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Intractable Partial Epilepsy: Evaluation and Treatment
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Intractable Partial Epilepsy: Evaluation and Treatment
GREGORY D. CASCINO, M.D., Department ofNeurology
Partial (focal or localization-related) epilepsy is the most common seizure disorder encountered in patients with epilepsy. These seizures are focal at onset-that is, emanating from a localized region of the brain. Patients with partial epilepsy may have seizures that are refractory to antiepileptic drug medication. The financial burden for these patients includes the cost of medical care and often the loss of employment. Psychosocial deterioration may be progressive as long as the seizures are intractable. Management includes confirmation of the type (or types) of seizures, exclusion ofan intracranial epileptogenic lesion, and use ofappropriate antiepileptic drug therapy. Referral of affected patients to a comprehensive epilepsy center for possible surgical treatment and investigational drug studies should be considered. In the care ofthe patient with intractable partial epilepsy, the goals should be to render the patient free of seizures and to allow the patient to become a participating and productive member of society.
Partial epilepsy affiicts an estimated 800,000 patients in the United States.':" The types of seizures represented are simple and complex partial seizures and secondarily generalized tonic-clonic seizures." Simple partial seizures are manifested by sensory, motor, autonomic, or psychic symptoms without an impairment of consciousness. Complex partial seizures are characterized by an alteration in mentation and may initially begin as a simple partial seizure. Classifying these seizures as psychomotor or temporal lobe seizures should be avoided be-
Address reprint requests to Dr. G. D. Cascino, Department of Neurology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 65:1578-1586, 1990
cause these terms are ambiguous and may lead to an incorrect localization ofthe site of onset of the seizures. Complex partial seizures constitute almost 55% of seizures in adults, and approximately 80% ofthese seizures are oftemporallobe origin." Most frequently, extratemporal partial seizures emanate from the frontal lobes. 5 Most generalized tonic-clonic or "grand mal" seizures in adults are of partial onset. Simple partial or complex partial seizures may progress to a secondarily generalized seizure." Approximately 30% of patients with partial epilepsy have mass lesions-for example, neoplasms or vascular malformations-as the cause of their seizure disorders." Underlying pathologic findings in partial epilepsy also include
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posttraumatic brain lesions and heterotopias. The most common pathologic alteration in patients with seizures beginning in the temporal lobe is mesial temporal sclerosis. 6 The relative biologic intractability of the partial epilepsies-that is, seizures refractory to medical therapy-has been substantiated. 1 Potential causes of poorly controlled seizures include incorrect classification of the seizures, inadequate antiepileptic drug (AED) therapy, poor compliance with AED therapy, competing epileptogenic drugs such as phenothiazines, and biologically intractable epilepsy.' Seizures are considered intractable when they persist despite maximally tolerated monotherapy or combination AED therapy. Approximately 45% of the patients with a partial seizure disorder, an estimated 360,000 patients in the United States, are medically refractory.l-? Potential variables that can adversely affect AED response include the presence of developmental delay, seizures related to a mass lesion-for example, a glioma-and an increased latency before institution of appropriate therapy.l-" Epilepsia partialis continua is a partial epileptic syndrome remarkable for continuous or frequent focal motor seizures that characteristically are refractory to AEDs.1 The long-term prognosis of patients with partial epilepsies may be indicated by the initial response to AED therapy, even within the first 2 years.i-? Psychosocial difficulties-for example, impaired socialization and inability to obtain an education and employment-can be progressive as long as the epilepsy is intractable.l-l'v'! Cognitive performance may be impaired not only by refractory epilepsy but also by the neurotoxicity of AED therapy, even at therapeutic plasma levels.l-P Successful treatment of the seizure disorder can appreciably improve psychologic, social, sexual, and behavioral functions.t''-!' Polypharmacy (that is, concurrent use of multiple AEDs) seems to produce more severe adverse behavioral effects than does single-drug therapy. 12 The cost of the medical care for assessing and treating patients with intractable epilepsy is considerable, but this investment must be com-
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pared with the financial burden of unemployment and AED therapy in these patients. Importantly, the care and management of the patient with epilepsy must go beyond rendering the patient free of seizures; an attempt must also be made to improve the quality of life for the patient.
ASSESSMENT OF PATIENTS
The initial steps in the assessment of the patient with presumed medically refractory partial epilepsy are to confirm the diagnosis of a seizure disorder and to classify the type of seizure. 1 Seizures are remarkable for being stereotypic, recurrent, and usually unprovoked clinical events. Behavior ofthe Patient.-Obtaining information about the ictal and postictal behavior may be useful in the classification of type of seizure. Some patients may have multiple types of seizures-for example, simple partial, complex partial, and simple partial progressing to secondarily generalized tonic-clonic seizures. Patients with complex partial seizures may be amnesic for the details of the ictal episodes and the postictal state;" therefore, a reliable observer who has witnessed the seizures should be interviewed. Patients with simple partial seizures may be appropriately aware of their ictal symptoms. 14 More than 50% of patients during complex partial seizures acknowledge the presence of an aura (the functional onset of seizure activity before an alteration in consciousness), which may be useful in localizing the onset of seizures.!" Examples of an aura are an emotional or a visceral sensation." Patients may quickly learn to recognize the aura as the onset of a seizure. The description of complex partial seizures usually emphasizes the lack of motor or verbal activity; often the patient is noted to have a motionless stare and does not respond appropriately to auditory stimulation.v" The patient may have associated spontaneous automatisms that are oroalimentary (such as lip smacking) or gestural (such as picking movements with the fingers)." Patients who have auras associated with complex partial seizures usually also have
