TREATMENT Seizures and Epilepsy
Therapy for a patient with a seizure disorder is almost always multimodal and includes treatment of underlying conditions that cause or contribute to the seizures, avoidance of precipitating factors, suppression of recurrent seizures by prophylactic therapy with antiepileptic medications or surgery, and addressing a variety of psychological and social issues. Treatment plans must be individualized, given the many different types and causes of seizures as well as the differences in efficacy and toxicity of antiepileptic medications for each patient. In almost all cases, a neurologist with experience in the treatment of epilepsy should design and oversee implementation of the treatment strategy. Furthermore, patients with refractory epilepsy or those who require polypharmacy with antiepileptic drugs should remain under the regular care of a neurologist. TREATMENT OF UNDERLYING CONDITIONS
If the sole cause of a seizure is a metabolic disturbance such as an abnormality of serum electrolytes or glucose, then treatment is aimed at reversing the metabolic problem and preventing its recurrence. Therapy with antiepileptic drugs is usually unnecessary unless the metabolic disorder cannot be corrected promptly and the patient is at risk of having further seizures. If the apparent cause of a seizure was a medication (e.g., theophylline) or illicit drug use (e.g., cocaine), then appropriate therapy is avoidance of the drug; there is usually no need for antiepileptic medications unless subsequent seizures occur in the absence of these precipitants.
Seizures caused by a structural CNS lesion such as a brain tumor, vascular malformation, or brain abscess may not recur after appropriate treatment of the underlying lesion. However, despite removal of the structural lesion, there is a risk that the seizure focus will remain in the surrounding tissue or develop de novo as a result of gliosis and other processes induced by surgery, radiation, or other therapies. Most patients are therefore maintained on an antiepileptic medication for at least 1 year, and an attempt is made to withdraw medications only if the patient has been completely seizure free. If seizures are refractory to medication, the patient may benefit from surgical removal of the epileptic brain region (see below). AVOIDANCE OF PRECIPITATING FACTORS
Unfortunately, little is known about the specific factors that determine precisely when a seizure will occur in a patient with epilepsy. An almost universal precipitating factor for seizures is sleep deprivation, so patients should do everything possible to optimize their sleep quality. Many patients can identify other particular situations that appear to lower their seizure threshold; these situations should be avoided. For example, patients may note an association between alcohol intake and seizures, and they should be encouraged to modify their drinking habits accordingly. There are also relatively rare cases of patients with seizures that are induced by highly specific stimuli such as a video game monitor, music, or an individual’s voice (“reflex epilepsy”). Because there is often an association between stress and seizures, stress reduction techniques such as physical exercise, meditation, or counseling may be helpful. ANTIEPILEPTIC DRUG THERAPY
Antiepileptic drug therapy is the mainstay of treatment for most patients with epilepsy. The overall goal is to completely prevent seizures without causing any untoward side effects, preferably with a single medication and a dosing schedule that is easy for the patient to follow. Seizure classification is an important element in designing the treatment plan, because some antiepileptic drugs have different activities against various seizure types. However, there is considerable overlap between many antiepileptic drugs such that the choice of therapy is often determined more by the patient’s specific needs, especially his or her assessment of side effects. When to Initiate Antiepileptic Drug Therapy
Antiepileptic drug therapy should be started in any patient with recurrent seizures of unknown etiology or a known cause that cannot be reversed. Whether to initiate therapy in a patient with a single seizure is controversial. Patients with a single seizure due to an identified lesion such as a CNS tumor, infection, or trauma, in which there is strong evidence that the lesion is epileptogenic, should be treated. The risk of seizure recurrence in a patient with an apparently unprovoked or idiopathic seizure is uncertain, with estimates ranging from 31 to 71% in the first 12 months after the initial seizure. This uncertainty arises from differences in the underlying seizure types and etiologies in various published epidemiologic studies. Generally accepted risk factors associated with recurrent seizures include the following: (1) an abnormal neurologic examination, (2) seizures presenting as status epilepticus, (3) postictal Todd’s paralysis, (4) a strong family history of seizures, or (5) an abnormal EEG. Most patients with one or more of these risk factors should be treated. Issues such as employment or driving may influence the decision whether to start medications as well. For example, a patient with a single, idiopathic seizure whose job depends on driving may prefer taking antiepileptic drugs rather than risk a seizure recurrence and the potential loss of driving privileges. Selection of Antiepileptic Drugs
Antiepileptic drugs available in the United States are shown in Table 418-8, and the main pharmacologic characteristics of commonly used drugs are listed in Table 418-9. Worldwide, older medications such as phenytoin, valproic acid, carbamazepine, phenobarbital, and ethosuximide are generally used as first-line therapy for most seizure disorders because, overall, they are as effective as recently marketed drugs and significantly less expensive overall. Enzyme-inducing antiepileptic drugs are associated with an increased incidence of long-term cardiovascular disease, potentially impacting choice in some patients. Most of the new drugs that have become available in the past decade are used as add-on or alternative therapy, although many are now being used as first-line monotherapy.
