Subject Review. Epilepsy: Contemporary Perspectives on Evaluation and Treatment

Transcription

1 Subject Review Epilepsy: Contemporary Perspectives on Evaluation and Treatment GREGORY D. CASCINO, M.D. Objective: To describe the classification of seizures and epilepsies and discuss the medical and surgical treatment options. Results: The correct classification of types of seizures is necessary for appropriate evaluation and treatment. A neurologic examination can include electroencephalography and magnetic resonance imaging (MRI). MRI has been shown to be diagnostically superior to computed tomography in detecting epileptogenic lesions. With varying degrees of sensitivity and specificity, MRI may identify the underlying pathologic features associated with symptomatic partial epilepsy. Carbamazepine, phenytoin, and valproate sodium are the preferred medical treatments because of their relatively low neurotoxicity. Despite appropriate use of these medications, less than 50% of all patients with epilepsy are rendered free of seizures and experience no antiepileptic drug toxicity. Medically refractory seizures are often physically disabling and may be associated with an alteration in neurocognitive performance and psychosocial debili- tation. Treatment options include the antiepileptic drugs felbamate and gabapentin, which have recently been approved in the United States. Surgical resection of epileptic brain tissue remains the most efficacious treatment for patients with intractable partial epilepsy. Conclusion: Recent developments in neurodiagnostic studies and treatment strategies have substantially altered the management of patients with epilepsy. Challenging problems include the management of a single seizure, pregnancy and epilepsy, the timing of withdrawal of antiepileptic drug therapy, driving and epilepsy, and the use of alcohol in patients with seizures. The therapeutic goals are to render the patient seizure free and allow the patient to become a productive and participating member of society. (Mayo Clin Proc 1994; 69: ) AED = antiepileptic drug; EEG = electroencephalography; EFA = Epilepsy Foundation of America; FDA = Food and Drug Administration; MRI = magnetic resonance imaging; MTS = mesial temporal sclerosis Epilepsy is a medical illness associated with unprovoked, recurrent seizures paroxysmal disorders of the central nervous system characterized by an abnormal cerebral neuronal discharge with or without loss of consciousness.1" 2 Seizures may recur in people who do not have a seizure disorder or epilepsy for example, a person may have multiple seizures because of alcohol withdrawal. Epilepsy, one of the most common chronic neurologic disorders, may have a variable clinical manifestation. The lifetime risk of epilepsy developing approaches 4%, and approximately 10% of people will experience at least a single seizure during their lifetime.33 Epilepsy can begin at any age, although the predilection is for the younger and older age-groups. The diagnosis of epilepsy is a clinically based decision; laboratory studies such as electroencephalography (EEG) From the Division of Epilepsy, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. G. D. Cascino, Division of Epilepsy, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN provide only supportive data. The type of seizure should be classified before an antiepileptic drug (AED) is selected. In select patients, avoidance of seizure précipitants, such as sleep deprivation, may influence seizure outcome. The success of medical therapy depends on several variables including type of seizure, age at onset of seizure, cause, and associated neurologic abnormalities. The duration of the seizure disorder before the institution of effective AED therapy may also be an important prognostic factor. CLASSIFICATION OF SEIZURES AND EPILEPSIES The current classification of seizures and epilepsies is based on the clinical and electrophysiologic localization of seizure activity.3b The main distinction is between the presence of partial (focal or localization-related) epilepsy and generalized epilepsy.4 The epilepsies are further categorized relative to the cause of the seizures symptomatic or idiopathic. The diagnosis of partial epilepsy indicates that the seizure is localized at onset. Patients with epilepsy may have more than one type of seizure. Mayo Clin Proc 1994; 69: Mayo Foundation for Medical Education and Research

2 1200 EPILEPSY Mayo Clin Proc, December 1994, Vol 69 The types of partial seizures include complex partial, simple partial, and secondarily generalized tonic-clonic seizures." Most adults who experience a generalized tonicclonic or "grand mal" seizure have partial epilepsy with a secondarily generalized seizure. The distinction between complex and simple partial seizures is based on state of consciousness during the seizure episodes. Complex partial seizures have previously been labeled temporal lobe or psychomotor seizures. These terms may be incorrect and imprecise, and their use should be discouraged. Complex partial seizures constitute almost 55% of seizures in adults. 5 Although most complex partial seizures emanate from the temporal lobe, an important minority of patients (approximately 20%) have seizures of extratemporal origin (mainly frontal lobe). 5 The site of onset affects the characteristic duration, ictal behavior, and frequency of the seizure. 5 During a complex partial seizure of temporal lobe origin, typical ictal behavior is a motionless stare with the absence of verbal or motor behavior. Automatisms, involuntary and purposeless motor responses such as lip smacking or picking movements, may be observed. The patient may seem to be awake but be unable to interact appropriately with the environment. The duration of a complex partial seizure may be brief (for example, 1 to 3 minutes) whereas that of the postictal state is longer (several minutes to several hours). Postictal dysphagia may suggest seizure onset in the language-dominant hemisphere. The patient may be amnesic for the details of the ictal behavior. Extracranial interictal (between the seizures when the patient is asymptomatic) EEG may reveal well-localized epileptiform discharges spike or sharp wave activity (or both) at the region of onset, the epileptogenic zone (Fig. 1 and 2). 6 Ictal (during the epileptic seizure) scalp-recorded EEG almost always shows some change from the interictal tracing. 7 The localizing effectiveness of scalp-recorded P2~ A 2 ~ΛΛ^^Λ/^^~-ΛνΛΛ/^ Μ F 3- A 1 ^V^^^v^y^^ij if! j C 3" A 1 ^W^*** "'^^ M ' ilk In '»Η^ A.- Pr A i «wviw'vflww^^ Or A 1 vw(/\wv^^ 2" A 2 */v^l*>wmto^^ F 8" A 2 ~νν^~~'^^ V A 1 Η"Μ**Ι^^ T 5-A 1.^WASAAAM^^V^^^ Bipolar ond referential display JiXlH T 6- A 2 ~wma*/yww;\a^//v^^ Eyelid flutter Twv j50jjv Fig. 1. Extracranial interictal electroencephalogram of 37-year-old Fig. 2. Extracranial ictal electroencephalogram of 32-year-old man woman with partial epilepsy of left anterior temporal lobe origin, with generalized epilepsy during clinical nonconvulsive seizure, showing focal or anatomically restricted spike discharges. (Illus- revealing generalized atypical spike and slow-wave complexes. tration courtesy of Dr. Frank W. Sharbrough, Department of Neu- (Illustration courtesy of Dr. Donald W. Klass, Division of Clinical rology, Mayo Clinic Rochester.) Neurophysiology, Mayo Clinic Rochester.)