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independent simple partial seizures.P Organized or purposeful behavior is unusual in patients during a complex partial seizure, although a postictal state may be confused with the ictal episode. A complex partial seizure may last for only several minutes; however, postictal confusion or altered behavior may persist for longer. The ictal behavior may indicate the localization of the onset of seizures-for example, partial seizures beginning in the primary motor or sensory cortex. 4 ,5 ,13,14 Clues about the lateralization of the onset of seizures include ictal paretic posturing of an upper extremity, ictal dysphasia, and the presence of a postictal neurologic deficit such as a hemiparesis.v" At onset, secondarily generalized seizures may not be associated with focal seizure activity that can be recognized clinically. Forced version manifested by maximal deviation of the head, neck, and trunk is a reliable indicator of the lateralization of the onset of seizures in patients with partial epilepsy.!" Unfortunately, partial seizures emanating from the temporal lobe, especially the mesial temporal region, may not be associated with ictal phenomena that allow lateralization of the onset of seizures." Ictal and postictal antegrade amnesia and confusion are unreliable lateralizing signs in patients with complex partial seizures.v-" History andExamination.-The neurologic history and examination may indicate the cause ofthe seizure disorder and the localization ofthe onset ofseizures. In 28% of patients with partial epilepsy, the cause ofthe seizures, such as stroke or head trauma, can be determined. 3 Patients with seizures symptomatic of a previous neurologic insult are more likely to have a medically refractory seizure disorder than are other patients.' The most common findings on examination are AED effects (for example, nystagmus and ataxia) and cognitive alterations (for example, memory loss). A focal neurologic deficit may indicate the lateralization of the onset of seizures. Electroencephalography.-Common diagnostic errors in patients with complex partial seizures are the classification of the type of seizure as "petit mal"-that is, absence seizures-
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or nonepileptic behavioral events.v'" Absence seizures are a type of primary generalized epilepsy that does not respond to the AEDs that are often used to treat partial epilepsy. Important differences are evident in the ictal behavior and the electroencephalographic (EEG) findings in patients with absence and complex partial seizures." The diagnostic confusion between nonepileptic events, especially psychogenic seizures, and complex partial seizures may necessitate prolonged video EEG monitoring for classification of the seizures.v" Patients with complex partial seizures may also have coexisting psychogenic seizures that complicate the medical treatment. 17 The EEG is the most commonly used diagnostic study in the assessment of patients with partial epilepsy.P-" The low diagnostic yield of the routine awake EEG recording in these patients has been reported. 18 Sleep deprivation and a sleep EEG recording may be useful for disclosing epileptiform activity that is not evident in the awake record'" (Fig. I), Activation procedures such as hyperventilation and photic stimulation may also be useful for recording epileptiform activity. The most reliable EEG abnormality in patients with complex partial seizures of temporal lobe origin is an interictal spike or sharp-wave discharge in one temporal lobe. 13 ,18 Intermittent focal rhythmic slow-wave activity may also occur without accompanying spikes.Pi'" The AED medication (including drug levels) and the time ofthe last seizure should be known when the EEG study is interpreted. Supplementary electrodes such as sphenoidal and anterior temporal electrodes may be useful for recording epileptiform activity emanating from the anterior temporal lobe. 13 ,19 A normal interictal (that is, between seizure episodes) wake and sleep EEG does not exclude a partial seizure disorder. The EEG may also be false positive-for example, nonepileptiform EEG alterations may be misinterpreted and lead to the incorrect diagnosis of a seizure disorder (Fig. 2), The limitations of interictal EEG recordings in patients with seizures have led to the expanded use of prolonged video EEG monitoring. Prolonged monitoring can be performed as
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RIGHT TEMPORAL SHARP WAVES
cJ Age: 22yrs
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INTRACTABLE PARTIAL EPILEPSY 1581
renchymal abnormalities in the brain. X-ray computed tomography and magnetic resonance imaging are noninvasive studies that can determine the cause ofthe seizure disorder and assist in localizing the epileptogenic area (the site of the onset ofthe seizuresl.P Magnetic resonance imaging has been demonstrated to be superior to computed tomography in imaging epileptogenic lesions in patients with intractable partial epilepsy'" (Fig. 3). Low-grade and malignant gliomas may not be detected by computed tomography; however, the sensitivity and specificity of magnetic resonance imaging for revealing these lesions have been shown.s! Magnetic resonance imaging is the structural imaging procedure of choice in patients with intractable partial epilepsy.24-26 The methods of magnetic resonance imaging are a critical determinant in the diagnostic yield of these studies in patients with epilepsy." A gadolinium-diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging scan may be useful in indicating the pathologic features of a mass lesion'" (Fig. 4). Gadolinium, however, does not seem to reveal abnormalities that are not identified in the unenhanced image in patients with epilepsy." Several contraindications to magnetic resonance imaging include the presence of a metallic foreign body in the head or neck, a cardiac pace-
an outpatient or inpatient procedure, and the EEG can be correlated with the video-recorded seizure.P-" During inpatient monitoring, AEDs can often be withdrawn to provide a better opportunity for ictal recordings. The utility of inpatient EEG monitoring has been demonstrated relative to the accurate classification of type of seizures, which allows selection of appropriate therapy." In patients in whom the clinical manifestations and interictal EEG studies do 9 Ag" 731" 19-20-841 Fp1-F7 ~~~._~-v~~._~~'--~,_ not provide the necessary information, prolonged F7-T3~~~~~.~'~ video EEG monitoring may be useful before T3-T5~v-"'~t'_·~~~ selection of potentially toxic AEDs. Importantly, T5-01~~~-~v,~~ the absence of scalp-recorded EEG alterations has been verified during partial seizures offronFp2-Fa~~~ tal lobe origin and during simple partial seiFa-T4 --~~--------------.,"""-'~~-w/Yv-_~~~~ zures.P A prominent activation of epileptiform activity may be identified after a seizure, which T6-02 ~~...rV~~~-r-A-.r"-~"Vv'~~~..rv---.iV~ may be useful for classification ofthe type of sei~50pV 1 sec zures and for localization of the onset ofthe seizures." Ultimately, epilepsy is a clinical diagnosis, and the EEG may provide only supportive Fig. 2. Electroencephalogram in 73-year-old woman, showing several benign sporadic sleep spikes (small sharp spikes) information. in left temporal region. These discharges are nonepileptiNeuroimaging.-In patients with partial form and are not associated with an increased epileptogenic epilepsy, neuroimaging may identify intrapa- potential.
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the hippocampal formation may detect hippocampal atrophy in patients with seizures emanating from the temporal lobe. 27 In the routine assessment of patients with partial epilepsy, no role exists for a conventional radionuclide brain scan or skull roentgenogram. Cerebral arteriography should be performed in patients with partial epilepsy who have a suspected vascular malformation or an intracranial aneurysm or before a surgical procedure for epilepsy or resection of an epileptogenic lesion.
