Epilepsy

P R I M A R Y C A R E
can both be characterized by loss of consciousness anda fall.9 Syncope is suggested by an onset while the pa-tient is erect and by a brief duration (10 seconds), EPILEPSY
flaccid muscle tone during the event, pale color, coldand clammy skin, or electrocardiographic abnormal- ities. Tonic–clonic seizure is suggested by an onset while the patient is asleep or awake and in any pos-ture, a duration of one minute or longer, increasedmuscle tone during the event, incontinence, biting of the tongue, flushed color, hot and sweaty skin, ster- United States have epilepsy,1,2 making the torous respiration, electroencephalographic abnormal- prevalence of this disorder similar to that of ities, or a family history of seizures.
type 1 diabetes mellitus.3 Each year, 100,000 new Both absence and complex partial seizures may be cases of epilepsy are diagnosed in the United States.1,4 characterized by loss of consciousness, with or with- Both the prevalence and the incidence of epilepsy out automatic behavior.10 It is often assumed that such are dramatically higher among elderly persons than clinical findings indicate absence seizures in children among those who are younger.1 Thus, many primary and complex partial seizures in adults. However, ei- care physicians care for a substantial number of pa- ther type of seizure can occur both in children and in adults. Absence seizure is suggested by a short du-ration (10 seconds), a rapid onset without warning, EVALUATION
very rapid recovery, or precipitation of the event by Diagnosis of a Seizure Disorder
hyperventilation; a pattern of a spike and a wave at The first step in the evaluation of a patient with pos- a frequency of 3 Hz on the electroencephalogram sible epilepsy is to determine whether the patient does provides confirmation. Complex partial seizure is sug- or does not have seizures. An incorrect diagnosis of a gested by a duration of one minute or more, an aura, seizure disorder can have many negative consequenc- and confusion after the event; temporal slowing or es for the patient, including expensive and potentially sharp waves on the electroencephalogram provide con- toxic medication regimens, loss of driving privileges, and loss of work. Disorders that must be differenti- Seizures often occur as part of an epileptic syn- ated from epilepsy include migraine, syncope, transient drome.5,7,8,11 An epileptic syndrome is a group of signs ischemic attack, nonepileptic seizure (psychogenic sei- and symptoms that customarily occur together.11 Iden- zure), the episodic dyscontrol syndrome (rage attacks), tification of the syndrome helps determine the appro- Meniere’s disease, and movement disorders.5 In chil- priate therapy and the prognosis. For example, juve- dren one must also consider breath-holding spells, pal- nile myoclonic epilepsy is a syndrome of myoclonic lid infantile syncope, tics, night terrors, somnambu- and tonic–clonic seizures that usually develop at 12 lism, and the long-QT syndrome.5 Once it has been to 18 years of age.12 Patients typically have a specific established that the patient has seizures, one must pattern of electroencephalographic abnormalities, with identify the type (or types) of seizures, since therapy no abnormalities observed on neurologic examination.
Although the prognosis for seizure control is favor- Seizures are classified as partial or generalized (Table able, lifelong treatment with antiepileptic drugs is usu- 1).5-8 Partial seizures involve only a portion of the ally necessary. Juvenile myoclonic epilepsy is a genet- brain at their onset. The most common types of partial ically heterogeneous syndrome involving a molecular seizures are simple partial seizures, complex partial sei- defect that remains unknown. Many of the epileptic zures, and partial seizures that are secondarily gener- syndromes have a genetic basis, and the genes and alized. The most common types of generalized sei- gene products responsible for these syndromes are be- zures are absence seizures and primarily generalized Two common problems in diagnosing a seizure dis- Diagnosis of the Underlying Cause
order are distinguishing tonic–clonic seizure from syn- Seizures are a symptom of an underlying disorder, cope and distinguishing absence seizures from com- which may be genetic, traumatic, metabolic, infectious, plex partial seizures. Tonic–clonic seizure and syncope malignant, or pharmacologic (i.e., drug intoxicationor withdrawal). In many cases, the underlying disordermust be identified and treated in order to control the From the Department of Neurology, Boston University School of Med- seizures and prevent further brain dysfunction.
