The Long-Term Therapeutic Management of Epilepsy

Epilepsy afflicts more than 50 million people worldwide, 5 million of whom have seizures more than once per month [1]. Data from the World Health Organization suggest that as many as 1 in 20 people may have an epileptic seizure during their lives and that at least 1 in 200 people will have epilepsy [2]. It is estimated that epilepsy occurs 10 times more often than multiple sclerosis and 100 times more than motoneuron disease [2]. Physicians treating patients with epilepsy have a complex task. Epilepsy is a chronic condition that requires long-term management. Long-term issues differ greatly among patients. For many patients, a therapy that brings the seizures under control is initiated soon after diagnosis. For these patients, long-term management consists of monitoring for the long-term adverse effects of medication; providing psychological, career, and social assistance, if necessary; and, ultimately, determining whether medication should be discontinued. For a second group of patients, medication substantially reduces seizure frequency, but seizures will not be completely eliminated. For this group, long-term management consists of determining the riskbenefit ratio of changing to new therapies, making sure that each therapy is used to its maximum benefit, and keeping side effects to a minimum. Finally, a group of patients exists who do not respond to any standard therapy. The first step in managing these patients is to determine whether continued seizures are actually due to treatment failure or whether there is another explanation, such as misclassification, noncompliance with medication regimen, or the presence of nonepileptic (pseudoepileptic, psychogenic) seizures. If failure is due to seizure intractability, long-term management for these, the most difficult patients, consists of a rational approach to choosing successive drug regimens. If conventional medications fail, the next step is to consider alternative medications or surgical intervention. These patients also need substantial emotional, psychological, and vocational support. To complicate matters, many patients are cared for by several physicians during the course of their treatment. A physician may assume care for a patient after treatment has been initiated or after several strategies have already been tried. Figure 1 provides a paradigm for the long-term treatment of epilepsy. In managing patients receiving long-term treatment, all types of side effectssystemic, behavioral, and cognitivemust be monitored. Some side effects may be subtle and may even be considered tolerable by the patient and the physician, but they still need to be taken into account in a regular reevaluation of treatment strategy. Figure 1. Long-term management paradigm for patients with epilepsy. Classification The first step in effective management of epilepsy is correctly classifying and diagnosing the condition. The 1981 classification scheme [3], revised by the International League Against Epilepsy in 1989 to include epilepsy syndromes [4], is widely accepted. A simplified version is presented in Table 1. Epilepsy can be classified in terms of epilepsy syndromes as well as seizure types. Seizure type is determined by electroencephalographic patterns observed when the seizure is occurring and by clinical seizure characteristics. Examples include absence seizures (previously known as petit mal), simple partial seizures (previously known as focal motor or aura), complex partial seizures (previously known as psychomotor or temporal lobe), and generalized tonic-clonic seizures (also known as grand mal). Once seizure types are identified, this information determines the epilepsy syndrome in conjunction with information about cause, age at onset, and interictal electroencephalographic abnormalities. Table 1. International Classification of Epilepsies and the Epileptic Syndromes* Epilepsy can be basically classified as idiopathic (no apparent structural injury, probable genetic cause) or symptomatic (structural brain abnormality of known or unknown cause) (Table 1). Further differentiation can be made based on whether seizures begin in a focal region (partial epilepsy) or begin diffusely (generalized epilepsy). Idiopathic generalized epilepsy is the most common childhood epilepsy; absence, myoclonic, and generalized tonic-clonic seizures may be seen. In adults, symptomatic partial epilepsy is most common and may cause simple partial, complex partial, or generalized tonic-clonic seizures. Some seizure types are specific to certain epilepsy syndromes, whereas others can be seen in various syndromes. It is often easy to determine the seizure type and the epilepsy syndrome on the basis of patient history and a routine electroencephalogram. For example, if a patient develops epilepsy after a head injury, the patient may describe seizures consisting of a warning of a peculiar smell followed by staring, lip smacking, and fumbling. The electroencephalogram