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When Medications Fail to Control Seizures: a Case for Nonpharmacologic Options

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When Medications Fail to Control Seizures: a Case for Nonpharmacologic Options When Medications Fail To Control Seizures: A Case for Nonpharmacologic Options SELIM R. BENBADIS, MD Director, Comprehensive Epilepsy Program Associate Professor, Departments of Neurology and Neurosurgery University of South Florida, Tampa General Hospital Introduction ith a prevalence of 1% to 2%, epilepsy is a com- mon neurologic disorder.1 Not only is it one of the most common conditions seen in neurology practices, but it also affects young people in their prime working and reproductive years. While Wabout 70% of patients with seizures are controlled with medica- tions, approximately 30% are not.1,2 Thus, a standard general neu- rology practice inevitably includes a sizable number of patients with refractory seizures. A growing concern is that neurologists fail to identify and refer these patients, or do so too late. This is vividly illustrated by 2 facts: 1) the average delay from onset to correct diagnosis of psychogenic nonepileptic seizure (PNES) is 7 years3; 2) for patients who ultimately become seizure-free after surgery, the average delay from seizure onset to referral to an epilepsy surgery center is >15 years.4 There are basically 3 reasons why drugs may not work, which will all be discussed in this review: 1. The seizure-like episodes are not epileptic; 2. The medications chosen are not effective for the given epilepsy type; or 3. The epilepsy is medically intractable. The Misdiagnosis of Epilepsy The erroneous diagnosis of epilepsy is not rare and represents a significant problem.5,6 About one quarter of patients previously diagnosed with epilepsy are eventually found to be misdiagnosed, both in a referral epilepsy clinic and in epilepsy monitoring units.5,6 Many patients misdiagnosed as having epilepsy are even- tually shown to have PNES7 or syncope.8,9 Occasionally, other paroxysmal conditions can be misdiagnosed as epilepsy,including complicated migraines, paroxysmal movement disorders, and sleep disorders. However, PNES and syncope are by far the most common conditions mistaken for epilepsy.Very often, electroen- cephalograms (EEGs) interpreted as providing evidence for epilepsy contribute to this misdiagnosis.4,5,10 Whenever an erroneous diagnosis of epilepsy is made,it is noto- riously difficult to “undo.” Subsequent normal EEGs, of course, never exclude the possibility of epilepsy, and it is necessary for the specialist (epileptologist, electroencephalographer) to obtain the actual EEG previously read as abnormal. Surprisingly, the majority of these records show “nameless variants,”ie,fluctuations 36 CNS NEWS • NOVEMBER 2002 Table. Goals That Can Be Achieved Through the Use of EEG Monitoring • Confirm the diagnosis of epilepsy. This is critical, since a sizable 15% to 30% of patients referred for refractory seizures do not have epilepsy, but have psychogenic nonepileptic seizures. • Determine whether the epilepsy is localiza- tion-related or generalized, as defined by the International League Against Epilepsy. • Distinguish, among generalized epilepsies, between the idiopathic (formerly called “primary,” now better termed genetic) type, and the symptomatic (cause known) and cryptogenic (cause unknown), formerly called “secondary” type. • Differentiate, among localization-related epilepsies, between mesiotemporal and extratemporal/neocortical epilepsy. of normal rhythms that do not fit into a well- misdiagnosed as epilepsy,largely because syncopal acid [Depakene/Depakote, Abbott; others], lamo- described EEG waveform.10 Variants of alpha activi- attacks are quite often associated with abnormal trigine [Lamictal, GlaxoSmithKline], topiramate ty are by far the main offender, especially the wide- movements. This issue has been studied by delib- [Topamax, Ortho-McNeil], levetiracetam [Keppra, spread, unusually sharply contoured variants, as erately inducing syncope in patients, either to test UCB Pharma], and zonisamide [Zonegran, Elan]) are well as during early periods of drowsiness, when automatic implantable defibrillators,15 during tilt- considered “broad-spectrum,”in the sense that they alpha waves become fragmented and isolated.10,11 table testing,9 or in healthy volunteers.16 In these work in all types of epilepsies—localization-related Psychogenic nonepileptic seizures are by far the situations, motor manifestations, either tonic-like and generalized. most common condition misdiagnosed as epilepsy. or clonic-like, are present in 45% to 90% of A clear syndromic diagnosis can usually be The estimated prevalence in the general population attacks,9,15,16 explaining why they could easily be established with an abnormal EEG, together with is 2 to 33 per 100,000, making this problem nearly