In addition to efficacy, factors influencing the choice of an initial medication include the convenience of dosing (e.g., once daily versus three or four times daily) and potential side effects. In this regard, a number of the newer drugs have the advantage of reduced drug–drug interactions and easier dosing. Almost all of the commonly used antiepileptic drugs can cause similar, dose-related side effects such as sedation, ataxia, and diplopia. Long-term use of some agents in adults, especially the elderly, can lead to osteoporosis. Close follow-up is required to ensure these side effects are promptly recognized and reversed. Most of the older drugs and some of the newer ones can also cause idiosyncratic toxicity such as rash, bone marrow suppression, or hepatotoxicity. Although rare, these side effects should be considered during drug selection, and patients must be instructed about symptoms or signs that should signal the need to alert their health care provider. For some drugs, laboratory tests (e.g., complete blood count and liver function tests) are recommended prior to the institution of therapy (to establish baseline values) and during initial dosing and titration of the agent.
An important recent advance in the care of patients with epilepsy has been the application of genetic testing to help guide the choice of therapy (as well as establishing the underlying cause of a patient’s syndrome). For example, the identification of a mutation in the SLC2A1 gene, which encodes the glucose type 1 transporter (GLUT-1) and is a cause of GLUT-1 deficiency, should immediately prompt treatment with the ketogenic diet. Mutations of the ALDH7A1 gene, which encodes antiquitin, can cause alterations in pyridoxine metabolism that are reversed by treatment with pyridoxine. There is also mounting evidence that certain gene mutations may indicate better or worse response to specific antiepileptic drugs. For example, patients with mutations in the sodium channel subunit SCN1A should generally avoid taking phenytoin or lamotrigine, whereas patients with mutations in the SCN2A or SCN8A sodium channel subunits appear to respond favorably to high-dose phenytoin. Genetic testing may also help predict antiepileptic drug toxicity. Studies have shown that Asian individuals carrying the human leukocyte antigen allele, HLA-B*1502, are at particularly high risk of developing serious skin reactions from carbamazepine, phenytoin, oxcarbazepine, and lamotrigine. HLA-A*31:01 has also been found to be associated with carbamazepine-induced hypersensitivity reactions in patients of European or Japanese ancestry. As a result, racial background and genotype are additional factors to consider in drug selection. Antiepileptic Drug Selection for Focal Seizures
Carbamazepine (or a related drug, oxcarbazepine), lamotrigine, phenytoin, and levetiracetam are currently the drugs of choice approved for the initial treatment of focal seizures, including those that evolve into generalized seizures. A recent large study demonstrated superior efficacy of lamotrigine compared with levetiracetam. Differences in pharmacokinetics and toxicity are the main determinants of choice of these many agents in a given patient. Overall they have very similar efficacy, but differences in pharmacokinetics and toxicity are the main determinants for use in a given patient. For example, an advantage of carbamazepine (which is also available in an extended-release form) is that its metabolism follows first-order pharmacokinetics, which allows for a linear relationship between drug dose, serum levels, and toxicity. Carbamazepine can cause leukopenia, aplastic anemia, or hepatotoxicity and would therefore be contraindicated in patients with predispositions to these problems. Oxcarbazepine has the advantage of being metabolized in a way that avoids an intermediate metabolite associated with some of the side effects of carbamazepine. Oxcarbazepine also has fewer drug interactions than carbamazepine. Lamotrigine tends to be well tolerated in terms of side effects. However, patients need to be particularly vigilant about the possibility of a skin rash during the initiation of therapy. This can be extremely severe and lead to Stevens-Johnson syndrome if unrecognized and if the medication is not discontinued immediately. This risk can be reduced by the use of low initial doses and slow titration. Lamotrigine must be started at lower initial doses when used as add-on therapy with valproic acid, because valproic acid inhibits lamotrigine metabolism and results in a substantially prolonged half-life. Phenytoin has a relatively long half-life and offers the advantage of once or twice daily dosing compared to two or three