3 Mayo Clin Proc, December 1994, Vol 69 EPILEPSY 1201 EEG depends on the site of seizure onset. The sensitivity and specificity of EEG are higher when the epileptogenic zone is localized in the temporal lobe rather than in the extratemporal structures. 7 Extracranial EEG uncommonly identifies a precise focal onset electrographic seizure in patients with partial seizures of extratemporal origin. 7 Usually, the patient and physician incorrectly presume that the complex partial seizure activity represents "petit mal" seizures. Most patients who have petit mal seizures have a partial seizure disorder. This assumption leads to serious errors in the diagnostic evaluation and treatment (see subsequent discussion). In adults, absence or petit mal seizures occur much less frequently than do partial seizures. A simple partial seizure implies the absence of an alteration in mentation during seizure activity. Patients with simple partial seizures usually experience an aberration in sensory, motor, or language function. 4 In such patients, the seizures remain anatomically well localized for example, in the motor cortex. In most patients during a simple partial seizure, scalp-recorded ictal EEG reveals no definite abnormality. 8 The lack of change on extracranial EEG in patients experiencing simple partial seizures or auras may lead to the incorrect diagnosis of a "functional" disorder. The generalized seizures include tonic-clonic, absence, tonic, clonic, myoclonic, atonic, and atypical absence seizures. 4 In patients with generalized epilepsy, ictal behavior and EEG reveal a seizure that is bihemispheric at onset. The tonic-clonic or grand mal seizure is the most obvious type of seizure and can occur in patients with partial or generalized seizure disorders. The tonic phase of the seizure is associated with sustained muscle contraction, and the clonic activity involves intermittent muscle relaxation that causes the obvious jerking movements. Scalp-recorded ictal EEG demonstrates a progressive generalized alteration that correlates with the phase of the tonic-clonic seizure. 4 An absence seizure is a brief momentary lapse in consciousness that may be associated with eye fluttering and automatisms. Patients may be unaware of absence seizure activity. Interictal or ictal EEG reveals generalized anterior predominant 3-Hz spike and wave discharges. Patients with symptomatic generalized epilepsy such as Lennox-Gastaut syndrome are often developmentally delayed and experience a combination of generalized seizures, especially atonic, tonic, and atypical absence. In such persons, seizures may be frequent and unresponsive to AED therapy. Atonic seizures manifest with sudden "drop attacks" and loss of postural tone. Patients have no advanced warning and fall to the ground, often injuring themselves. Atypical absence seizures are more prolonged than "typical" absence seizures and may be associated with recurrent episodes of nonconvulsive status epilepticus. Interictal EEG reveals prominent generalized background slowing with generalized spike and wave discharges, which often occur at 2.0 to 2.5 Hz. Tonic seizures are associated with sustained muscular contraction. Ictal EEG may reveal generalized paroxysmal fast activity during these seizures. DIAGNOSTIC EVALUATION The initial assessment of a patient with seizures involves eliciting a neurologic history and performing an examination. Patients with partial epilepsy may have a history of a symptomatic neurologic disorder, such as meningoencephalitis or a complex febrile seizure. In 28% of patients with partial epilepsy, the cause of the seizures can be determined. 2 Patients with a remote symptomatic illness are most likely to have a medically refractory seizure disorder. lb Abnormal findings on a neurologic examination, such as hemiparesis, may indicate the lateralization of seizure onset. In most patients, the only abnormal findings, such as ataxia and nystagmus, are caused by AED medication. EEG is the most important diagnostic study in patients with epilepsy. 6 The diagnostic yield of EEG for recording interictal epileptiform discharges is increased by performing standard activating procedures, such as hyperventilation and photic stimulation. 6 The importance of EEG recordings in patients with partial epilepsy while they are asleep has been emphasized. 6 Closely spaced scalp electrodes, sphenoidal electrodes, and computer-assisted EEG monitoring may increase the localizing efficacy of EEG in patients with partial epilepsy. 7 Normal findings on repeated interictal extracranial EEG studies do not exclude the diagnosis of epilepsy but are uncommon. 7 The sensitivity of interictal EEG is decreased in patients with infrequent seizures and partial epilepsy of extratemporal lobe origin. 7 Long-term EEG monitoring with prolonged video EEG or ambulatory EEG may be necessary to classify the types of seizures in select patients before therapy is initiated. 7 Empiric AED treatment (see subsequent discussion) should be discouraged in patients who have "spells" but no evidence to support the diagnosis of epilepsy. Structural neuroimaging studies may indicate the cause of the seizure disorder and suggest the localization of the epileptogenic zone (Fig. 3 through 6). 9 Magnetic resonance imaging (MRI) is the structural imaging procedure of choice in patients with partial epilepsy (Fig. 3 through 7) MRI has been demonstrated to be superior to computed tomography for diagnostic efficacy. 9 MRI studies should not be restricted to patients with medically refractory seizure disorders. An MRI study of patients with partial epilepsy of temporal lobe origin should include images in the obliquecoronal plane to assess atrophy and the presence of a mass lesion. The detection of a neuroimaging lesion may directly influence the selection of treatment. 911 MRI is highly sensi-

4 1202 EPILEPSY Mayo Clin Proc, December 1994, Vol 69 Fig. 3. Magnetic resonance image of patient with intractable partial epilepsy, showing intracranial mass in left posterior mesial temporal lobe (arrow). Grade I to II astrocytoma was subsequently resected. (Note: left cerebral hemisphere is on right side of photograph.) (From Fried I, Cascino GD. Lesionai surgery. In: Engel J Jr, editor. Surgical Treatment of the Epilepsies. 2nd ed. New York: Raven Press, 1993: By permission.) tive and specific in detecting foreign-tissue lesions such as tumors and vascular malformations (Fig. 3 through 5).9 MRI has also been shown to be a reliable indicator of mesial temporal sclerosis (MTS), the most common pathologic condition identified in partial epilepsy of temporal lobe origin (Fig. 7).10"15 A method to obtain MRI hippocampal formation volume measurements has been developed by Dr. Clifford R. Jack at the Mayo Clinic.10 " 1315 Hippocampal volumetry may reveal hippocampal atrophy in patients with partial epilepsy of temporal lobe origin related to MTS "15 MRI-based volume loss has correlated with hippocampal neuronal cell loss and has prognostic importance in patients undergoing surgical excision of the anterior temporal lobe due to intractable partial epilepsy TREATMENT OF SEIZURES AND EPILEPSY The management of patients with epilepsy begins with an intelligent discussion of the diagnosis. Any misinformation, such as the belief that epilepsy is a type of mental illness or mental retardation, needs to be clarified immediately. Critical issues that must be considered are necessary medication and alteration of lifestyle, including avoidance of sleep deprivation. Facts must be carefully separated from opinions when discussing "sensitive issues": intake of alcohol, birth control, and parenting (see subsequent discussion). A patient may be devastated when a seizure disorder