Medically Refractory SeizuresDavid R. Chabolla, M.D.
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Table 1. Features Of Medically Intractable Seizures |
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| Etiologies: | mesiotemporal sclerosis, tuberous sclerosis, Sturge-Weber syndrome, cerebral tumors, hamartoma, AVMs, developmental malformations, and sequela of cerebral infections, infarcts or trauma |
| Catastrophic epilepsies: | West syndrome, Lennox-Gastaut syndrome, progressive myoclonic epilepsy, and cerebral metabolic disorders |
| Common seizure types: | complex partial, tonic, atonic, and atypical absence |
| Common clinical features: | mental retardation, focal neurologic deficits, and concurrent psychiatric illness |
The direct cost of assessing and treating patients with intractable epilepsy ranges from 3 to 4 billion dollars annually (16 billion combined direct and indirect costs) in the United States.3 The burden of epilepsy, however, is much greater than the heavy financial costs. Epilepsy adversely affects quality of life and often impacts multiple members of a family.
Medically refractory seizures produce many psychological and social difficulties. Recurrent seizures impair socialization and psychological development during formative years and may lead to an inability to obtain an education, gainful employment, or driving privileges. The development of a learned helplessness and low self-esteem can worsen as long as epilepsy is intractable. Cognitive performance may be impaired by refractory epilepsy as well as by the effects of AED therapy. Successful treatment of a seizure disorder can appreciably improve psychological, social, sexual, and behavioral functions.
The initial steps in the assessment of a patient with medically refractory epilepsy are to confirm the diagnosis of a seizure disorder and to classify the seizure type(s). At a minimum, classification entails categorizing a seizure disorder into either partial onset or primarily generalized onset forms of epilepsy. Prognosis, etiology, and treatment options are all predicated on the distinction between partial onset and primarily generalized onset epilepsy.
Obtaining information about the ictal and post-ictal seizure behavior may be useful in the classification of seizure type. Some patients may describe multiple types of seizures that may aid in the classification. For example, descriptions of simple partial seizures, complex partial seizures, and partial seizures progressing to secondarily generalized tonic clonic seizures may be obtained in a single patient. Individuals with complex partial seizures or primarily generalized seizures may be amnestic for the details of their seizures; therefore, a reliable observer who has witnessed these seizures should be interviewed. In some cases, video-EEG recording and review may be the only method of arriving at an accurate seizure classification.
Most individuals with complex partial seizures acknowledge the initial presence of an aura that may be useful in localizing the onset zone of the seizures. Examples of auras may be emotional or visceral sensations. There are no standardized descriptions of auras or other seizures that can reliably confirm the diagnosis or clarify the seizure type in all cases. Tongue biting, urinary incontinence, post-ictal confusion and nocturnal seizures can be helpful clues to the presence of a seizure disorder, but are not pathognomonic. Many of the epilepsy mimickers (such as convulsive syncope or psychogenic seizures) may also be associated with these signs or symptoms. For these reasons, individuals with medically refractory seizures require both EEG and MRI (or other neuroimaging) evaluations to provide supporting laboratory evidence for the diagnosis.
The neurological history and examination may identify epilepsy risk factors such as a history of severe head trauma, family history of epilepsy, history of febrile convulsions as an infant or young child, or a history of meningoencephalitis. In those with partial seizure disorders, a history of a previous neurological insult is commonly associated with medically refractory seizures. A focal neurological deficit on examination may indicate the presence of a structural brain lesion. The most common findings on examination, however, are due to the adverse effects of AEDs (for example, nystagmus, ataxia or memory loss).
It is essential to consider errors in diagnosis in every case of intractable epilepsy. Before complex therapies are initiated, a review of the evidence for the diagnosis of epilepsy should be performed. Up to 30% of all cases referred to epilepsy centers due to presumed intractable epilepsy, in fact, have non-epileptic seizures.4 It is common for these patients to have long histories of seizures with multiple hospitalizations and numerous extensive evaluations. They often have a history of complicated treatment regimens, atypical response to therapy, unusual course of epilepsy, changing seizure types, and sometimes evidence for psychopathology. Capturing the seizures on video-EEG recording may reveal their true nature.
A failure to correctly classify the seizure type (i.e., treating complex partial seizures associated with episodes of unresponsiveness as primarily generalized absence seizures) may result in the wrong choice of drug and medically refractory seizures. A classic example is to misdiagnose juvenile myoclonic epilepsy and not treat with sodium valproate.