Fig. 3. Magnetic resonance image, showing an abnormality in left frontal lobe. Cortical dysplasia was demonstrated at time of surgical resection. (Note: The left cerebral hemisphere is on the right side of the photograph.)
maker, excessive patient body size, and patient claustrophobia." Sedation of the patient may be necessary. If a magnetic resonance imaging study is not possible, noncontrast and contrastenhanced computed tomography should be performed. If the initial computed tomographic study shows no abnormalities, a repeat scan should be obtained 6 to 12 months later because of the possibility of a false-negative study in patients with a neoplastic lesion. Computed tomography may complement magnetic resonance imaging in patients with calcified lesions and bony abnormalities. 19 The limitations of computed tomography and magnetic resonance imaging in depicting a sclerotic lesion, such as mesial temporal sclerosis or cortical gliosis, have been demonstrated.w" Unfortunately, despite the sensitivity and specificity of magnetic resonance imaging in detecting mass lesions, results of the studies are normal in a substantial percentage of patients with intractable partial epilepsy.25-27 Additional magnetic resonance imaging techniques such as volume measurements of
MANAGEMENT The treatment of patients with partial epilepsy begins with the appropriate counseling for the patient and family about the diagnosis of a seizure disorder. Misconceptions (for example, that epilepsy is a form of mental illness) need to be clarified immediately. Questions concerning employment, driving, parenting children, and the cost of medical care should be addressed. If the physician is unfamiliar with driving laws in a particular state, the information can be obtained through a department of motor vehicle registration or the Epilepsy Foundation of America (4351 Garden City Drive, Landover, MD 20785). The patient should be encouraged to obtain further information about epilepsy from this organization. The assistance of social services in obtaining benefits for the patient with intractable epilepsy is often essential in providing high-quality medical care for the patient. Patients who are unable to work because of their seizures may be entitled to disability funds. Certain "environmental hazards"-for example, lack of transportation and inability to afford AEDs-have a negative effect on treatment. Drug Therapy.-The selection of an AED is the most important decision the physician will make after conclusion of the diagnostic evaluation. Empiric trials of AEDs in attempts to clarify the diagnosis are discouraged because of the intermittence of the symptoms and the potential toxicity associated with the treatment. Many patients with intractable partial epilepsy who take multiple AEDs are noted to have symptoms of chronic AED toxicity, including
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Fig. 4. Gadolinium-diethylenetriaminepentaacetic acidenhanced magnetic resonance image, revealing a lesion that proved to be a grade 2 oligodendroglioma in the right temporal lobe. (Note: The right cerebral hemisphere is on the left side of the photograph.) (From Cascino and associates.P By permission of Edgell Communications, Inc.)
drowsiness, ataxia, and diplopia. AED toxicity may occur even with therapeutic or subtherapeutic AED levels." The secondarily generalized tonic-clonic seizures are often more responsive to AED treatment than are the simple and complex partial seizures. Even in patients who seem medically refractory, consideration of high-dose monotherapy may be appropriate. 28 Documentation ofAED levels for previously used AEDs is essential. Patients may require higher levels of AEDs than the "therapeutic range."13,28 Monotherapy is associated with less toxicity at higher drug levels and better AED compliance than is polypharmacy. Knowledge about the pharmacokinetics of AEDs is essential for the correct use of these medications. Unnecessarily frequent dosing intervals, such as phenobarbital administered three times daily, may lead to noncompliance. Addition of a second AED is associated with complete seizure control in only 11 to 13% of patients and the development of AED toxicity in 90% of patients.29,30 Overuse of
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AED plasma levels may not allow patients the maximal benefit from a specific drug. Patients should receive maximally tolerated monotherapy before substituting AED medication. 13,28 Reducing the dosage of an AED because of a "high" plasma level in a patient who is seizurefree and tolerating a medicine well is a potential hazard of frequent AED level determinations. The drugs of choice for the partial epilepsies, including the secondarily generalized seizures, are carbamazepine and phenytoin. 13,30-32 The preference ofcarbamazepine or phenytoin as the initial AED depends on several factors, including the cost of medication, frequency of drug dosing, drug-related side effects, and previous experience with the medication.P! The drugs have different potential idiosyncratic and doserelated toxicity; however, at present, no definite evidence shows that one is more effective than the other." If a previous AED history is unavailable, maximally tolerated monotherapy with carbamazepine or phenytoin should be considered before medically refractory partial epilepsy is diagnosed. Other potentially useful medications include valproate sodium, phenobarbital, and primidone. 13,31,32 None of these drugs has been proved to be more efficacious than the two aforementioned primary AEDs. Phenobarbital and primidone are barbiturates and may be associated with increased drowsiness, irritability, hyperkinetic activity in children, and memory loss. 1,31 Valproate sodium is an excellent drug for the primary generalized epilepsies; ongoing trials are studying its efficacy in the partial epilepsies. Third-line AEDs that may be considered include clonazepam, clorazepate dipotassium, and methsuximide."! The benzodiazepine drugs, clonazepam and clorazepate, have toxicity similar to that for the barbiturates, and tachyphylaxis may develop. Methsuximide is a potentially effective AED; however, toxicity is also a definite problem. Other AEDs that have been used in the treatment of the partial epilepsies include acetazolamide, ethotoin, mephenytoin, and phenacemide." Because of inferior efficacy in comparison with the other AEDs or considerable toxicity (or both), these AEDs are rarely
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used. Unfortunately, most patients who fail to obtain adequate control of seizures with highdose monotherapy with carbamazepine or phenytoin do not become seizure-free with use of other AEDs.