is diagnosed. Discrimination of patients with epilepsy is often a greater handicap man is the seizure activity. Physicians should refer patients and family members to the Epilepsy Foundation of America (EFA) (toll-free phone number, EFA-1000) and local epilepsy support groups for further contemporary information. Educational materials from the EFA can be given to the patient when me diagnosis has been confirmed. Vocational rehabilitation should begin before the patient enters a seizure remission. The initial pharmacologie strategy of epilepsy treatment is the selection of a single nonsedating AED based on type of seizure. The three "conventional" (first-line) AEDs for adult patients that are most commonly considered "drugs of choice" are phenytoin, carbamazepine, and valproate sodium. Phénobarbital, primidone, ethosuximide, and clonazepam are other important AEDs currently available in the United States.30 Newer medications that should be considered major AEDs will be discussed in a subsequent section (see Alternative Treatment). The goals of therapy are to render the patient free of seizures, avoid AED-induced toxicity, and improve the patient's quality of life. Monotherapy is preferred because of potential AED interactions and drug toxicity associated with polypharmacy or combination therapy. Addition of a second AED improves seizure control in only 11% of patients with intractable epilepsy but increases drug toxicity in 90%.16 Drug metabolism may change substantially when multiple AEDs are used to treat epilepsy. AED levels are of limited value in determining the necessary drug dosage. The most important factors in determining drug dosage are seizure frequency and the presence of drug-induced toxicity. EEG is useful for seizure classification but may not be useful for determining drug dosage. AED levels have not been shown to affect rates of interictal EEG spiking in patients with partial epilepsy that is, increasing the doses of AED therapy will not reduce spiking unless seizure activity is decreased.17 A seizure disorder should not be considered refractory to an AED until the medication has been increased to symptomatic toxicity. Potential limitations associated with monitoring blood levels are increasing an AED dosage based only on a "low" blood level in a seizure-free patient and decreasing a drug dosage in a patient with a "high" blood level who has no AED-induced toxicity. Dose-related toxicity should be determined by the neurologic history and examination, not by an increased plasma concentration. Idiosyncratic ("allergic") reactions include a skin rash (most common), hepatitis, pancreatitis, and toxic epidermal necrolysis (rare). The success of medical treatment in patients with epilepsy depends on multiple factors. Patients with a generalized seizure disorder, normal findings on a

5 Mayo Clin Proc, December 1994, Vol 69 EPILEPSY 1203 Fig. 4. Magnetic resonance image of patient with simple partial seizures consisting of sensory symptoms in left arm, revealing neuronal migration abnormality in right frontal lobe. (Note: right cerebral hemisphere is on left side of photograph.) IP = inferoposterior. Fig. 5. Magnetic resonance image after injection of gadolinium and diethylenetriamine pentaacetic acid, revealing arteriovenous malformation in left posterior temporal lobe (arrow). (Note: left temporal lobe is on right side of photograph.) neurologic history and examination, and an idiopathic cause are likely to be rendered seizure free when taking AED medication. Studies have indicated that 41 to 76% of patients with epilepsy ultimately achieve seizure remission while receiving medical therapy.lb Unfortunately, less than 50% of patients are seizure free and experience no AEDinduced toxicity. Therapy for Partial Seizures. The conventional drugs of choice for partial epilepsy are carbamazepine and phenytoin. No definite difference in efficacy has been noted Fig. 6. Magnetic resonance images, showing agenesis of corpus callosum. A, Coronal reconstruction. B, Sagittal reconstruction.

6 1204 EPILEPSY Mayo Clin Proc, December 1994, Vol 69 Fig. 7. Magnetic resonance image in oblique-coronal plane of patient with mesial temporal sclerosis, revealing atrophy of left hippocampal formation (arrow). Hippöcampal volume loss was confirmed with quantitative magnetic resonance image analysis. (Note: left hippocampus is on right side of photograph.) IP = inferoposterior. between the two AEDs Both have been demonstrated to be more effective and less toxic than phénobarbital and primidone in the management of partial epilepsy Neurotoxicity associated with barbiturates and benzodiazepines has limited the utility of these drugs. Probably no substantial difference in efficacy exists between the primary AEDs in the treatment of secondarily generalized tonic-clonic seizures. The ultimate decision about drug preference (carbamazepine or phenytoin) is based on cost, potential adverse reactions, and the physician's familiarity with the drugs. Carbamazepine. Carbamazepine is available in three orally administered forms: a 200-mg scored tablet, a 100-mg chewable tablet, and a 100-mg/5 ml suspension. Carbamazepine is highly insoluble and unavailable for parenteral administration. Its short half-life with long-term use necessitates multiple doses per day for example, three times per day. A controlled-release variant that allows oncea-day dosing is available in Canada but not in the United States. Carbamazepine is appropriate treatment for partial epilepsy and is not restricted to patients with complex partial seizures. Most adult patients require 600 to 1,200 mg/day of carbamazepine for adequate seizure control. The initial dose can be 100 mg twice a day (half of the 200-mg tablet twice a day), and the dosage can be increased to 200 mg twice a day or three times a day for several days. Sedation associated with the introduction of carbamazepine is usually transient. Polypharmacy may accelerate carbamazepine metabolism and produce subtherapeutic levels at "high" doses. Combining AED medications may increase the metabolism of carbamazepine to the active metabolite 10,11-epoxide, an outcome that can be associated with toxicity. Both erythromycin and propoxyphene inhibit carbamazepine metabolism and can cause symptomatic toxicity. Common dose-related side effects associated with carbamazepine are similar to those with phenytoin. Diplopia is common at high drug levels. Carbamazepine can also cause a syndrome of inappropriate antidiuretic hormone (persistent hyponatremia). Evidence shows that hyponatremia may be renally mediated. Inappropriate concern about hématologie idiosyncratic toxicity that is, aplastic anemia has unfortunately affected the use of this drug. Hématologie adverse reactions are not unique to carbamazepine and occur with other AEDs. Leukopenia may occur in patients receiving carbamazepine but is seldom a source of concern unless the granulocyte count is lower than 1,000/mm3. Obtaining unnecessary complete blood cell counts for patients receiving carbamazepine has increased medical costs and caused undue anxiety. Only minimal evidence shows that frequent or periodic monitoring of hématologie groups will identify the rare person in whom a fatal hématologie complication will develop. Phenytoin. Phenytoin can be administered as a 100- or 30-mg capsule or as a 50-mg chewable tablet. A phenytoin suspension, 30- or 125-mg/5 ml, is also available; however, it may be poorly absorbed when administered with tube feedings or antacids. In most patients, once-a-day or twicea-day dosing is appropriate. Unnecessary frequent administration, "100 mg three times a day," may lead to drug noncompliance. An oral loading dose of 15 to 20 mg/kg can be administered in divided doses during a 24-hour period. This approach may produce a therapeutic blood level within 24 hours. The "usual" maintenance dose in adults is approximately 3 to 8 mg/kg. The metabolism of phenytoin depends on the drug level; it is first order at low concentrations and zero order at high concentrations. Therefore, a small dose adjustment (increase or decrease) of phenytoin at high levels may produce a considerable plasma concentration change. A common mistake is to increase the dose by 100 mg/day in a patient with recurrent seizures who has a "substantial" drug level. This approach may lead to symptomatic drug toxicity. An increase of 30 to 60 mg may be appropriate. Another