Another serious mistake is a failure to recognize an underlying disorder such as a brain tumor, metabolic dysfunction, or infection that may be responsible for the
persistence of the seizures, especially when the cause requires active treatment. In neonates and infants the possibility of a deficiency of pyridoxine or biotin should be considered.5 It is also important to inquire about possible triggering factors such as alcohol, stimulants (caffeine, herbs, weight loss remedies and illicit drugs), medications and sleep deficiencies.
Poor compliance is a common cause of pseudo-intractability. This may relate to inadequate patient education, failure to establish a good relationship with the patient, or a complex dosing schedule. Drug blood levels may be helpful in the detection of noncompliance; however, incorrect interpretation of blood levels may be problematic and result in inappropriate medication adjustments. The most common error is dose reduction due to "elevated levels" when a more appropriate indication to reduce the dosage is adverse symptoms due to the medication. Another common error is the misinterpretation of non-trough (or random) drug levels. Correct interpretation of `therapeutic ranges' requires trough drug levels obtained at least 6 to 8 hours after the last dose.
Table 2. Summary Of Differential Considerations |
Errors in Diagnosis
Errors in drug choice or management
Poor medication compliance
True pharmacological intractability |
Epilepsy is still shrouded by many myths and misconceptions among the public. Although it is difficult to reverse centuries of sanctioned stigmatization concerning epilepsy, the treatment of patients with epilepsy begins with appropriate counseling for both the patient and the family. This is the first step in eliminating the misconceptions concerning epilepsy. It is important to discuss in simple terms the causes of seizures, endogenous and environmental triggers of seizures, and issues concerning safety and driving privileges at the time the diagnosis is presented. Opportunity to re-address these issues and to discuss other issues, such as pregnancy and the teratogenic effects of AEDs, should be made available.
One of the most devastating events in a person's life is losing the privilege to drive. Individuals with medically refractory seizures should be advised not to drive by their physician. In Florida, physicians are authorized to report to the DMV patients with a seizure disorder, but reporting is not mandatory.
In Florida, a person with epilepsy may apply for legal permission to drive upon their doctor's recommendation after they have been seizure-free for six months, as long as they are under regular medical supervision and submit a current neurological evaluation. This application should be submitted to the DMV to obtain legal permission to drive regardless if the person has been reported to the DMV or not. The application is reviewed by the Medical Advisory Board (MAB) and a recommendation is submitted to the DMV. If the MAB believes there are particular factors that would make it unsafe for a person to drive even though the person has been seizure-free for six months, they may recommend a longer seizure-free period. An evaluation is not needed for applicants who have been seizure-free for 2 years. Applicants with only chronic nocturnal seizures will be considered on an individual basis. Information concerning the legal issues pertaining to driving and seizures can be obtained through the local Department of Highway Safety and Motor Vehicles (DMV) or the Epilepsy Foundation of America (www.efa.org).
The most commonly performed neurodiagnostic study in the evaluation of patients with seizures is the EEG. A relatively low diagnostic yield is obtained from a routine awake-only EEG recording lasting 20 to 30 minutes in duration. A more prolonged recording including sleep, however, may be helpful in identifying potentially epileptogenic activity that is not evident in the awake-only recording.
The most reliable EEG abnormalities are the primarily generalized spike and wave discharge and the focal spike or sharp wave discharges over the frontal or temporal lobes. These are highly epileptogenic findings and typically greater than 85% of individuals with these findings experience clinically significant seizures.6 Focal slow-wave abnormalities may also be helpful in localizing a region of cerebral dysfunction, but this finding is not specific for seizure onset localization or diagnostic classification.
A normal EEG does not exclude the diagnosis of a seizure disorder. Recording serial
EEGs, including an EEG during a sleep deprived state, may improve the sensitivity of
recording potentially epileptogenic activity such as a spike
or a sharp wave. The EEG may also be falsely positive. Up to 2% of
non-seizure-experiencing individuals may have potentially epileptogenic activity on their
EEG.7 A seizure disorder, therefore, is a clinical diagnosis that should not be
made solely based on EEG findings.
The limitations of the standard EEG recordings have led to expanded use of prolonged EEG recording, with and without concurrent video recording. The combined use of video and EEG recording improves the sensitivity and specificity over EEG recording alone. Since seizures typically occur in an unpredictable fashion, prolonged recording is necessary to record seizures for analysis and improves the sensitivity of recording interictal epileptiform activity.
Prolonged recording of video-EEG is an extremely helpful tool in the evaluation of medically intractable seizure patients and can be performed as an outpatient or as an inpatient. Inpatient monitoring is often necessary when AEDs are withdrawn to enhance the chance of recording a seizure during monitoring. A typical duration of inpatient monitoring is 3 to 5 days.