icine, and the Neurology Service, Department of Veterans Affairs BostonHealthcare System (T.R.B.); and the Department of Neurology, HarvardMedical School and Children’s Hospital (G.L.H.) — all in Boston. Address reprint requests to Dr. Browne at the Department of Neurology, Boston The history obtained from the patient and witness- University School of Medicine, 315 Albany St., C-314, Boston, MA 02118,or at tbrowne@bu.edu.
es is often the most important information in estab- N Engl J Med, Vol. 344, No. 15 · April 12, 2001 · www.nejm.org · 1145
Downloaded from nejm.org on May 23, 2011. For personal use only. No other uses without permission. Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 1. PRINCIPAL TYPES OF SEIZURES.
ELECTROENCEPHALOGRAPHIC
TYPE OF SEIZURE
CLINICAL FEATURES
FEATURES*
Signs and symptoms may be motor, sensory, Focal slowing or sharp-wave ac- location of the electrical discharge; con-sciousness is not impaired Seizure may begin with no warning or with Focal slowing or sharp-wave ac- signs or symptoms; consciousness is im-paired; automatisms (automatic acts of which the patient has no recollection) may occur; seizure is often followed by a peri-od of confusion Seizures may begin with motor, sensory, au- Focal slowing or sharp-wave ac- consciousness is lost, with tonic increase in muscle tone; subsequent rhythmic (clonic) jerks subside slowly; patient is comatose after seizure and recovers slowly; tongue biting or incontinence, or both, may occur Seizure begins rapidly, with a brief period of Spike–wave pattern (3 Hz) unresponsiveness (average, 10 seconds) and rapid recovery; there may be increased or decreased muscle tone, automatisms, or mild clonic movements. Seizure can be precipitated by hyperventilation; age at first seizure, 3–20 yr Loss of consciousness occurs without warn- Spike–wave pattern (3–5 Hz) ing or is preceded by myoclonic jerks; clin-ical features are similar to those of a sec-ondarily generalized partial seizure *The electroencephalographic features listed are those observed on routine electroencephalography during which a sei- lishing the diagnosis of a seizure disorder. One should signs of head trauma, infections of the ears or sinuses begin by asking the patient and observers to describe (which may spread to the brain), congenital abnormal- in detail the events before, during, and after the sei- ities (e.g., tuberous sclerosis), focal or diffuse neuro- zure. Partial seizures may begin with motor, sensory, logic abnormalities, alcohol or drug abuse, and cancer.
autonomic, or psychic symptoms.6 Generalized sei- Hyperventilation for three minutes will trigger a sei- zures may begin with bilateral myoclonic jerks. Once zure in most patients with untreated absence seizures.
started, a seizure may cause an alteration of conscious-ness; tonic or clonic movements, or both; tongue bit- Electroencephalographic Studies
ing; incontinence; automatic behavior; and postictal The electroencephalogram provides three types of behavior. A history of minor types of seizures (e.g., information: confirmation of the presence of abnormal myoclonic or absence seizures) in a person presenting electrical activity, information about the type of sei- with a possible tonic–clonic seizure helps establish the zure disorder, and the location of the seizure focus.14-18 diagnosis of a seizure disorder. This information may It is customary to perform electroencephalographic not be obtained from the history unless specific ques- studies 48 hours or more after a suspected seizure, be- cause obtaining an electroencephalogram shortly af- To determine the cause of a seizure, the clinician ter a seizure may yield misleading findings. The elec- should determine whether there is a family history of troencephalogram should include recordings during epilepsy or a personal history of head trauma, birth sleep, photic stimulation, and hyperventilation, be- complications, febrile convulsions, middle-ear or si- cause certain types of paroxysmal activity are most like- nus infections, alcohol or drug abuse, or symptoms In approximately 50 percent of patients who have epilepsy, a single electroencephalogram shows no ab- Physical Examination
normalities. If the electroencephalographic findings A physical examination is performed to look for are normal and the suspicion of epilepsy is high, an- signs of disorders associated with epilepsy, including other electroencephalogram should be obtained, this 1146 · N Engl J Med, Vol. 344, No. 15 · April 12, 2001 · www.nejm.org
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time with the use of special (temporal and sphenoidal) lished, an antiepileptic drug appropriate for that type electrodes, after the patient has been deprived of sleep.