7 Mayo Clin Proc, December 1994, Vol 69 EPILEPSY 1205 common pitfall is to decrease the dose of phenytoin by 100 mg in a patient who has adequate seizure control but a "toxic" blood level. This situation may cause a substantial decrease in the drug level and recurrent seizure activity. Oral phenytoin therapy is remarkably well tolerated but may be associated with dose-related toxicity. Usual toxic symptoms at increased blood levels (more than 30 μg/ml with monotherapy phenytoin) are unsteady gait, irritability, dizziness, and diplopia. Long-term use of phenytoin may cause gingival hyperplasia or hirsutism in approximately 20% of patients. A predominantly distal, symmetric peripheral neuropathy may occur with long-term use but is usually not severe. Phenytoin can also be administered intravenously when a therapeutic level needs to be attained more rapidly for example, in patients with status epilepticus. In emergent situations, phenytoin is preferred to phénobarbital because of the pronounced sedation and respiratory depressant effect associated with barbiturates. The current preparation of intravenous phenytoin therapy contains propylene glycol and alcohol. The potential toxicity associated with intravenous phenytoin therapy includes hypotension, cardiac arrhythmias, and cellulitis at the site of injection. The drug should only be administered intravenously with normal saline, at less than 50 mg per minute; electrocardiography should be performed and blood pressure monitored. Fosphenytoin, a type of phenytoin currently under investigation, may be safer for intravenous administration than is phenytoin. Therapy for Generalized Seizures. The treatment of the generalized epilepsies depends on the type of seizure. All the primary AEDs (and the barbiturates) are potentially efficacious in treating primary generalized tonic-clonic seizures. Ethosuximide and valproate are highly effective in managing typical absence seizures. 30 Myoclonic seizures may be treated with valproate or clonazepam. Benzodiazepines may be associated with the development of tolerance, an outcome that necessitates an increase in drug dosage. 30 Valproate is the drug of choice for idiopathic generalized epilepsy associated with multiple types of seizures for example, absence, myoclonic, and generalized tonic-clonic seizures and secondary generalized epilepsy. 30 It is available in several forms, including valproic acid (250 mg), divalproex sodium (125 mg, 250 mg, and 500 mg), and syrup (250 mg/5 ml). A sprinkle form of divalproex sodium (125 mg) is also marketed, and intravenous valproate therapy is currently under investigation. The blood levels of valproate may be even less useful than those of other AEDs. Initially, patients should receive 15 mg/kg in divided doses, and the dose can be increased if necessary to 50 to 60 mg/kg as tolerated. The divalproex sodium variant is enteric coated and causes minimal gastrointestinal upset. In most patients, irritation to the stomach is transient and abates without a dose reduction. Administration of the medication with meals may help patients who experience nausea and vomiting. The common dose-related side effects that often occur with long-term valproate use are hair loss, weight gain, and tremor. Decreasing the valproate dose may diminish these side effects; however, some patients will prefer to take another AED medication. Physicians should be careful about combining valproate with other AEDs because of potential toxicity. Valproate inhibits phénobarbital metabolism and can cause a considerable increase in the plasma concentration of the latter drug. Valproate also competes with phenytoin for protein binding and thus causes an increase in the unbound or "free" fraction of phenytoin. Valproate accelerates the metabolism of carbamazepine to the 10,11-epoxide. Some physicians have excluded valproate as a first-line AED because of potential hepatotoxicity. Such exclusion in adult patients is unjustified. The fatal hepatotoxicity associated with valproate has not occurred in patients older than 10 years of age who receive monotherapy. An allergic hepatitis associated with phenytoin and carbamazepine may occur at any age; it is not restricted to younger persons. The population at greatest risk for the development of valproate-induced hepatic dysfunction are children, often younger than 2 years of age, who have developmental delay, inborn metabolic disorders, and medical illness and who are receiving AED polypharmacy. Symptoms related to hepatotoxicity include nausea, vomiting, drowsiness, peripheral edema, abdominal pain, and poor seizure control. A genetic predisposition has been identified in some patients. A mild increase of liver transaminases in asymptomatic patients receiving AEDs is common and is not a reason to withdraw therapy. Valproate may also cause hyperammonemia and encephalopathy in the absence of liver disease. ALTERNATIVE TREATMENT A seizure disorder is considered intractable when the seizures are refractory to medical therapy and the patient's quality of life is impaired because of the epilepsy or the medical therapy (or both). Patients should be referred to a neurologist with a subspecialty interest in epilepsy if the seizures have not been controlled after 3 months of AED therapy. Of the 800,000 patients in the United States with partial epilepsy, almost 45% have a medically refractory disorder Approximately 75,000 of these patients are potential candidates for surgical treatment (see subsequent discussion). 21 Patients with poorly controlled seizures may be physically and socially disabled. A patient's condition is not considered medically refractory until the drugs of choice at maximally tolerated doses have failed. In such patients, treatment options include the newer AEDs, surgical intervention, and investigational drug studies Social service

8 1206 EPILEPSY Mayo Clin Proc, December 1994, Vol 69 agencies may need to work closely with the medical team to determine if the patient has adequate health insurance or qualifies for funds for medical care. New AEDs and Investigational Studies. The development of AEDs in the United States involves clinical trials of patients with medically refractory seizures before a drug is approved by the Food and Drug Administration (FDA). 23 Felbamate and gabapentin have recently been approved by the FDA. Lamotrigine is expected to be approved by the FDA soon. All three drugs are available only for oral administration and have compared favorably in clinical trials to previously approved medication. 23 " Felbamate, gabapentin, and lamotrigine have favorable pharmacokinetic profiles, including low protein binding The mechanism of action of felbamate and gabapentin is primarily unknown. 23 Lamotrigine seems to interfere with the excitatory neurotransmitter glutamate. 