Video-EEG monitoring has been demonstrated to accurately differentiate between epileptic and non-epileptic seizures, to distinguish between primarily generalized and partial onset seizures, and to determine seizure onset localization and lateralization.8 In many cases of medically refractory seizures, video-EEG recording of the patient's symptoms should be performed as a first study in the proper classification of the seizure disorder.
Neuroimaging modalities that are proven helpful in the evaluation of patients with medically refractory partial epilepsy include magnetic resonance imaging (MRI), computed tomography (CT), positron-emission tomography (PET) and single-photon emission computed tomography (SPECT).
A "standard of care" is a MRI-of-the-brain specially tailored with an imaging protocol to emphasize the potential pathologies suspected of generating specific seizure disorders. Routine "screening" MRI-of-the-brain protocols are typically inadequate for the evaluation of most seizure disorders and have a depressingly low yield. Modern high-resolution scanners, special sequences such as fluid-attenuation-inversion- recovery (FLAIR), and specialized epilepsy imaging protocols are significantly improving the yield of MRI and our understanding of the pathological substrates of epilepsy. Imaging may also be helpful in determining the long-term seizure prognosis. In those patients considered for surgical therapy, the presence of a focal neuroimaging abnormality can improve the prognosis for an excellent outcome.
Magnetic resonance imaging has been demonstrated to be superior to CT in imaging epileptic lesions in those with intractable partial epilepsy.9 Some low grade malignancies, mesiotemporal sclerosis, and neuronal migrational abnormalities/heterotopias might be missed on CT imaging. Therefore, MRI imaging is the structural imaging procedure of choice in those with intractable partial epilepsy. The methods for MRI imaging are critical in determining the diagnostic yield of these studies in a patient with epilepsy. Gadolinium enhancement rarely has been shown to reveal abnormalities that are not identified in unenhanced images with epilepsy.10 However, once a mass lesion is identified on the unenhanced image, gadolinium enhancement may be useful in indicating the pathological features of a mass lesion. For patients with suspected temporal lobe epilepsy, coronal images acquired perpendicular to the axis of the hippocampus with thin slices throughout the length of the temporal lobe are critical in identifying hippocampal formation abnormalities. FLAIR has enhanced sensitivity compared to T1 and T2 weighted images.11 If MRI imaging is not possible, CT imaging should be performed. With the generalized epilepsies no abnormalities are typically seen on MRI or CT of the brain.
Several contraindications to MRI imaging include the presence of metallic foreign bodies within the head or neck, a cardiac pacemaker, excessive patient body size or severe claustrophobia. MRI imaging of the brain should be performed before vagal nerve stimulator implantation.
Computer tomography may complement MRI in those with calcified lesions and bony abnormalities. Despite the sensitivity and specificity of MRI in detecting mass lesions, the results of these studies are often normal in a substantial percentage of patients with epilepsy. Within comprehensive epilepsy programs, additional techniques such as SPECT and PET may be utilized effectively in pre-surgical evaluations.
Cerebral arteriography should be performed in those with partial epilepsies having suspected vascular malformations or an intracranial aneurysm. It is also performed pre-operatively for epilepsy surgery and can be combined with an intra-carotid amobarbital study (Wada study) for language and memory assessment.
Table 3. Elements Of Successful Treatment
Goal: Complete seizure control without side effects |
The selection of an antiepileptic medication is the most important decision the physician will make after conclusion of the diagnostic evaluation (see Table 3). For the non-neurologist, it is advisable to obtain detailed knowledge about the pharmacokinetics of two or three of the currently available AEDs that can be routinely prescribed. It is important to note that noncompliance with the medication may be a primary reason for what seems to be medical intractability. Unnecessarily frequent dosing intervals, such as T.I.D. dosing of carbamazepine, may lead to non compliance. Alternatives, such as extended release Tegretol®, Carbatrol®, or oxcarbazepine (Trileptal®) allow for less frequent dosing intervals and improved side effect profiles that are preferred over the generic formulation. |
Maximally tolerated monotherapy, even if necessary at a supratherapeutic level should be employed before substituting an alternate AED medication or adding a second medication. A gradual titration in a planned sequence of dosing changes to test the effects of individual drugs is usually best tolerated.
The long-standing `drugs of choice' for partial seizure disorders, including the secondarily generalized seizures, are carbamazepine, phenytoin, and sodium valproate. The currently approved medications for monotherapy and adjunctive treatment of seizure disorders are listed in Tables 4 and 5.