described as “convulsions.” Because syncopal the history and examination, but if the routine as common as multiple sclerosis or trigeminal neu- episodes are usually not frequent (unlike PNES), EEG is normal, the diagnosis may require EEG ralgia.12 A number of “red flags,” in addition to the and cannot be induced by suggestion, EEG video video monitoring. lack of response to antiepileptic drugs (AEDs), are monitoring is of less value in the diagnosis of the useful in clinical practice, and should raise the sus- condition. Occasionally, tilt-table testing can trig- Medically Intractable Epilepsy picion that “seizures” may be psychogenic rather ger a typical attack and lead to the correct diagno- Definition of intractability. Exactly how many than epileptic. Certain characteristics of the motor sis, but usually the clinician has to rely on patient AEDs should be tried, in what combination, and for (“convulsive”) phenomena are associated with history alone (precipitating circumstances, pro- how long, before deeming epilepsy “intractable” is PNES:slow or very gradual onset or termination;dis- dromes, etc). no longer debated. It is now well known that the continuous, interrupted, irregular, or asynchronous likelihood of achieving seizure control declines (out-of-phase) movements; other specific types of Epilepsy With Incorrect Syndromic rapidly after the first few unsuccessful trials, and movements (side-to-side head shaking, pelvic thrust- Diagnosis clinical practice supports the view that when the ing, opisthotonic posturing, bilateral movements The treatment of a “seizure disorder”without any first few regimens fail,the probability of future con- with preserved awareness); and weeping. attempt at a more precise syndromic diagnosis can trol with an AED drops precipitously.Several recent Electroencephalogram video monitoring allows result in ineffective treatment.17,18 The most com- studies have documented this important con- the diagnosis of PNES to be made with near certainty. mon situation encountered in practice is the use of cept,2,21,22 and there is now convincing evidence In some instances,it is helpful to use provocative tech- a narrow-spectrum AED in a patient with an idio- that intractability reveals itself early. While the niques or “inductions”—many epilepsy centers use pathic generalized epilepsy (IGE) syndrome, such chances of success with new medications are prob- such techniques to aid in the diagnosis. When cor- as juvenile myoclonic epilepsy.19 Narrow-spectrum ably never zero (ie, a new drug may prove to be rectly performed and interpreted (paying specific AEDs include phenytoin (Dilantin, Pfizer; Phenytek, effective in a given patient), these data would sup- attention to confirming that the habitual episode was Bertek; others), carbamazepine (Carbatrol, Shire US; port the idea that nonpharmacologic options induced), specificity of provocative techniques for Tegretol, Novartis; others), oxcarbazepine (Trilep- should be examined early, as is generally recom- diagnosis of PNES approaches 100%, a rare luxury in tal, Novartis), gabapentin (Neurontin, Pfizer), and mended.21,23,24 It is also important to recognize that medicine. Inductions have many advantages, but are tiagabine (Gabitril, Cephalon). While the choice of drug failure should be defined as either persistent somewhat controversial.13,14 However, many ethical AED is of little consequence when treating a local- seizures, or seizure control obtained only at the objections are circumvented by the fact that activa- ization-related epilepsy, the use of these narrow- expense of causing unacceptable side effects (ie, tions can be performed without the use of placebos.13 spectrum agents in IGE typically fails to control being seizure-free but unable to walk, think, and/or Despite the availability of EEG video monitoring, seizures,and in fact may worsen seizure types other see because of side effects constitutes a drug fail- which allows PNES to be diagnosed with nearly than generalized tonic-clonic, such as absence and ure). Finally, it should be emphasized that in addi- 100% certainty, the average delay in diagnosis of myoclonic seizures.19,20 Since phenytoin and carba- tion to seizure severity and frequency,psychosocial PNES remains long,3 indicating that the index of mazepine are the 2 most commonly used first-line morbidity may be important in the indication for suspicion for PNES may not be high enough. agents in the United States, this situation arises nonpharmacologic treatments, including surgery. Syncope is the second most common condition quite often.Other AEDs (eg,phenobarbital,valproic For example, a seizure frequency of 3 per year is CNS NEWS • NOVEMBER 2002 37 enough to prevent driving and can cer- 4. Benbadis SR, Heriaud L, Tatum WO,Vale F.Epilepsy surgery, First Things First: An delays, and referral patterns. Seizure.In press. tainly affect
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