is administered if the patient has had two or more sei- This approach may reveal abnormalities. If no abnor- zures. A patient who has had a single seizure is treated malities are detected on these two electroencephalo- with medication if there are one or more risk factors grams, prolonged electroencephalography and video for recurrent seizures, such as evidence of a structur- monitoring may reveal evidence of a clinical event or al lesion, electroencephalographic abnormalities (Ta- paroxysmal activity that establishes the diagnosis of a ble 1), a seizure of the partial type, or a family his- seizure disorder.15-18 In approximately 10 percent of tory of seizures.21 Otherwise, a patient who has had persons with true seizures, multiple electroencephalo- a single seizure is usually monitored but not given graphic studies show no abnormalities.
If the diagnosis is uncertain after all the above steps Laboratory Tests and Neuroimaging
have been taken, one must act on the basis of the avail- The studies performed to determine the cause of able information. A trial of an antiepileptic drug is be- a newly diagnosed seizure disorder include electrolyte gun if the information strongly suggests that more and liver-function tests in adults (such screening is not than one seizure has occurred. Otherwise, follow-up routinely performed in children14), electroencephalog- raphy in the waking and sleeping states, and magnetic In most states, licensed drivers are required to re- resonance imaging (MRI) or computed tomography port a seizure condition to the Department of Mo- (CT). MRI scanning is preferable to CT because it is tor Vehicles at the time of the diagnosis, and physi- more likely to reveal small lesions such as tumors or cians may not report a patient’s condition without mesial temporal sclerosis.14,19,20 A screening test for written permission from the patient. However, there toxic substances is performed if alcohol or drug abuse are exceptions. A summary of the requirements in or withdrawal is suspected, and a lumbar puncture is each state is available from the Epilepsy Foundation performed if infection or cancer is suspected.
The American Academy of Neurology has published practice guidelines for neuroimaging studies (MRI and SELECTION AND ADJUSTMENT
CT) in patients who have had a first seizure.14,19,20 Neu- OF MEDICATIONS
roimaging should be performed immediately in pa- Treatment is started with an average dose of a first- tients who may have a serious structural lesion. These line antiepileptic drug. First-line drugs are those that include patients who have new focal deficits, a persist- are most effective and least toxic. For partial seizures, ently altered mental status (with or without intoxica- first-line drugs include carbamazepine, divalproex so- tion), fever, recent trauma, persistent headache, or a dium, oxcarbazepine, and phenytoin.22-25 On the basis history of cancer or anticoagulant therapy and those of comparative trials, carbamazepine, oxcarbazepine, who may have the acquired immunodeficiency syn- and phenytoin appear to be the most effective and least drome.19,20 Emergency neuroimaging should also be toxic drugs for the initial treatment of partial sei- performed in children with a postictal focal deficit or zures.22-25 All three drugs have similar efficacy. Oxcar- altered mental status that does not resolve rapidly.14 In bazepine may have less initial toxicity than carbamaz- addition, neuroimaging on an emergency basis should be considered if the patient is over 40 years old or has Ethosuximide and divalproex sodium are the usual first-line drugs for absence (petit mal) seizures.26 Both Nonemergency neuroimaging studies should be drugs are effective in controlling absence seizures,27 considered for an adult or child in whom no cause but ethosuximide has fewer side effects. However, only of the seizure has been determined, in a child with a divalproex sodium is effective against tonic–clonic sei- seizure of focal onset, in a child under the age of one zures, which often accompany absence seizures. The year who has had a nonfebrile seizure, and in a child usual first-line drugs for primarily generalized tonic– with unexplained cognitive or motor dysfunction or clonic seizures are divalproex sodium and phenyto- abnormalities on neurologic examination.14,19,20 in.24,26 The dosages for these drugs are summarizedin Table 2.