Table 4. FDA-Approved Monotherapy |
Table 5. FDA-Approved |
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Partial Seizures
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Primarily Generalized Seizures
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The preference of which medication to use initially depends on several factors, including the cost of medication, frequency of drug dosing, drug-related side effects, and physician experience with the medication. Although these drugs have different potential idiosyncratic and dose-related side effects, no single drug is more effective than another. The choice of medication for a specific individual is ultimately based on an educated attempt to minimize adverse effects or an attempt to treat concurrent illnesses (for example, utilizing sodium valproate for those individuals with both epilepsy and frequent migraine headaches). I generally prefer to prescribe an extended-release formulation of carbamazepine for new-onset partial seizure disorder patients based on favorable efficacy, side effect, and cost profiles. Several common medications, however, may interact with carbamazepine and physicians need to be familiar with its use.
Phenytoin has cosmetic effects that are unpleasant for women, commonly causes gingival hyperplasia, and long-term use may lead to an increased risk of osteoporosis due to its effects on vitamin D metabolism. Sodium valproate is a "broad spectrum" AED with proven efficacy in both partial and generalized onset epilepsies. Although it is generally well tolerated and can be successfully utilized in B.I.D. dosing, the adverse effects of weight gain, hair loss, and tremulousness may be unacceptable. A discussion of the management of intractable seizures in neonates and children is available elsewhere.12,13 Although phenobarbital and primidone are well established AEDs, their adverse effect profiles, especially with medically intractable seizure patients who require combination therapies, outweigh the benefits of utilizing these medications routinely.
A discussion of some of the newer antiepileptic medications (gabapentin, lamotrigine, topiramate, tiagabine, and felbamate) has been recently published.14 There is some evidence that carbamazepine and gabapentin may each exacerbate myoclonic seizures. Vigabatrin (not approved by the FDA) may be selectively active in the treatment of infantile spasms, especially when caused by tuberous sclerosis.15 Felbamate and lamotrigine may be selectively active in the treatment of atonic seizures in children.16, 17
Several empirical trials of AEDs in an attempt to clarify the diagnosis should be discouraged. Many patients with intractable epilepsy who take multiple AEDs are noted to have chronic AED toxicity. These may consist of drowsiness, ataxia, diplopia, and cognitive difficulties. The adverse effects of AEDs may occur even with therapeutic or subtherapeutic blood levels.
Although the addition of a second antiepileptic medication can improve seizure control in 10% to 20%4, 12, 13 of patients, achievement of complete seizure control is not common if an individual has not been seizure-free on monotherapy. The risks of adverse effects and deterioration in quality of life, however, increase significantly with the addition of a second drug.
It is often appropriate to consider high-dose monotherapy at supratherapeutic levels prior to adding a second medication. If signs of toxicity or increasing seizures develop, determination of blood levels and those of active metabolites may be helpful. These studies, in conjunction with a detailed understanding of the temporal relationship of medication dosing to the seizures and all concurrent medications, can direct changes in the daily distribution of doses.
In medically intractable partial epilepsy, surgical resection of the focal epileptogenic cortex is the most effective method currently available to render children and adults seizure-free. Potential candidates include patients with medically refractory partial epilepsy who have seizures emanating from a localized region of the brain that can be resected without neurologic morbidity. This can potentially be achieved in each of the eight major cortical regions of the brain (frontal, parietal, occipital, and temporal lobes of each hemisphere).
In general, the surgical therapy of epilepsy should not be considered as the last resort after all combinations of AEDs have been tried. For example, temporal lobe epilepsy due to mesiotemporal sclerosis typically has a poor prognosis with AED therapy; yet, temporal lobe epilepsy has an excellent prognosis with anterior temporal lobectomy. The goals of the surgical treatment are to eliminate seizures, reduce AED toxicity and avoid neurologic morbidity.
The anterior temporal lobectomy is the most common surgical procedure performed for medically refractory epilepsy. Approximately 60% to 80% of medically intractable patients are rendered seizure-free after temporal lobectomy.18, 19 An additional 10% to 20% of patients have a substantial reduction in seizure activity following this surgery. Ten percent or less of patients are no better after this procedure. Those patients who remain seizure-free for two to three years after surgery can be considered for AED withdrawal. Individuals who remain seizure-free off of AEDs can be considered "cured" from their epilepsy. The operative mortality rate for surgical treatment of epilepsy is approximately 1 in 400.20 The potential morbidity depends on the localization of the epileptogenic zone.