Comprehensive Epilepsy Program.-If
seizures persist despite use of the foregoing therapeutic regimens, referral of the patient to a comprehensive epilepsy program should be considered. The names and addresses of epilepsy centers in the United States can be obtained from The National Association of EpilepsyCenters, 2701 University Avenue SE, Suite 105, Minneapolis, MN 55414. Additional medication trials with use of currently available AEDs may be undertaken. Two potential therapeutic programs that can be considered are enrollment in an investigational drug study and a surgical procedure for epilepsy. Investigational Drug Studies.-Many AEDs that have not been approved by the Food and Drug Administration are being evaluated at several epilepsy centers. These medications include nimodipine, felbamate, gabapentin, vigabatrin, and lamotrigine.>' Several of these drugs may be approved by the Food and Drug Administration in the next few years. These drug studies have strict inclusion criteria, and not all patients will be considered appropriate candidates. Recurrent visits to the epilepsy center, the need for careful monitoring of the frequency of seizures, and the occurrence ofdrug side effects are required. Despite the promise of these new AEDs, most patients in investigational drug studies do not become seizure-free. To obtain a driver's license in most states, the applicant must be seizure-free for an established period. Surgical Treatment.-An ablative surgical procedure, such as resection of focal epileptogenic cortex, is the most effective method currently available to render children and adults with intractable partial epilepsy seizure-free." Potential candidates include patients (even infants) with medically refractory partial epilepsy who have seizures emanating from a localized region of the brain that can be resected without neurologic morbidity.Pr" Patients with severe
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psychiatric disease, mental retardation, involvement of essential cortex such as sensory or motor areas, or a multifocal seizure disorder are excluded. 3 3 ,34 Surgical treatment has also been attempted in infants with intractable seizure disorders. In general, the seizures must be socially disabling, and the patient should be motivated to undergo the presurgical evaluation and the operative procedure." An important issue that must be considered is the potential for improvement in the quality oflife after successful surgical treatment.v" Patients with generalized or bilateral independent interictal epileptiform activity should not be excluded without appropriate ictal EEG recordings. 33 Drug-related toxicity leading to noncompliance may not be a reason for exclusion of a surgical candidate. Patients with an epileptogenic area in the language dominant hemisphere may also be appropriate operative candidates." Surgical treatment of epilepsy should not be considered as a last resort after all combinations of AEDs have been tried. The longer the duration of intractability, the greater the risk of psychosocial deterioration and secondary epileptogenesis.' If after 2 years of appropriate AED trials with use of the first- and second-line AEDs the patient is medically refractory, referral to a comprehensive epilepsy program should be considered. The most common surgical procedure performed for partial epilepsy is a focal cortical resection in the temporal lobe, an anterior temporallobectomy. The goals of surgical treatment are to eliminate seizures, reduce AED toxicity, and avoid neurologic morbidity.P Approximately 60% of patients will be seizure-free after an anterior temporal lobectomy, and almost 80% of patients will experience a substantial reduction in seizure activity.?" In select patients, depending on the surgical outcome and postoperative EEG recordings, AEDs may ultimately be completely withdrawn. The surgical outcome is not as favorable for extratemporal surgical procedures, especially frontal lobe operations." Freedom from complex partial and secondarily generalized tonicclonic seizures postoperatively may be consid-
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ered a favorable surgical outcome, even ifsimple partial seizure activity persists. The operative mortality rate for surgical treatment ofepilepsy is approximately 1 in 400. 13 The potential morbidity depends on the localization of the epileptogenic area. A comprehensive presurgical evaluation is necessary, including an ictal EEG recording, neuropsychologic and speech-language studies, testing of visual perimetry, a magnetic resonance imaging scan of the head (preferably with quantitative temporal volume studies), and cerebral arteriography. 34 Functional imaging studies for assessment of cerebral metabolism (positron emission tomography) and blood flow (single photon emission computed tomography) may also be included in the diagnostic evaluation at some centers. 19,33,34 An intracarotid amobarbital sodium study is performed to determine language dominance and to assess memory in the contralateral temporal lobe. Chronic intracranial EEG monitoring with use of depth electrodes and subdural grids may be necessary for localization of the epileptogenic area." Intraoperative or extraoperative functional mapping may be used to delineate functional areas of the cerebral cortex. The cost of the presurgical evaluation and the operative procedure is considerable-approximately $20,000 when chronic intracranial monitoring is not performed. 13 Most patients who undergo a surgical procedure for epilepsy are young adults who are otherwise in good health; therefore, their reduced cost for future medical care and their potential earnings need to be considered. An estimated 75,000 of the 360,000 patients in the United States with intractable partial seizure disorders are candidates for surgical treatment; however, only several hundred surgical procedures for epilepsy are performed in the United States each year. 37 ,38 A major reason for this underutilization is the lack of referral of patients with intractable epilepsy to centers that perform such operations. Importantly, patients are referred to a comprehensive epilepsy program not strictly for a "surgical procedure" but for an assessment to determine an appropriate treatment for the seizure disorder.
Overall.-Finally, a critical element in the patient's care is an empathetic and interested physician who exudes a sense of hope to the patient. In patients with intractable epilepsy who are not candidates for surgical treatment or investigational drug studies, the appropriate approach may be to use high-dose monotherapy with carbamazepine or phenytoin, or two AEDs in combination, in an attempt to avoid the most cognitively impairing drugs. 13,39 The goals in these patients may be to reduce the frequency of seizures that are most likely to cause injury (complex partial seizures and secondarily generalized tonic-clonic seizures). Recognizing and avoiding precipitants of seizures such as sleep deprivation may decrease the frequency of the seizures. Importantly, vocational rehabilitation and counseling about education and employment should not be deferred because of the intractable seizures.
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Jack CR Jr, Sharbrough FW, Twomey CK, Cascino GD, Hirschorn KA, Marsh WR, Zinsmeister AR, Scheithauer B: Temporal lobe seizures: lateralization with MR volume measurements of the hippocampal formation. Radiology 175:423-429, 1990 Lesser RP, Pippenger CE, Luders H, Dinner DS: High-dose monotherapy in treatment of intractable seizures. Neurology 34:707-711,1984 Schmidt D: Two antiepileptic drugs for intractable epilepsy with complex-partial seizures. J Neurol Neurosurg Psychiatry 45:1119-1124,1982 Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, Williamson PD, Treiman DM, McNamara JO, McCutchen CB, Homan RW, Crill WE, Lubozynski MF, Rosenthal NP, MayersdorfA: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 313:145-151, 1985 Engel J Jr: Seizures and Epilepsy. Philadelphia, FA Davis Company, 1989, pp 410-442 Schmidt D: Drug-resistant partial epilepsy: clinical and pharmacological criteria. In Presurgical Evaluation of Epileptics. Edited by HG Weiser, CE Elger. Berlin, Springer-Verlag, 1987, pp 321-324 Engel J Jr: Seizures and Epilepsy. Philadelphia, FA Davis Company, 1989, pp 443-474 Andermann F: Identification of candidates for surgical treatment of epilepsy. In Surgical Treatment of the Epilepsies. Edited by J Engel Jr. New York, Raven Press, 1987, pp 51-70 Chugani HT, Shewmon DA, Peacock WJ, Shields WD, Mazziotta JC, Phelps ME: Surgical treatment of intractable neonatal-onset seizures: the role of positronemission tomography. Neurology 38:1178-1188, 1988 Walczak TS, Radtke RA, McNamara JO, Lewis DV, Luther JS, Thompson E, Wilson WP, Friedman AH, Nashold BS: Anterior temporal lobectomy for complex partial seizures: evaluation, results, and longterm follow-up in 100 cases. Neurology 40:413-418, 1990 Crandall PH: Role of neurosurgery in management of medication-resistant epilepsy. In Plan for Nationwide Action on Epilepsy. Vol 2, Part 2. Publication No. NIH 78-277. Washington, DC, US Government Printing Office, 1977, pp 327-334 Hauser A: Postscript: how should outcome be determined and reported? In Surgical Treatment of the Epilepsies. Edited by J Engel Jr. New York, Raven Press, 1987, pp 573-579 Theodore WH, Porter RJ: Removal of sedative-hypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann Neurol 13:320324, 1983
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Intractable Partial Epilepsy: Evaluation and Treatment
GREGORY D. CASCINO, M.D., Department ofNeurology
Partial (focal or localization-related) epilepsy is the most common seizure disorder encountered in patients with epilepsy. These seizures are focal at onset-that is, emanating from a localized region of the brain. Patients with partial epilepsy may have seizures that are refractory to antiepileptic drug medication. The financial burden for these patients includes the cost of medical care and often the loss of employment. Psychosocial deterioration may be progressive as long as the seizures are intractable. Management includes confirmation of the type (or types) of seizures, exclusion ofan intracranial epileptogenic lesion, and use ofappropriate antiepileptic drug therapy. Referral of affected patients to a comprehensive epilepsy center for possible surgical treatment and investigational drug studies should be considered. In the care ofthe patient with intractable partial epilepsy, the goals should be to render the patient free of seizures and to allow the patient to become a participating and productive member of society.