23 The future of felbamate is uncertain because of the observed development of aplastic anemia and liver disease in select patients. The safety of these AEDs during pregnancy has not been adequately established. Of importance, the clinical trials of patients with intractable partial epilepsy have revealed that, although most of the new AEDs have a beneficial effect on seizure frequency, less than 10% of patients are rendered seizure free. 23 Felbamate. The approved indications for felbamate include treatment of patients 14 years and older with partial epilepsy and those with Lennox-Gastaut syndrome. 23 ' 26 In the latter group of patients, felbamate has been shown to have a positive effect on alertness and neurocognitive performance. 26 Felbamate may be used alone or in combination with other AEDs. Felbamate is available as a 400- or 600- mg scored tablet and as a 600 mg/5 ml suspension. Its halflife is approximately 25 hours, and 20% of the drug is protein bound. In adults, the usual initial dosage is 600 mg twice a day. The medication can be gradually increased every 2 to 4 weeks as tolerated to 3,600 mg/day in divided doses. Typically, a patient will receive 1,200 mg of felbamate three times a day. Patients have received higher doses without clinical toxicity. Food and antacids do not affect felbamate absorption. During the first several weeks of felbamate therapy, headache, nausea, vomiting, dizziness, and "flulike" symptoms are common. These symptoms are usually transient and often necessitate only reassurance and a slower increase in drug dosage. During long-term therapy, felbamate is usually well tolerated, with little or no evidence of neurotoxicity for example, sedation or learning difficulties. The adverse effects that may occur with long-term usage are predominantly weight loss and insomnia. Periodic monitoring of the patient's weight and food intake is appropriate. The insomnia may respond to a decrease in caffeine, an alteration in the timing and dose of felbamate, and an increase in physical activity during the day. If necessary, diphenhydramine hydrochloride or chloral hydrate can be administered at bedtime. If a mood disorder is contributing to the insomnia, an antidepressant with a high anticholinergic effect can be used with felbamate. Another concern with felbamate is the effect of the drug on other AED levels. Drug interactions may be clinically significant and affect efficacy or toxicity (or both). Felbamate produces approximately a 20% increase in the phenytoin and valproate levels, which may cause symptomatic toxicity. Felbamate may lower the carbamazepine level and increase the carbamazepine 10,11-epoxide level. Many early side effects associated with felbamate may relate to modifying the other AED levels. Felbamate levels are also affected by other AEDs. Phenytoin and carbamazepine decrease felbamate levels, whereas valproate either has no substantial effect or produces a slight increase in the felbamate level. Unfortunately, the use of felbamate was suspended by the FDA in August 1994 because of the occurrence of aplastic anemia in treated patients. The incidence of aplastic anemia is estimated to be about 1 case in 2,000 patients. Later, felbamate was associated with hepatic failure. At the time of this writing, the drug remains FDA approved. Routine monitoring of hématologie and chemistry groups is necessary. The FDA has indicated that the use of felbamate should be restricted to patients with the most severe and refractory types of epilepsy. Gabapentin. Gabapentin was recently approved by the FDA as adjunctive therapy for patients 12 years of age and older with partial epilepsy It is available in 100-, 300-, and 400-mg capsules. Gabapentin is not significantly metabolized and is mainly unbound (less than 3%) to plasma proteins. Gabapentin has virtually no interaction with other AEDs. It does not significantly alter the pharmacokinetic profiles of oral contraceptives or warfarin. Because antacids may decrease the bioavailability of gabapentin, it should be taken at least 2 hours after the consumption of an antacid. The drug is essentially excreted unchanged by the kidney, and the dose must be modified in patients with impaired renal function. The elimination half-life of gabapentin is 5 to 7 hours; thus, multiple doses per day are necessary. Dosages of 900 to 1,800 mg/day of gabapentin may be effective. Patients have tolerated 2,400 and 3,600 mg/day. In a patient with normal renal function, gabapentin can be administered as follows: 300 mg the first day, 300 mg twice a day the second day, and 300 mg three times a day the third day. The first dose of gabapentin should be administered at bedtime because of the mild sedative effect. Thereafter, the dose can be increased as needed and tolerated. Common dose-related side effects include dizziness, somnolence, and fatigue.

9 Mayo Clin Proc, December 1994, Vol 69 EPILEPSY 1207 Lamotrigine. Lamotrigine therapy has been used extensively in Europe 23,3133 and has been shown to be efficacious for multiple types of seizures. Its relatively prolonged half-life of 24 hours can be altered by other AEDs. The hepatic enzyme-inducing drugs (for example, phenytoin and carbamazepine) shorten the half-life of lamotrigine to 12 hours, whereas the enzyme-inhibiting drug valproate significantly prolongs it to 48 hours. Less than 55% of lamotrigine is protein bound. The only significant effect of lamotrigine on other AEDs is an increase in the 10,11-epoxide level in patients receiving carbamazepine. Lamotrigine can be administered alone or in combination with valproate as one daily dose. The drug is available in 50-, 100-, and 250-mg tablets. The required daily dose is usually 100 to 500 mg/ day. Lamotrigine therapy is usually begun at 50 mg/day and gradually increased as needed and tolerated in 50-mg increments. The proposed therapeutic level is 1 to 5 μg/ml; however, monitoring blood levels is not critical with lamotrigine treatment. Side effects are relatively minor, similar to those with felbamate and gabapentin, including somnolence, dizziness, and skin rash. Other Drugs. Other drugs that are currently being evaluated in the United States include tiagabine, topiramate, and vigabatrin Vigabatrin has already been approved for the treatment of epilepsy in Europe and Canada. 23 One or more of these AEDs may be approved by the FDA after clinical trials. Unfortunately, drug studies have strict inclusion criteria, and not all patients with intractable seizure disorders may be appropriate candidates. Potential exclusionary criteria include a previous history of AED noncompliance, psychogenic seizures, status epilepticus, and an inability to assess seizure frequency adequately. Patients must have no progressive neurologic disorder, such as a brain tumor, and women must use an acceptable type of birth control while participating in the study. Periodic office visits are necessary for assessing drug effectiveness and safety. Investigational drug studies are particularly useful for patients without medical insurance because the cost of the drug and the medical examination (office visit and laboratory studies) may be deferred. Patients who are not surgical candidates and whose condition is refractory to conventional AEDs should be encouraged to consider investigational drug studies. The names and addresses of US epilepsy centers can be obtained from the National Association of Epilepsy Centers, 2701 University Avenue SE, Suite 105, Minneapolis, MN Surgical Procedures. Surgical ablation of the epileptogenic zone is the most effective method of rendering a patient with intractable partial epilepsy seizure free Surgical treatment should not be considered a "procedure of last resort," when all medical treatments have failed. 