times daily dosing for many of the other drugs. However, phenytoin shows properties of nonlinear kinetics, such that small increases in phenytoin doses above a standard maintenance dose can precipitate marked side effects. This is one of the main causes of acute phenytoin toxicity. Long-term use of phenytoin is associated with untoward cosmetic effects (e.g., hirsutism, coarsening of facial features, gingival hypertrophy) and effects on bone metabolism. Due to these side effects, phenytoin is often avoided in young patients who are likely to require the drug for many years. Levetiracetam has the advantage of having no known drug–drug interactions, making it especially useful in the elderly and patients on other medications. However, a significant number of patients taking levetiracetam complain of irritability, anxiety, and other psychiatric symptoms. Topiramate can be used for both focal and generalized seizures. Similar to some of the other antiepileptic drugs, topiramate can cause significant psychomotor slowing and other cognitive problems. Additionally, it should not be used in patients at risk for the development of glaucoma or renal stones.
Valproic acid is an effective alternative for some patients with focal seizures, especially when the seizures generalize. Gastrointestinal side effects are fewer when using the delayed-release formulation (Depakote). Laboratory testing is required to monitor toxicity because valproic acid can rarely cause reversible bone marrow suppression and hepatotoxicity. This drug should generally be avoided in patients with preexisting bone marrow or liver disease. Valproic acid also has relatively high risks of unacceptable adverse effects for women of childbearing age, including hyperandrogenism that may affect fertility and teratogenesis (e.g., neural tube defects) in offspring. Irreversible, fatal hepatic failure appearing as an idiosyncratic rather than dose-related side effect is a relatively rare complication; its risk is highest in children <2 years old, especially those taking other antiepileptic drugs or with inborn errors of metabolism.
Zonisamide, brivaracetam, tiagabine, gabapentin, and lacosamide are additional drugs currently used for the treatment of focal seizures with or without evolution into generalized seizures. Phenobarbital and other barbiturate compounds were commonly used in the past as first-line therapy for many forms of epilepsy. However, the barbiturates frequently cause sedation in adults, hyperactivity in children, and other more subtle cognitive changes; thus, their use should be limited to situations in which no other suitable treatment alternatives exist. Antiepileptic Drug Selection for Generalized Seizures
Lamotrigine, valproic acid and levetiracetam are currently considered the best initial choice for the treatment of primary generalized, tonic-clonic seizures. Topiramate, zonisamide, phenytoin, carbamazepine, and oxcarbazepine are suitable alternatives, although carbamazepine, oxcarbazepine, and phenytoin can worsen certain types of generalized seizures. Valproic acid is particularly effective in absence, myoclonic, and atonic seizures. It is therefore commonly used in patients with generalized epilepsy syndromes having mixed seizure types. However, levetiracetam, rather than valproic acid, is increasingly considered the initial drug of choice for women with epilepsies having mixed seizure types given the adverse effects of valproic acid for women of childbearing age. Lamotrigine is also an alternative to valproate, especially for absence epilepsies. Ethosuximide is a particularly effective drug for the treatment of uncomplicated absence seizures, but it is not useful for tonic-clonic or focal seizures. Periodic monitoring of blood cell counts is required since ethosuximide rarely causes bone marrow suppression. INITIATION AND MONITORING OF THERAPY
Because the response to any antiepileptic drug is unpredictable, patients should be carefully educated about the approach to therapy. The goal is to prevent seizures and minimize the side effects of treatment; determination of the optimal dose is often a matter of trial and error. This process may take months or longer if the baseline seizure frequency is low. Most antiepileptic drugs need to be introduced relatively slow to minimize side effects. Patients should expect that minor side effects such as mild sedation, slight changes in cognition, or imbalance will typically resolve within a few days. Starting doses are usually the lowest value listed under the dosage column in Table 418-9. Subsequent increases should be made only after achieving a steady state with the previous dose (i.e., after an interval of five or more half-lives).