Partial epilepsy affiicts an estimated 800,000 patients in the United States.':" The types of seizures represented are simple and complex partial seizures and secondarily generalized tonic-clonic seizures." Simple partial seizures are manifested by sensory, motor, autonomic, or psychic symptoms without an impairment of consciousness. Complex partial seizures are characterized by an alteration in mentation and may initially begin as a simple partial seizure. Classifying these seizures as psychomotor or temporal lobe seizures should be avoided be-
Address reprint requests to Dr. G. D. Cascino, Department of Neurology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 65:1578-1586, 1990
cause these terms are ambiguous and may lead to an incorrect localization ofthe site of onset of the seizures. Complex partial seizures constitute almost 55% of seizures in adults, and approximately 80% ofthese seizures are oftemporallobe origin." Most frequently, extratemporal partial seizures emanate from the frontal lobes. 5 Most generalized tonic-clonic or "grand mal" seizures in adults are of partial onset. Simple partial or complex partial seizures may progress to a secondarily generalized seizure." Approximately 30% of patients with partial epilepsy have mass lesions-for example, neoplasms or vascular malformations-as the cause of their seizure disorders." Underlying pathologic findings in partial epilepsy also include
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posttraumatic brain lesions and heterotopias. The most common pathologic alteration in patients with seizures beginning in the temporal lobe is mesial temporal sclerosis. 6 The relative biologic intractability of the partial epilepsies-that is, seizures refractory to medical therapy-has been substantiated. 1 Potential causes of poorly controlled seizures include incorrect classification of the seizures, inadequate antiepileptic drug (AED) therapy, poor compliance with AED therapy, competing epileptogenic drugs such as phenothiazines, and biologically intractable epilepsy.' Seizures are considered intractable when they persist despite maximally tolerated monotherapy or combination AED therapy. Approximately 45% of the patients with a partial seizure disorder, an estimated 360,000 patients in the United States, are medically refractory.l-? Potential variables that can adversely affect AED response include the presence of developmental delay, seizures related to a mass lesion-for example, a glioma-and an increased latency before institution of appropriate therapy.l-" Epilepsia partialis continua is a partial epileptic syndrome remarkable for continuous or frequent focal motor seizures that characteristically are refractory to AEDs.1 The long-term prognosis of patients with partial epilepsies may be indicated by the initial response to AED therapy, even within the first 2 years.i-? Psychosocial difficulties-for example, impaired socialization and inability to obtain an education and employment-can be progressive as long as the epilepsy is intractable.l-l'v'! Cognitive performance may be impaired not only by refractory epilepsy but also by the neurotoxicity of AED therapy, even at therapeutic plasma levels.l-P Successful treatment of the seizure disorder can appreciably improve psychologic, social, sexual, and behavioral functions.t''-!' Polypharmacy (that is, concurrent use of multiple AEDs) seems to produce more severe adverse behavioral effects than does single-drug therapy. 12 The cost of the medical care for assessing and treating patients with intractable epilepsy is considerable, but this investment must be com-
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pared with the financial burden of unemployment and AED therapy in these patients. Importantly, the care and management of the patient with epilepsy must go beyond rendering the patient free of seizures; an attempt must also be made to improve the quality of life for the patient.
ASSESSMENT OF PATIENTS
The initial steps in the assessment of the patient with presumed medically refractory partial epilepsy are to confirm the diagnosis of a seizure disorder and to classify the type of seizure. 1 Seizures are remarkable for being stereotypic, recurrent, and usually unprovoked clinical events. Behavior ofthe Patient.-Obtaining information about the ictal and postictal behavior may be useful in the classification of type of seizure. Some patients may have multiple types of seizures-for example, simple partial, complex partial, and simple partial progressing to secondarily generalized tonic-clonic seizures. Patients with complex partial seizures may be amnesic for the details of the ictal episodes and the postictal state;" therefore, a reliable observer who has witnessed the seizures should be interviewed. Patients with simple partial seizures may be appropriately aware of their ictal symptoms. 14 More than 50% of patients during complex partial seizures acknowledge the presence of an aura (the functional onset of seizure activity before an alteration in consciousness), which may be useful in localizing the onset of seizures.!" Examples of an aura are an emotional or a visceral sensation." Patients may quickly learn to recognize the aura as the onset of a seizure. The description of complex partial seizures usually emphasizes the lack of motor or verbal activity; often the patient is noted to have a motionless stare and does not respond appropriately to auditory stimulation.v" The patient may have associated spontaneous automatisms that are oroalimentary (such as lip smacking) or gestural (such as picking movements with the fingers)." Patients who have auras associated with complex partial seizures usually also have
1580 INTRACTABLE PARTIAL EPILEPSY
independent simple partial seizures.P Organized or purposeful behavior is unusual in patients during a complex partial seizure, although a postictal state may be confused with the ictal episode. A complex partial seizure may last for only several minutes; however, postictal confusion or altered behavior may persist for longer. The ictal behavior may indicate the localization of the onset of seizures-for example, partial seizures beginning in the primary motor or sensory cortex. 4 ,5 ,13,14 Clues about the lateralization of the onset of seizures include ictal paretic posturing of an upper extremity, ictal dysphasia, and the presence of a postictal neurologic deficit such as a hemiparesis.v" At onset, secondarily generalized seizures may not be associated with focal seizure activity that can be recognized clinically. Forced version manifested by maximal deviation of the head, neck, and trunk is a reliable indicator of the lateralization of the onset of seizures in patients with partial epilepsy.!" Unfortunately, partial seizures emanating from the temporal lobe, especially the mesial temporal region, may not be associated with ictal phenomena that allow lateralization of the onset of seizures." Ictal and postictal antegrade amnesia and confusion are unreliable lateralizing signs in patients with complex partial seizures.v-" History andExamination.-The neurologic history and examination may indicate the cause ofthe seizure disorder and the localization ofthe onset ofseizures. In 28% of patients with partial epilepsy, the cause ofthe seizures, such as stroke or head trauma, can be determined. 3 Patients with seizures symptomatic of a previous neurologic insult are more likely to have a medically refractory seizure disorder than are other patients.' The most common findings on examination are AED effects (for example, nystagmus and ataxia) and cognitive alterations (for example, memory loss). A focal neurologic deficit may indicate the lateralization of the onset of seizures. Electroencephalography.-Common diagnostic errors in patients with complex partial seizures are the classification of the type of seizure as "petit mal"-that is, absence seizures-