34 Considering highly favorable surgical candidates (see subsequent discussion) for a preoperative assessment may be appropriate even if the patient has received none of the new AEDs. The rationale for this decision is the relative lack of efficacy of AED therapy for intractable partial epilepsy in comparison with surgical excision of epileptic brain tis- The most common surgical procedure performed for epilepsy is an anterior temporal lobectomy Other potential surgical procedures are resection of extratemporal epileptic brain tissue, extirpation of foreign-tissue lesions, corpus callosotomy, and hemispherectomy. 3d 22 Patients may be considered surgical candidates within 1 year after epilepsy has been diagnosed if the seizures are socially disabling and refractory to maximally tolerated AED medica- sue tion. 34 Surgical treatment is most effective in improving the patient's quality of life if the operation occurs before psychosocial debilitation before the patient becomes unable to obtain education and employment due to seizures. Older patients may not be "ideal" candidates because of difficulty in attaining psychosocial rehabilitation after a successful operation. Although children and young adults are the preferred surgical candidates, operative procedures may decrease seizures in patients in the sixth decade of life or older. Mental retardation and psychiatric disease are not absolute contraindications to surgical procedures unless these disorders are severe and more disabling to the patient than is the seizure activity. The presurgical assessment depends on the type of the seizure and the proposed surgical treatment. Identifying patients with partial epilepsy to undergo a focal cortical resection or corticectomy involves a comprehensive preoperative outpatient and inpatient examination Favorable surgical candidates include patients with lesionai epileptic syndromes (tumor or vascular malformation) and MTS (Fig. 3 through 5) The clinical characteristics associated with MTS are early age at onset of seizure and a history of febrile convulsions. Without use of long-term EEG monitoring, the cost of the presurgical assessment and the operative procedure at one institution is approximately $30, Patients undergo outpatient studies, including neuropsychometry, speech-language testing, MRI, and visual perimetry. MRI has been shown to be of prognostic importance in patients being considered for surgical treatment of epilepsy MRI-identified changes consistent with MTS or lesionai pathologic conditions are predictive of a favorable outcome that is, a decrease in seizure tendency Independently, MRI findings affect patient selection for surgical intervention and alter the diagnostic examination and operative strategy Positron emission tomography and single photon emission computed tomography are functional neuroimaging studies that may indicate an alteration in cerebral metabolism and blood flow, respectively, that corresponds with the

10 1208 EPILEPSY Mayo Clin Proc, December 1994, Vol 69 region of epileptogenicity. 3d Single photon emission computed tomography has the advantage of providing a practical means of obtaining ictal imaging studies. Positron emission tomography-identified interictal hypometabolism has been shown to be intimately associated with the site of ictal onset and early seizure propagation. Inpatient long-term ictal EEG monitoring to localize the epileptogenic zone has become a standard preoperative procedure. Electrophysiologic studies must be done in an inpatient setting in order to allow recording of the ictal behavior with video monitoring and allow a decrease in AED therapy. Extracranial EEG recordings may or may not adequately localize the site of seizure onset. Long-term intracranial monitoring with depth or subdural electrodes (or both) may be needed. The necessity of "invasive" recordings depends on the site of seizure onset. In a few patients with frontal lobe epilepsy, scalp EEG effectively localizes the epileptogenic zone. 7 A cerebral arteriogram is routinely obtained preoperatively. An amobarbital sodium study may be useful at the time of angiography for assessing the likelihood of language and memory problems after a cortical resection. Electrocorticography may be performed intraoperatively before and after cortical resection to delineate further the limit of the epileptogenic zone, as initially determined by interictal EEG. Long-term follow-up shows that approximately 60% of patients are rendered seizure free after an anterior temporal lobectomy for intractable partial epilepsy. 35 Almost 80% of patients experience a significant decrease in seizures after a temporal lobe operation. 35 The surgical outcome is not as satisfactory for patients who undergo an extratemporal operation. Most of mese patients experience a significant decrease in seizures, but only about 20% with nonlesional extratemporal epilepsy are rendered seizure free. 37 SELECT PROBLEMS Select challenging problems that are often discussed with an epileptologist include management of a single unprovoked seizure, pregnancy and epilepsy, withdrawal of AED therapy, driving and epilepsy, and social use of alcohol in patients with a history of seizures. Single Seizure Episode. By definition, patients with single unprovoked seizure episodes do not have epilepsy that is, recurrent epileptic seizures. Studies have indicated that patients with isolated seizures have a 16 to 61% chance for recurrent seizures. lb The likelihood of recurrence is increased in patients with remote symptomatic neurologic disease, a family history of epilepsy, partial seizure activity, and abnormal findings on a neurologic examination. EEGidentified interictal epileptiform activity may also be prognostically important. In the vast majority of patients, seizures recur within the first year (usually during the first 3 months) after the initial seizure. The seizure tendency is gradually decreased if the patient remains seizure free within 3 years after the single seizure. After a patient has had a second unprovoked seizure, recurrence is high (79 to 90%).,b The management of a patient with a single seizure is controversial. Diagnostic studies should include EEG and MRI while the patient is asleep as well as awake. One option is to observe the patient without administering AED therapy until seizure activity recurs. AED medication may be considered in select patients who seem to have a "high risk" for seizure recurrence. The presumed consequence of recurrent seizure activity may affect the decision to treat with AEDs. The problem with initiating AEDs is that one cannot be certain how long to continue a drug. Compliance becomes an issue in patients who have remained seizure free. Institution of an AED may also be associated with serious idiosyncratic and dose-related toxicity (see previous discussion). In children, observation may be appropriate because of the potential deleterious effects of AEDs on learning and behavior. The presence of one or more potential prognostic factors (as previously discussed) may influence patient management. Risk of recurrence may not be significantly lower in patients who receive AED therapy in comparison with those who do not. lb If the patient is to be treated, the physician should select a nonsedating AED and administer the medication at a nontoxic dose. The duration of therapy is unknown; however, if a patient is seizure free for several years, an increased risk of seizure is unlikely, and the medication can be gradually withdrawn (see subsequent discussion). If a patient has been seizure free for an established period (longer than 3 months) and has received no AED therapy, observation is most appropriate. Pregnancy and Epilepsy. The management of a woman with epilepsy involves several issues, including methods of birth control and the potential teratogenic effect of AEDs. These issues should be discussed with the patient before pregnancy occurs. Other important topics that are not discussed herein include the safety of a mother breast-feeding while receiving AEDs and the effect of pregnancy on a patient's seizure disorder. Of importance, structural neuroimaging studies should not be performed in a patient who may be pregnant unless the indication is emergent, inasmuch as the safety of MRI has not been appropriately evaluated. An important concern of patients may be continued effective birth control while receiving AED therapy. Women who elect to take an oral contraceptive drug for birth control must be aware of the potential interaction with AEDs. 3c Hepatic enzyme-inducing drugs (carbamazepine, phenytoin, and phénobarbital) may increase the metabolism of oral contraceptives and cause them to be ineffective. Valproate is the preferred AED for women taking oral contraceptives