shows a focal interictal spike. This evidence overwhelmingly points to partial epilepsy, manifested by simple partial seizures evolving to complex partial seizures. However, a substantial proportion of patients with epilepsy have confusing or conflicting information, making seizure and syndromic classification more difficult. For example, a patient may have no clear cause for epilepsy, may have seizures that are exclusively grand mal without warning, and may present with a normal routine electroencephalogram. Grand mal seizures may be the result of an idiopathic (genetic) generalized epilepsy or may occur in partial epilepsy if a focal onset is followed by rapid secondary generalization. In such a patient, every effort must be made to obtain further electrographic and historical information until the patient can be appropriately classified. Classification helps in selecting appropriate treatment, and in some circumstances, also determines prognosis and appropriate workup. Idiopathic epilepsy syndromes need little or no evaluation with imaging studies. In contrast, partial epilepsy is the result of a focal brain abnormality, and presentation of this syndrome in adults may warrant a search for underlying neoplasms or for other treatable diseases [5]. The choice of the initial anticonvulsant regimen differs, depending on the epilepsy syndrome classification. Table 2 indicates drugs of choice for the most common epilepsy syndromes and seizure types. When accurately diagnosed, seizures may be controlled by fewer or decreased concentrations of medication, with the potential advantages of fewer side effects, improved compliance, and enhanced well-being [6]. Table 2. Antiepileptic Drug Choices for Major Epilepsy Syndromes and Seizure Types* Selection of an Antiepileptic Drug Once it has been determined that recurring seizures are not the result of a correctable problem, antiepileptic drug therapy should be initiated. Because all of the available antiepileptic drugs have different side effects, the types and severity of these effects must be considered when selecting an antiepileptic drug for an individual patient [7]. This decision must be made with the understanding of the long-term consequences because most patients receive medication for at least 2 years, and many continue for their lifetime. Unfortunately, with the currently available antiepileptic drugs, side effects are more the rule than the exception. Some patients tolerate medication without difficulty, but many have at least a mild alteration in some aspect of functioning. Clearly, life-threatening side effects are unacceptable for all patients, but less severe effects may be acceptable to one patient and not to another. Because side effects differ somewhat from one drug to the next, the patient and that patient's specific situation in life must be kept in the physician's mind as initial therapy and subsequent choices are made. The physician and patient must become partners in the search for the regimen that produces the best quality of life. Conventional Antiepileptic Drugs: Long-Term Considerations The following discussion of toxicity is not meant to be encyclopedic. A specific discussion of antiepileptic drug toxicities can be found in many textbooks [8, 9]. Rather, this section focuses on long-term side effects and on issues that might affect long-term consequences of choosing one antiepileptic drug instead of another. Table 3 contains information about therapeutic ranges, half-lives, and pharmacokinetic properties for the drugs listed below. Table 3. Pharmacokinetics of Common Antiepileptic Drugs Phenytoin Although phenytoin (Dilantin; >Parke-Davis, Morris Plains, New Jersey) is primarily indicated for the management of tonic-clonic and partial seizures, it is also among the drugs of choice for treatment of most epileptic seizures, with the exception of absence and myoclonic seizures [10]. Within normal therapeutic ranges (5 to 20 g/dL in most laboratories), phenytoin is usually well tolerated but may cause lethargy, abnormal movements, mental confusion, and cognitive changes [11]. At toxic concentrations that may be necessary to produce seizure control, phenytoin can cause nystagmus, ataxia, dysarthria, and encephalopathy [11]. Long-term phenytoin therapy can cause gingival hyperplasia, acne, hirsutism [12], and hypertrophy of subcutaneous facial tissue, resulting in an appearance known as dilantin facies [13]. These cosmetic effects may upset young women, and the potential consequences should be considered before beginning therapy. Scrupulous dental care can help prevent gingival hypertrophy, and visits to the dentist every 3 months are advised. Another long-term consequence of phenytoin therapy is osteoporosis [14]. If osteoporosis is diagnosed, vitamin D therapy may be necessary in conjunction with phenytoin, particularly for women [15]. Occasionally, a peripheral neuropathy can occur with chronic phenytoin use [12]. Cerebellar atrophy may also occur after decades of phe