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or nonepileptic behavioral events.v'" Absence seizures are a type of primary generalized epilepsy that does not respond to the AEDs that are often used to treat partial epilepsy. Important differences are evident in the ictal behavior and the electroencephalographic (EEG) findings in patients with absence and complex partial seizures." The diagnostic confusion between nonepileptic events, especially psychogenic seizures, and complex partial seizures may necessitate prolonged video EEG monitoring for classification of the seizures.v" Patients with complex partial seizures may also have coexisting psychogenic seizures that complicate the medical treatment. 17 The EEG is the most commonly used diagnostic study in the assessment of patients with partial epilepsy.P-" The low diagnostic yield of the routine awake EEG recording in these patients has been reported. 18 Sleep deprivation and a sleep EEG recording may be useful for disclosing epileptiform activity that is not evident in the awake record'" (Fig. I), Activation procedures such as hyperventilation and photic stimulation may also be useful for recording epileptiform activity. The most reliable EEG abnormality in patients with complex partial seizures of temporal lobe origin is an interictal spike or sharp-wave discharge in one temporal lobe. 13 ,18 Intermittent focal rhythmic slow-wave activity may also occur without accompanying spikes.Pi'" The AED medication (including drug levels) and the time ofthe last seizure should be known when the EEG study is interpreted. Supplementary electrodes such as sphenoidal and anterior temporal electrodes may be useful for recording epileptiform activity emanating from the anterior temporal lobe. 13 ,19 A normal interictal (that is, between seizure episodes) wake and sleep EEG does not exclude a partial seizure disorder. The EEG may also be false positive-for example, nonepileptiform EEG alterations may be misinterpreted and lead to the incorrect diagnosis of a seizure disorder (Fig. 2), The limitations of interictal EEG recordings in patients with seizures have led to the expanded use of prolonged video EEG monitoring. Prolonged monitoring can be performed as
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RIGHT TEMPORAL SHARP WAVES
cJ Age: 22yrs
Fp1- F7 --v-''--'~~~~~'\r-'-v-v'''--'~-v''-~'''''''''-
Ft: T3 "'V'"~~~~~""--,,-,"",,,,J',r.A,,,,-,/~~~,,,",-~ T3- T5
--.rv--~'-..J"""v-oIVVV~---.J"\rv"'--~""",'--v--~~"",
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INTRACTABLE PARTIAL EPILEPSY 1581
renchymal abnormalities in the brain. X-ray computed tomography and magnetic resonance imaging are noninvasive studies that can determine the cause ofthe seizure disorder and assist in localizing the epileptogenic area (the site of the onset ofthe seizuresl.P Magnetic resonance imaging has been demonstrated to be superior to computed tomography in imaging epileptogenic lesions in patients with intractable partial epilepsy'" (Fig. 3). Low-grade and malignant gliomas may not be detected by computed tomography; however, the sensitivity and specificity of magnetic resonance imaging for revealing these lesions have been shown.s! Magnetic resonance imaging is the structural imaging procedure of choice in patients with intractable partial epilepsy.24-26 The methods of magnetic resonance imaging are a critical determinant in the diagnostic yield of these studies in patients with epilepsy." A gadolinium-diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging scan may be useful in indicating the pathologic features of a mass lesion'" (Fig. 4). Gadolinium, however, does not seem to reveal abnormalities that are not identified in the unenhanced image in patients with epilepsy." Several contraindications to magnetic resonance imaging include the presence of a metallic foreign body in the head or neck, a cardiac pace-
an outpatient or inpatient procedure, and the EEG can be correlated with the video-recorded seizure.P-" During inpatient monitoring, AEDs can often be withdrawn to provide a better opportunity for ictal recordings. The utility of inpatient EEG monitoring has been demonstrated relative to the accurate classification of type of seizures, which allows selection of appropriate therapy." In patients in whom the clinical manifestations and interictal EEG studies do 9 Ag" 731" 19-20-841 Fp1-F7 ~~~._~-v~~._~~'--~,_ not provide the necessary information, prolonged F7-T3~~~~~.~'~ video EEG monitoring may be useful before T3-T5~v-"'~t'_·~~~ selection of potentially toxic AEDs. Importantly, T5-01~~~-~v,~~ the absence of scalp-recorded EEG alterations has been verified during partial seizures offronFp2-Fa~~~ tal lobe origin and during simple partial seiFa-T4 --~~--------------.,"""-'~~-w/Yv-_~~~~ zures.P A prominent activation of epileptiform activity may be identified after a seizure, which T6-02 ~~...rV~~~-r-A-.r"-~"Vv'~~~..rv---.iV~ may be useful for classification ofthe type of sei~50pV 1 sec zures and for localization of the onset ofthe seizures." Ultimately, epilepsy is a clinical diagnosis, and the EEG may provide only supportive Fig. 2. Electroencephalogram in 73-year-old woman, showing several benign sporadic sleep spikes (small sharp spikes) information. in left temporal region. These discharges are nonepileptiNeuroimaging.-In patients with partial form and are not associated with an increased epileptogenic epilepsy, neuroimaging may identify intrapa- potential.
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the hippocampal formation may detect hippocampal atrophy in patients with seizures emanating from the temporal lobe. 27 In the routine assessment of patients with partial epilepsy, no role exists for a conventional radionuclide brain scan or skull roentgenogram. Cerebral arteriography should be performed in patients with partial epilepsy who have a suspected vascular malformation or an intracranial aneurysm or before a surgical procedure for epilepsy or resection of an epileptogenic lesion.
Fig. 3. Magnetic resonance image, showing an abnormality in left frontal lobe. Cortical dysplasia was demonstrated at time of surgical resection. (Note: The left cerebral hemisphere is on the right side of the photograph.)
maker, excessive patient body size, and patient claustrophobia." Sedation of the patient may be necessary. If a magnetic resonance imaging study is not possible, noncontrast and contrastenhanced computed tomography should be performed. If the initial computed tomographic study shows no abnormalities, a repeat scan should be obtained 6 to 12 months later because of the possibility of a false-negative study in patients with a neoplastic lesion. Computed tomography may complement magnetic resonance imaging in patients with calcified lesions and bony abnormalities. 19 The limitations of computed tomography and magnetic resonance imaging in depicting a sclerotic lesion, such as mesial temporal sclerosis or cortical gliosis, have been demonstrated.w" Unfortunately, despite the sensitivity and specificity of magnetic resonance imaging in detecting mass lesions, results of the studies are normal in a substantial percentage of patients with intractable partial epilepsy.25-27 Additional magnetic resonance imaging techniques such as volume measurements of
MANAGEMENT The treatment of patients with partial epilepsy begins with the appropriate counseling for the patient and family about the diagnosis of a seizure disorder. Misconceptions (for example, that epilepsy is a form of mental illness) need to be clarified immediately. Questions concerning employment, driving, parenting children, and the cost of medical care should be addressed. If the physician is unfamiliar with driving laws in a particular state, the information can be obtained through a department of motor vehicle registration or the Epilepsy Foundation of America (4351 Garden City Drive, Landover, MD 20785). The patient should be encouraged to obtain further information about epilepsy from this organization. The assistance of social services in obtaining benefits for the patient with intractable epilepsy is often essential in providing high-quality medical care for the patient. Patients who are unable to work because of their seizures may be entitled to disability funds. Certain "environmental hazards"-for example, lack of transportation and inability to afford AEDs-have a negative effect on treatment. Drug Therapy.-The selection of an AED is the most important decision the physician will make after conclusion of the diagnostic evaluation. Empiric trials of AEDs in attempts to clarify the diagnosis are discouraged because of the intermittence of the symptoms and the potential toxicity associated with the treatment. Many patients with intractable partial epilepsy who take multiple AEDs are noted to have symptoms of chronic AED toxicity, including
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Fig. 4. Gadolinium-diethylenetriaminepentaacetic acidenhanced magnetic resonance image, revealing a lesion that proved to be a grade 2 oligodendroglioma in the right temporal lobe. (Note: The right cerebral hemisphere is on the left side of the photograph.) (From Cascino and associates.P By permission of Edgell Communications, Inc.)
drowsiness, ataxia, and diplopia. AED toxicity may occur even with therapeutic or subtherapeutic AED levels." The secondarily generalized tonic-clonic seizures are often more responsive to AED treatment than are the simple and complex partial seizures. Even in patients who seem medically refractory, consideration of high-dose monotherapy may be appropriate. 28 Documentation ofAED levels for previously used AEDs is essential. Patients may require higher levels of AEDs than the "therapeutic range."13,28 Monotherapy is associated with less toxicity at higher drug levels and better AED compliance than is polypharmacy. Knowledge about the pharmacokinetics of AEDs is essential for the correct use of these medications. Unnecessarily frequent dosing intervals, such as phenobarbital administered three times daily, may lead to noncompliance. Addition of a second AED is associated with complete seizure control in only 11 to 13% of patients and the development of AED toxicity in 90% of patients.29,30 Overuse of
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AED plasma levels may not allow patients the maximal benefit from a specific drug. Patients should receive maximally tolerated monotherapy before substituting AED medication. 13,28 Reducing the dosage of an AED because of a "high" plasma level in a patient who is seizurefree and tolerating a medicine well is a potential hazard of frequent AED level determinations. The drugs of choice for the partial epilepsies, including the secondarily generalized seizures, are carbamazepine and phenytoin. 13,30-32 The preference ofcarbamazepine or phenytoin as the initial AED depends on several factors, including the cost of medication, frequency of drug dosing, drug-related side effects, and previous experience with the medication.P! The drugs have different potential idiosyncratic and doserelated toxicity; however, at present, no definite evidence shows that one is more effective than the other." If a previous AED history is unavailable, maximally tolerated monotherapy with carbamazepine or phenytoin should be considered before medically refractory partial epilepsy is diagnosed. Other potentially useful medications include valproate sodium, phenobarbital, and primidone. 13,31,32 None of these drugs has been proved to be more efficacious than the two aforementioned primary AEDs. Phenobarbital and primidone are barbiturates and may be associated with increased drowsiness, irritability, hyperkinetic activity in children, and memory loss. 1,31 Valproate sodium is an excellent drug for the primary generalized epilepsies; ongoing trials are studying its efficacy in the partial epilepsies. Third-line AEDs that may be considered include clonazepam, clorazepate dipotassium, and methsuximide."! The benzodiazepine drugs, clonazepam and clorazepate, have toxicity similar to that for the barbiturates, and tachyphylaxis may develop. Methsuximide is a potentially effective AED; however, toxicity is also a definite problem. Other AEDs that have been used in the treatment of the partial epilepsies include acetazolamide, ethotoin, mephenytoin, and phenacemide." Because of inferior efficacy in comparison with the other AEDs or considerable toxicity (or both), these AEDs are rarely
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used. Unfortunately, most patients who fail to obtain adequate control of seizures with highdose monotherapy with carbamazepine or phenytoin do not become seizure-free with use of other AEDs.