The surgical outcome is not as favorable for cortical regions outside of the temporal lobes.19 Evolving diagnostic and imaging techniques of the last few years, however, have improved the efficacy of surgery in these situations. Success rates approaching 80% are now becoming possible in several non-temporal lobe seizure disorders. A comprehensive pre-surgical evaluation is necessary to pinpoint the seizure onset site as well as to identify the risk of neurologic morbidity. These evaluations typically include ictal video-EEG recording, neuropsychological and speech-language studies, and brain imaging. Chronic intracranial EEG monitoring with the use of subdural grids or depth electrodes may be necessary for localization of the epileptogenic zone. Intraoperative functional mapping may be used to delineate functional areas of the cerebral cortex.
The cost of the presurgical evaluation and operative procedure is considerable20 (approximately $20,000-$30,000 when chronic intracranial monitoring is not performed). Most individuals who undergo surgical therapy for epilepsy are young and otherwise in good health; therefore, their reduced costs of future medical care, potential for earnings, reduced need for social assistance, and improved quality of life need to be considered as offsetting benefits.
It is estimated that 75,000 of the 360,000 persons in the U.S. with medically intractable partial seizure disorders are candidates for a seizure-eliminating surgery;21 however, only a few thousand surgical procedures are performed in the U.S. The major reason for this underutilization is the lack of referral of patients with intractable epilepsy to centers that perform such procedures.
Those patients who are medically refractory and are not candidates for a brain surgical procedure may be evaluated as potential candidates for the vagal nerve stimulator. At the present time, the vagal nerve stimulator is only approved for the treatment of medically refractory partial epilepsies in those >12 years of age who are not surgical candidates. However, it is anticipated that an indication for treatment of generalized epilepsies will be obtained.
Efficacy studies have demonstrated that approximately one-third of those treated with vagal nerve stimulation have a greater than 50% reduction in their seizure frequency.22 Another one-third have less than a 50% reduction in seizure frequency with the vagal nerve stimulator, and the remaining one-third have no improvement.22 The vagal nerve stimulator can be considered equally efficacious as the addition of a second or third AED to a patient's regimen, but does not have the added systemic toxic effects.
Personal experience has shown that vagal nerve stimulation is generally well tolerated, although minor side effects of neck pain, hoarseness, and a brief cough can be associated with the activation of the stimulator. Drawbacks are the need for surgical implantation and the high cost (the combined cost of the device and surgical implantation with subsequent follow-up is estimated to be over $40,000).
Ketosis and acidosis, similar to that observed in a state of starvation, have been observed for centuries to exert anticonvulsant effects. The efficacy of a daily regimen of 1g/kg of protein, enough fat to make up the desired caloric requirements and a very small amount of carbohydrates for establishing anticonvulsant levels of ketosis has been well established.
For best results, the diet should be initiated by a team thoroughly educated in the use of the diet and by a family dedicated to rigorous monitoring. This diet has been most successful in children with medically refractory seizures, especially handicapped children less than 10 years old. In the most notable study of the ketogenic diet,23 38% of medically intractable children had a seizure reduction of almost 50%, and 29% of patients became seizure free. The primary drawback to the diet is poor compliance, although some institutions had found good acceptance and compliance with the traditional diet.
If a patient continues to have seizures despite treatment trials with monotherapy AED pushed to maximum tolerability, then referral of the patient to a comprehensive epilepsy program should be considered. Ideally, the determination of medical intractability and the need for a comprehensive epilepsy evaluation can be made within the first 1 to 2 years of epilepsy. This allows for a second opinion concerning the diagnosis and includes a comprehensive search for etiological factors. Comprehensive epilepsy programs offer a wide array of diagnostic tools and therapeutic options. Prolonged video-EEG recording of the patient's symptoms is a vital part of the evaluation. Therapeutic options range from innovative approaches to FDA-approved AEDs and investigational pharmacotherapies, to alternative therapies such as the ketogenic diet, vagal nerve stimulator, and surgical therapies. It should be kept in mind that the longer the duration of intractable seizures, the greater the risks for psychosocial deterioration, loss of development, and secondary epileptogenesis.
Epilepsy can be a life-altering and debilitating illness that can rob individuals of their independence and can cause profound behavioral, psychological, social, financial and legal consequences. Those people with medically refractory seizures are the most severely effected. Over the last 50 years, tremendous advances in the knowledge of seizures and epilepsy have occurred. More recently, scientific and technical advances have improved the tools for the evaluation and treatment of seizures. In some cases, the most intractable seizure disorders of 10 to 20 years ago are now disorders that can be effectively treated. With current brain surgery techniques, some forms of medically refractory epilepsy may even be cured. Patients should be offered our best efforts to control their seizures and to improve their quality of life. The message to physicians in the year 2000 is to recognize those patients with a medically refractory seizure disorder early in the course of the illness and refer them to an appropriate epilepsy specialist or comprehensive epilepsy program.
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