11 Mayo Clin Proc, December 1994, Vol 69 EPILEPSY 1209 because it does not produce this effect. Gabapentin has not been shown to affect the metabolism of oral contraceptive drugs. A potential teratogenic effect of AEDs has been confirmed. 39 " 43 This issue must be discussed with the patient before conception because the most susceptible period of fetal development may be before the mother knows she is pregnant. The physician's sensitivity is critical in effectively communicating the facts, not just the fear, about this problem. Literature for patients that summarizes the current information may be useful. AED-related teratogenesis has been referred to as the fetal hydantoin syndrome because of the observation of birth defects in mothers receiving phenytoin. This syndrome is nonspecific for phenytoin and should be termed the "fetal AED syndrome." Malformations have been reported to occur with all the primary AEDs, including phénobarbital. The risk of teratogenesis is minimal. More than 90% of patients who receive AEDs have a successful pregnancy outcome. 42 The potential teratogenesis is decreased by administering a single AED at a low plasma concentration, taking multivitamins with folate, and avoiding other "toxic substances" such as alcohol and tobacco. Patients with epilepsy who are receiving no AEDs also have an increased risk of fetal malformations, a suggestion of a genetic factor in some patients. In mothers receiving AEDs, most anomalies are minor skeletal and facial defects. Major anomalies, including congenital heart disease, are much less common. Valproate is associated with an increased risk of neural tube defects in approximately 1 to 2% of mothers who take this drug. 4 ' Serum oc-fetoprotein determinations, ultrasonography, and amniocentesis may be useful in patients receiving valproate. The selection of an AED in a potential mother is best determined by the type of seizures. The decision about the use of an AED in a woman contemplating pregnancy depends on the potential risk of seizure activity versus the risk of teratogenesis. Frequent or prolonged generalized tonic-clonic seizures may be associated with fetal death. In patients who may require no AEDs, medication may be withdrawn before pregnancy, as subsequently outlined. Withdrawal of AED Therapy. Physicians are comfortable with the decision to initiate AEDs but may be uncertain about when to consider withdrawal of AED therapy. Often, patients understand that the duration of treatment is likely "lifelong." A seizure remission a 5-year period with no seizures occurred in 67% of pediatrie and adult patients with epilepsy in one study. 44 In patients who are receiving long-term AED therapy, medication may be withdrawn without seizure recurrence." 3 The reasons to consider AED withdrawal include the potential toxicity associated with these medications and the expense. Candidates for AED withdrawal are those who experience AED toxicity, have seizures that are refractory to an AED, and achieve remission of their seizure disorder (2 to 5 years without seizures). Substitution, not addition, of a drug should be the rule for the first two patient groups who will continue to require AED therapy. The problems associated with polypharmacy have been previously discussed. Most studies have indicated that approximately one-fourth to one-third of patients will have recurrent seizures after medication has been withdrawn. The prognostic factors that are likely to indicate an unsuccessful withdrawal include abnormal findings on a neurologic examination, difficulty in establishing effective seizure control with initial AED therapy, and the presence of a remote symptomatic neurologic disorder. EEG-identified epileptiform activity before or during AED withdrawal increases the risk of recurrence." 1 The duration for tapering AED therapy is probably not critical in determining the success of withdrawal. No evidence shows that the tapering process must be conducted for several years. Studies have suggested that the likelihood of recurrence does not differ for patients in whom a drug was withdrawn during 2 to 3 months in comparison with 6 months. Most seizures recurred during the first year after the medication was withdrawn. For patients receiving polypharmacy, one AED at a time should be discontinued; preferably the medication that has been the most toxic or the least effective (or both) should be withdrawn first. Driving and Epilepsy. One of the treatment goals for patients with seizures is to function normally in society. Often, this situation involves the ability to operate a motor vehicle for employment and educational opportunities. Many patients view a driver's license as evidence of independence. Patients with medical conditions that are prone to impair consciousness or alter motor function are required by law to provide reassurance from a physician that the disorder is being successfully treated. These laws are not restricted to patients with seizures. Usually, a defined symptom-free period is necessary before a license can be obtained. The laws about driving and epilepsy vary from state to state. A physician does not have the right to make a decision independently about the ability of a patient to drive. Obtaining a driver's license is a legal, not a medical, decision. It is inappropriate for a physician to indicate to an asymptomatic patient who is in long-term seizure-free remission that driving is not permitted. Often, physicians are concerned about potential liability if a patient becomes involved in a motor vehicle accident. The physician's responsibility is to instruct the patient about the law in a particular state concerning driving and epilepsy and to complete the necessary medical forms. Patients who drive a vehicle despite inadequate seizure control should be reminded about a state law and be urged not to drive. Physicians should note in the patient's medical history that the noncompliant person was informed