Comprehensive Epilepsy Program.-If
seizures persist despite use of the foregoing therapeutic regimens, referral of the patient to a comprehensive epilepsy program should be considered. The names and addresses of epilepsy centers in the United States can be obtained from The National Association of EpilepsyCenters, 2701 University Avenue SE, Suite 105, Minneapolis, MN 55414. Additional medication trials with use of currently available AEDs may be undertaken. Two potential therapeutic programs that can be considered are enrollment in an investigational drug study and a surgical procedure for epilepsy. Investigational Drug Studies.-Many AEDs that have not been approved by the Food and Drug Administration are being evaluated at several epilepsy centers. These medications include nimodipine, felbamate, gabapentin, vigabatrin, and lamotrigine.>' Several of these drugs may be approved by the Food and Drug Administration in the next few years. These drug studies have strict inclusion criteria, and not all patients will be considered appropriate candidates. Recurrent visits to the epilepsy center, the need for careful monitoring of the frequency of seizures, and the occurrence ofdrug side effects are required. Despite the promise of these new AEDs, most patients in investigational drug studies do not become seizure-free. To obtain a driver's license in most states, the applicant must be seizure-free for an established period. Surgical Treatment.-An ablative surgical procedure, such as resection of focal epileptogenic cortex, is the most effective method currently available to render children and adults with intractable partial epilepsy seizure-free." Potential candidates include patients (even infants) with medically refractory partial epilepsy who have seizures emanating from a localized region of the brain that can be resected without neurologic morbidity.Pr" Patients with severe
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psychiatric disease, mental retardation, involvement of essential cortex such as sensory or motor areas, or a multifocal seizure disorder are excluded. 3 3 ,34 Surgical treatment has also been attempted in infants with intractable seizure disorders. In general, the seizures must be socially disabling, and the patient should be motivated to undergo the presurgical evaluation and the operative procedure." An important issue that must be considered is the potential for improvement in the quality oflife after successful surgical treatment.v" Patients with generalized or bilateral independent interictal epileptiform activity should not be excluded without appropriate ictal EEG recordings. 33 Drug-related toxicity leading to noncompliance may not be a reason for exclusion of a surgical candidate. Patients with an epileptogenic area in the language dominant hemisphere may also be appropriate operative candidates." Surgical treatment of epilepsy should not be considered as a last resort after all combinations of AEDs have been tried. The longer the duration of intractability, the greater the risk of psychosocial deterioration and secondary epileptogenesis.' If after 2 years of appropriate AED trials with use of the first- and second-line AEDs the patient is medically refractory, referral to a comprehensive epilepsy program should be considered. The most common surgical procedure performed for partial epilepsy is a focal cortical resection in the temporal lobe, an anterior temporallobectomy. The goals of surgical treatment are to eliminate seizures, reduce AED toxicity, and avoid neurologic morbidity.P Approximately 60% of patients will be seizure-free after an anterior temporal lobectomy, and almost 80% of patients will experience a substantial reduction in seizure activity.?" In select patients, depending on the surgical outcome and postoperative EEG recordings, AEDs may ultimately be completely withdrawn. The surgical outcome is not as favorable for extratemporal surgical procedures, especially frontal lobe operations." Freedom from complex partial and secondarily generalized tonicclonic seizures postoperatively may be consid-
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ered a favorable surgical outcome, even ifsimple partial seizure activity persists. The operative mortality rate for surgical treatment ofepilepsy is approximately 1 in 400. 13 The potential morbidity depends on the localization of the epileptogenic area. A comprehensive presurgical evaluation is necessary, including an ictal EEG recording, neuropsychologic and speech-language studies, testing of visual perimetry, a magnetic resonance imaging scan of the head (preferably with quantitative temporal volume studies), and cerebral arteriography. 34 Functional imaging studies for assessment of cerebral metabolism (positron emission tomography) and blood flow (single photon emission computed tomography) may also be included in the diagnostic evaluation at some centers. 19,33,34 An intracarotid amobarbital sodium study is performed to determine language dominance and to assess memory in the contralateral temporal lobe. Chronic intracranial EEG monitoring with use of depth electrodes and subdural grids may be necessary for localization of the epileptogenic area." Intraoperative or extraoperative functional mapping may be used to delineate functional areas of the cerebral cortex. The cost of the presurgical evaluation and the operative procedure is considerable-approximately $20,000 when chronic intracranial monitoring is not performed. 13 Most patients who undergo a surgical procedure for epilepsy are young adults who are otherwise in good health; therefore, their reduced cost for future medical care and their potential earnings need to be considered. An estimated 75,000 of the 360,000 patients in the United States with intractable partial seizure disorders are candidates for surgical treatment; however, only several hundred surgical procedures for epilepsy are performed in the United States each year. 37 ,38 A major reason for this underutilization is the lack of referral of patients with intractable epilepsy to centers that perform such operations. Importantly, patients are referred to a comprehensive epilepsy program not strictly for a "surgical procedure" but for an assessment to determine an appropriate treatment for the seizure disorder.
Overall.-Finally, a critical element in the patient's care is an empathetic and interested physician who exudes a sense of hope to the patient. In patients with intractable epilepsy who are not candidates for surgical treatment or investigational drug studies, the appropriate approach may be to use high-dose monotherapy with carbamazepine or phenytoin, or two AEDs in combination, in an attempt to avoid the most cognitively impairing drugs. 13,39 The goals in these patients may be to reduce the frequency of seizures that are most likely to cause injury (complex partial seizures and secondarily generalized tonic-clonic seizures). Recognizing and avoiding precipitants of seizures such as sleep deprivation may decrease the frequency of the seizures. Importantly, vocational rehabilitation and counseling about education and employment should not be deferred because of the intractable seizures.
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Jack CR Jr, Sharbrough FW, Twomey CK, Cascino GD, Hirschorn KA, Marsh WR, Zinsmeister AR, Scheithauer B: Temporal lobe seizures: lateralization with MR volume measurements of the hippocampal formation. Radiology 175:423-429, 1990 Lesser RP, Pippenger CE, Luders H, Dinner DS: High-dose monotherapy in treatment of intractable seizures. Neurology 34:707-711,1984 Schmidt D: Two antiepileptic drugs for intractable epilepsy with complex-partial seizures. J Neurol Neurosurg Psychiatry 45:1119-1124,1982 Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, Williamson PD, Treiman DM, McNamara JO, McCutchen CB, Homan RW, Crill WE, Lubozynski MF, Rosenthal NP, MayersdorfA: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 313:145-151, 1985 Engel J Jr: Seizures and Epilepsy. Philadelphia, FA Davis Company, 1989, pp 410-442 Schmidt D: Drug-resistant partial epilepsy: clinical and pharmacological criteria. In Presurgical Evaluation of Epileptics. Edited by HG Weiser, CE Elger. Berlin, Springer-Verlag, 1987, pp 321-324 Engel J Jr: Seizures and Epilepsy. Philadelphia, FA Davis Company, 1989, pp 443-474 Andermann F: Identification of candidates for surgical treatment of epilepsy. In Surgical Treatment of the Epilepsies. Edited by J Engel Jr. New York, Raven Press, 1987, pp 51-70 Chugani HT, Shewmon DA, Peacock WJ, Shields WD, Mazziotta JC, Phelps ME: Surgical treatment of intractable neonatal-onset seizures: the role of positronemission tomography. Neurology 38:1178-1188, 1988 Walczak TS, Radtke RA, McNamara JO, Lewis DV, Luther JS, Thompson E, Wilson WP, Friedman AH, Nashold BS: Anterior temporal lobectomy for complex partial seizures: evaluation, results, and longterm follow-up in 100 cases. Neurology 40:413-418, 1990 Crandall PH: Role of neurosurgery in management of medication-resistant epilepsy. In Plan for Nationwide Action on Epilepsy. Vol 2, Part 2. Publication No. NIH 78-277. Washington, DC, US Government Printing Office, 1977, pp 327-334 Hauser A: Postscript: how should outcome be determined and reported? In Surgical Treatment of the Epilepsies. Edited by J Engel Jr. New York, Raven Press, 1987, pp 573-579 Theodore WH, Porter RJ: Removal of sedative-hypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann Neurol 13:320324, 1983