Monitoring of serum antiepileptic drug levels can be very useful for establishing the initial dosing schedule. However, the published therapeutic ranges of serum drug concentrations are only an approximate guide for determining the proper dose for a given patient. The key determinants are the clinical measures of seizure frequency and presence of side effects, not the laboratory values. Conventional assays of serum drug levels measure the total drug (i.e., both free and protein bound). However, it is the concentration of free drug that reflects extracellular levels in the brain and correlates best with efficacy. Thus, patients with decreased levels of serum proteins (e.g., decreased serum albumin due to impaired liver or renal function) may have an increased ratio of free to bound drug, yet the concentration of free drug may be adequate for seizure control. These patients may have a “subtherapeutic” drug level, but the dose should be changed only if seizures remain uncontrolled, not just to achieve a “therapeutic” level. It is also useful to monitor free drug levels in such patients. In practice, other than during the initiation or modification of therapy, monitoring of antiepileptic drug levels is most useful for documenting adherence or assessing clinical suspicion of toxicity.
If seizures continue despite gradual increases to the maximum tolerated dose and documented compliance, then it becomes necessary to switch to another antiepileptic drug. This is usually done by maintaining the patient on the first drug while a second drug is added. The dose of the second drug should be adjusted to decrease seizure frequency without causing toxicity. Once this is achieved, the first drug can be gradually withdrawn (usually over weeks unless there is significant toxicity). The dose of the second drug is then further optimized based on seizure response and side effects. Monotherapy should be the goal whenever possible. WHEN TO DISCONTINUE THERAPY
Overall, about 50–60% of patients who have their seizures completely controlled with antiepileptic drugs can eventually discontinue therapy. The following patient profile yields the greatest chance of remaining seizure free after drug withdrawal: (1) complete medical control of seizures for 1–5 years; (2) single seizure type, with generalized seizures having a better prognosis than focal seizures; (3) normal neurologic examination, including intelligence; (4) no family history of epilepsy; and (5) normal EEG. The appropriate seizure-free interval is unknown and undoubtedly varies for different forms of epilepsy. However, it seems reasonable to attempt withdrawal of therapy after 2 years in a patient who meets all of the above criteria, is motivated to discontinue the medication, and clearly understands the potential risks and benefits. In most cases, it is preferable to reduce the dose of the drug gradually over 2–3 months. Most recurrences occur in the first 3 months after discontinuing therapy, and patients should be advised to avoid potentially dangerous situations such as driving or swimming during this period. TREATMENT OF REFRACTORY EPILEPSY
Approximately one-third of patients with epilepsy do not respond to treatment with a single antiepileptic drug, and it becomes necessary to try a combination of drugs to control seizures. Patients who have focal epilepsy related to an underlying structural lesion or those with multiple seizure types and developmental delay are particularly likely to require multiple drugs. There are currently no clear guidelines for rational polypharmacy, although in theory a combination of drugs with different mechanisms of action may be most useful. In most cases, the initial combination therapy combines first-line drugs (i.e., carbamazepine, oxcarbazepine, lamotrigine, valproic acid, levetiracetam, and phenytoin). If these drugs are unsuccessful, then the addition of other drugs such as zonisamide, brivaracetam, topiramate, lacosamide, or tiagabine is indicated. Patients with myoclonic seizures resistant to valproic acid may benefit from the addition of clonazepam or clobazam, and those with absence seizures may respond to a combination of valproic acid and ethosuximide. The same principles concerning the monitoring of therapeutic response, toxicity, and serum levels for monotherapy apply to polypharmacy, and potential drug interactions need to be recognized. If there is no improvement, a third drug can be added while the first two are maintained. If there is a response, the less effective or less well tolerated of the first two drugs should be gradually withdrawn. SURGICAL TREATMENT OF REFRACTORY EPILEPSY
Approximately 20–30% of patients with epilepsy continue to have seizures despite efforts to find an effective combination of antiepileptic drugs. For some, surgery can be extremely effective in substantially reducing seizure frequency and even providing complete seizure control. Understanding the potential value of surgery is especially important when a patient’s seizures are not controlled with initial treatment, as such patients often do not respond to subsequent medication trials. Rather than submitting the patient to years of unsuccessful medical therapy and the psychosocial trauma and increased mortality associated with ongoing seizures, the patient should have an efficient but relatively brief attempt at medical therapy and then be referred for surgical evaluation.