12 1210 EPILEPSY Mayo Clin Proc, December 1994, Vol 69 about driving laws and epilepsy. In the event of an accident, the consequences may not only be serious injury to the patient and others but also failure of the patient's automobile insurance company to provide appropriate financial support. Alcohol and Epilepsy. For patients with seizures, physicians have often recommended complete avoidance of alcohol-containing beverages. The rationale for this position is based on the observation that persons with alcoholism seem to have an increased risk of seizure activity. Seizures that occur in patients who abuse alcohol are primarily related to episodes of alcohol withdrawal after a state of alcohol dependency and associated neurologic disorders such as subdural hematomas. Alcohol consumption may be a risk factor for new onset of recurrent unprovoked seizures. 45 Appropriate clinical studies of patients with epilepsy have demonstrated no evidence that light alcohol use, one to two drinks, is associated with an increase in seizure activity, a decrease in AED levels, or a change in findings on interictal EEC 46 No evidence shows that light alcohol consumption alters seizure tendency in nonalcoholic patients with epilepsy Heavy alcohol consumption, more than five drinks, seems to exert a definite antiepileptic effect, as demonstrated by a decrease in interictal EEG-identified epileptiform activity. 47 Heavy alcohol use may be associated with an increased seizure tendency during alcohol withdrawal. Long-term alcohol use may increase the metabolism of AEDs and decrease plasma concentrations. 48 Patients should be discouraged from alcohol use if they have a history of alcohol dependency, alcohol-withdrawal seizures, drug abuse, neurotoxicity related to AEDs, medically intractable seizures, or an unusual "sensitivity" to alcohol. 45 REFERENCES 1. Hauser WA, Hesdorffer DC. Epilepsy: Frequency, Causes, and Consequences. New York: Demos, 1990: (a) 1-51; (b) Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, Epilepsia 1975; 16: Engel J Jr. Seizures and Epilepsy. Philadelphia: FA Davis, 1989: (a) 22-37; (b) ; (c) ; (d) Gastaut H, Broughton R. Epileptic Seizures. Springfield (IL): Charles C Thomas, 1972: Wieser H-G, Williamson PD. Ictal semiology. In: Engel JJr, editor. Surgical Treatment of the Epilepsies. 2nd ed. New York: Raven Press, 1993: Klass DW. Electroencephalographic manifestations of complex partial seizures. Adv Neurol 1975;11: Quesney LF, Gloor P. Localization of epileptic foci. Electroencephalogr Clin Neurophysiol Suppl 1985; 37: Devinsky O, Sato S, Kufta CV, Ito B, Rose DF, Theodore WH, et al. Electroencephalographic studies of simple partial seizures with subdural electrode recordings. Neurology 1989; 39: Bergen D, Bleck T, Ramsey R, Clasen R, Ristanovic R, Smith M, et al. Magnetic resonance imaging as a sensitive and specific predictor of neoplasms removed for intractable epilepsy. Epilepsia 1989;30: Jack CR Jr, Sharbrough FW, Twomey CK, Cascino GD, Hirschorn KA, Marsh WR, et al. Temporal lobe seizures: lateralization with MR volume measurements of the hippocampal formation. Radiology 1990; 175: Cascino GD, Jack CR Jr, Parisi JE, Sharbrough FW, Hirschorn KA, Meyer FB, et al. Magnetic resonance imaging-based volume studies in temporal lobe epilepsy: pathological correlations. Ann Neurol 1991;30: Jackson GD, Berkovic SF, Tress BM, Kalnins RM, Fabinyi GC, Bladin PF. Hippocampal sclerosis may be reliably detected by magnetic resonance imaging. Neurology 1990; 40: Jack CR Jr, Sharbrough FW, Cascino GD, Hirschorn KA, O'Brien PC, Marsh WR. Magnetic resonance image-based hippocampal volumetry: correlation with outcome after temporal lobectomy. Ann Neurol 1992;31: Lencz T, McCarthy G, Bronen RA, Scott TM, Inserni JA, Sass KJ, et al. Quantitative magnetic resonance imaging in temporal lobe epilepsy: relationship to neuropathology and neuropsychological function. Ann Neurol 1992; 31: Trenerry M, Jack CR Jr, Ivnik RJ, Sharbrough FW, Cascino GD, Hirschorn KA, et al. MRI hippocampal volumes and memory function before and after temporal lobectomy. Neurology 1993;43: Schmidt D. Two antiepileptic drugs for intractable epilepsy with complex-partial seizures. J Neurol Neurosurg Psychiatry 1982;45: Gotman J, Koffler DJ. Interictal spiking increases after seizures but does not after decrease in medication. Electroencephalogr Clin Neurophysiol 1989; 72: Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado- Escueta AV, Browne TR, et al. Comparison of carbamazepine, phénobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313: Dreifuss FE. Postscript: establishment of what constitutes medical failure. In: Engel J Jr, editor. Surgical Treatment of the Epilepsies. 2nd ed. New York: Raven Press, 1993: Ward AA Jr. Perspectives for surgical therapy of epilepsy. In: Ward AA Jr, Penry JK, Purpura DP, editors. Epilepsy. New York: Raven Press, 1983: Crandall PH. Role of neurosurgery in management of medication-resistant epilepsy. In: Plan for Nationwide Action on Epilepsy. Vol 2, Part 2. Washington (DC): US Government Printing Office, 1977: (Publication No. NIH ) 22. Engel J Jr, Van Ness PC, Rasmussen TB, Ojemann LM. Outcome with respect to epileptic seizures. In: Engel J Jr, editor. Surgical Treatment of the Epilepsies. 2nd ed. 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13 Mayo Clin Proc, December 1994, Vol 69 EPILEPSY Sachdeo R, Kramer LD, Rosenberg A, Sachdeo S. Felbamate monotherapy: controlled trial in patients with partial onset seizures. Ann Neural 1992; 32: Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). NEnglJMed 1993;328: ChadwickD. Gabapentin. Epilepsy Res Suppl 1991; 3: Schear MJ, Wiener JA, Rowan AJ. Long-term efficacy of gabapentin in the treatment of partial seizures [abstract]. Epilepsia 1991; 32(Suppl3):6 29. UK Gabapentin Study Group. Gabapentin in partial epilepsy. Lancet 1990;335: Leppik IE, Shellenberger MK, Anhut H. Two open-label, multicenter studies of the safety and efficacy of gabapentin as add-on therapy in patients with refractory partial seizures [abstract]. Epilepsia 1992; 33(Suppl3): Yuen AW. Lamotrigine. Epilepsy Res Suppl 1991; 3: BrodieMJ. Lamotrigine. Lancet 1992;339: Peck AW. Clinical pharmacology of lamotrigine. Epilepsia 1991;32(Suppl2):S9-S Engel J Jr, Shewmon DA. Overview: who should be considered a surgical candidate? In: Engel J Jr, editor. Surgical Treatment of the Epilepsies. 2nd ed. New York: Raven Press, 1993: Walczak TS, Radtke RA, McNamara JO, Lewis DV, Luther JS, Thompson E, et al. Anterior temporal lobectomy for complex partial seizures: evaluation, results, and long-term follow-up in 100 cases. Neurology 1990;40: Sharbrough FA. Complex partial seizures. In: Lüders H, Lesser RP, editors. Epilepsy: Electroclinical Syndromes. Berlin: Springer-Verlag, 1987: Cascino GD, Jack CR Jr, Parisi JE, Marsh WR, Kelly PJ, Sharbrough FW, et al. MRI in the presurgical evaluation of patients with frontal lobe epilepsy and children with temporal lobe epilepsy: pathologic correlation and prognostic importance. Epilepsy Res 1992;11: Cascino GD, Kelly PJ, Sharbrough FW, Hulihan JF, Hirschorn KA, Trenerry MR. Long-term follow-up of stereotactic lesionectomy in partial epilepsy: predictive factors and electroencephalographic results. Epilepsia 1992; 33: Annegers JF, Hauser WA, Elveback LR, Anderson VE, Kurland LT. Congenital malformations and seizure disorders in the offspring of parents with epilepsy. Int J Epidemiol 1978; 7: Lowe CR. Congenital malformations among infants born to epileptic women. Lancet 1973;1: Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects [letter]. Lancet 1982; 2: Yerby MS, Leppik I. Epilepsy and the outcomes of pregnancy. J Epilepsy 1990;3: Jones KL, Lacro RV, Johnson KA, Adams J. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989; 320: Annegers JF, Hauser WA, Elveback LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979; 20: Ng SKC, Hauser WA, Brust JCM, Susser M. Alcohol consumption and withdrawal in new-onset seizures. N Engl J Med 1988;319: Höppener RJEA. The effect of social alcohol use on seizures in patients with epilepsy. In: Porter RJ, Mattson RH, Cramer JA, Diamond I, Schoenberg DG, editors. Alcohol and Seizures. Philadelphia: FA Davis, 1990: Mattson RH, Fay ML, Sturman JK, Cramer JA, Wallace JD, Mattson EM. The effect of various patterns of alcohol use on seizures in patients with epilepsy. In: Porter RJ, Mattson RH, Cramer JA, Diamond I, Schoenberg DG, editors. Alcohol and Seizures. Philadelphia: FA Davis, 1990: Cramer JA, Scheyer RD. The effect of alcohol use on antiepileptic drugs. In: Porter RJ, Mattson RH, Cramer JA, Diamond I, Schoenberg DG, editors. Alcohol and Seizures. Philadelphia: FA Davis, 1990: