adverse events. Overtreatment may, however, also occur in patients with unequivocal epileptic seizures. Although complete seizure

Special treatment needs

One of the standards of good clinical care is to individualize the treatment of epilepsy to the special needs of the individual with epilepsy. Here we focus on the elderly and those with mental health problems. Other important patient groups are discussed elsewhere [9].

Stopping therapy with antiepileptic drugs

Starting an AED is much easier than stopping treatment. The possibility that the patient may have developed serious or cognitive adverse events is an argument in favor of discontinuing AEDs. On the other hand, a seizure relapse may have grave social consequences, particularly in an adult. Drug discontinuation after seizure freedom results in relapse in one-third of patients. Reinstitution of a medication that worked for years fails to achieve control in one of four patients. These risks need to

Conclusion

The majority of patients with epilepsy will achieve lasting remission on drug treatment. Of those who do not, significant risks of mortality and morbidity exist due to uncontrolled seizures. Seizure freedom is therefore very important. Several new drugs have been added to the armamentarium and these should be tried in each refractory patient. These are not always effective, however, and surgical options should be explored.

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