The most common surgical procedure for patients with temporal lobe epilepsy involves resection of the anteromedial temporal lobe (temporal lobectomy) or a more limited removal of the underlying hippocampus and amygdala (amygdalohippocampectomy). Focal seizures arising from extratemporal regions may be abolished by a focal neocortical resection with precise removal of an identified lesion (lesionectomy). Localized neocortical resection without a clear lesion identified on MRI is also possible when other tests (e.g., MEG, PET, SPECT) implicate a focal cortical region as a seizure onset zone. When the cortical region cannot be removed, multiple subpial transection, which disrupts intracortical connections, is sometimes used to prevent seizure spread. Hemispherectomy or multilobar resection is useful for some patients with severe seizures due to hemispheric abnormalities such as hemimegalencephaly or other dysplastic abnormalities, and corpus callosotomy has been shown to be effective for disabling tonic or atonic seizures, usually when they are part of a mixed-seizure syndrome (e.g., Lennox-Gastaut syndrome).
Presurgical evaluation is designed to identify the functional and structural basis of the patient’s seizure disorder. Inpatient video-EEG monitoring is used to define the anatomic location of the seizure focus and to correlate the abnormal electrophysiologic activity with behavioral manifestations of the seizure. Routine scalp or scalp-sphenoidal recordings and a high-resolution MRI scan are usually sufficient for localization of the epileptogenic focus, especially when the findings are concordant. Functional imaging studies such as SPECT, PET, and MEG are adjunctive tests that may help to reveal or verify the localization of an apparent epileptogenic region. Once the presumed location of the seizure onset is identified, additional studies, including neuropsychological testing, the intracarotid amobarbital test (Wada test), and functional MRI may be used to assess language and memory localization and to determine the possible functional consequences of surgical removal of the epileptogenic region. In some cases, standard noninvasive evaluation is not sufficient to localize the seizure onset zone, and invasive electrophysiologic monitoring, such as implanted depth or subdural electrodes, is required for more definitive localization. The exact extent of the resection to be undertaken can also be determined by performing cortical mapping at the time of the surgical procedure, allowing for a tailored resection. This involves electrocorticographic recordings made with electrodes on the surface of the brain to identify the extent of epileptiform disturbances. If the region to be resected is within or near brain regions suspected of having sensorimotor or language function, electrical cortical stimulation mapping is performed on the awake patient to determine the function of cortical regions in question in order to avoid resection of so-called eloquent cortex and thereby minimize postsurgical deficits.
Advances in presurgical evaluation and microsurgical techniques have led to a steady increase in the success of epilepsy surgery. Clinically significant complications of surgery are <5%, and the use of functional mapping procedures has markedly reduced the neurologic sequelae due to removal or sectioning of brain tissue. For example, about 70% of patients treated with temporal lobectomy will become seizure free, and another 15–25% will have at least a 90% reduction in seizure frequency. Marked improvement is also usually seen in patients treated with hemispherectomy for catastrophic seizure disorders due to large hemispheric abnormalities. Postoperatively, patients generally need to remain on antiepileptic drug therapy, but the marked reduction of seizures following resective surgery can have a very beneficial effect on quality of life.
Not all medically refractory patients are suitable candidates for resective surgery. For example, some patients have seizures arising from more than one location, making the risk of ongoing seizures or potential harm from the surgery unacceptably high. Vagus nerve stimulation (VNS) has been used in some of these cases, although the results are limited and it is difficult to predict who will benefit. An implantable device that can detect the onset of a seizure (in some instances before the seizure becomes clinically apparent) and deliver an electrical stimulation to abort the seizure (Responsive NeuroStimulation) has proved to be of benefit in selected patients. Studies are currently evaluating the efficacy of stereotactic radiosurgery, laser thermoablation, and deep brain stimulation (DBS) as other options for surgical treatment of refractory epilepsy.