Diagnostic Formulation and Treatment Plan
If the average dose of a first-line drug controls the It is usually possible to diagnose a seizure disorder seizures and does not have side effects, no adjustment by using a combination of information from the his- is needed. However, it is often necessary to adjust the tory, physical examination, and electroencephalogram.
dose of an antiepileptic drug because of toxicity or in- If the presence of a seizure disorder or its type can- adequate control of seizures, or both.
not be established, one should attempt to obtain fur- The therapeutic range of plasma drug concentra- ther information about the event (e.g., from additional tions, which is only a rough guide for determining the witnesses), perform repeated electroencephalographic appropriate dose, has been established for some anti- studies under the conditions noted above, or both.
epileptic drugs.28,29 It is important, however, to treat Once the type of seizure disorder has been estab- the patient, not the plasma drug concentration. If the N Engl J Med, Vol. 344, No. 15 · April 12, 2001 · www.nejm.org · 1147
Downloaded from nejm.org on May 23, 2011. For personal use only. No other uses without permission. Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 2. USUAL DOSAGES OF ANTIEPILEPTIC DRUGS IN PATIENTS 16 YEARS OF AGE OR OLDER.*
THERAPEUTIC
STARTING
MAINTENANCE
DOSE FREQUENCY
DOSE INCREASE
CONCENTRATIONS
XR , twice a day; Tegretol or generic, three times a day bedtime; days 4–6, 100–125 mg twice a day; days 7–9, 100–125 mg three times a day; day 10, 250 mg three times a day *Data are from Browne and Holmes.5 Information on dosages for younger patients is also available from this source.
†The information shown is for persons who are taking lamotrigine in combination with an enzyme-inducing antiepileptic drug (carbamaz- epine, phenobarbital, phenytoin, or primidone) and who are not taking valproic acid. For persons who are not taking an enzyme-inducingantiepileptic drug or who are taking valproic acid, the dose schedule is different. Consult the package insert.
‡After four weeks, the daily dose can be increased by 100 mg every two weeks.
§The dose should be increased at a rate of 30 to 50 mg per day at four-week intervals when the phenytoin plasma concentration is higher concentration is at the upper end of the therapeutic Initial Toxicity
range, the patient is still having seizures, and the drug Sedation, dizziness, ataxia, headache, and nausea has no side effects, the dose should be increased. Plas- are common during the initiation of treatment with ma drug concentrations within the therapeutic range antiepileptic drugs.22,23,31 The toxic effects can be man- may have toxic effects. In some patients, seizures are aged by reducing the dose by 25 to 50 percent and controlled with plasma drug concentrations that are waiting two weeks for tolerance to develop. Treatment with the initial dose or a regimen of gradually in- Titration of the dose of phenytoin deserves special attention because phenytoin has nonlinear pharma- Most antiepileptic drugs can cause a rash during the cokinetics.30 When the plasma phenytoin concentra- first weeks of therapy.31,32 Although the rash usually tion is higher than 10 µg per milliliter, an increase resolves without sequelae, in some cases it progresses in the dose results in a disproportionate increase in to the Stevens–Johnson syndrome or other serious the plasma concentration, which can lead to toxic ef- conditions. Rashes caused by antiepileptic drugs are fects; conversely, a decrease in the dose results in a erythematous maculopapular or morbilliform erup- disproportionate decrease in the plasma concentra- tions, often beginning on the trunk, face, or upper tion, which can lead to breakthrough seizures. The arms. Danger signs — indicating the risk of a severe practical solution to this problem is to increase or reaction — include a temperature that exceeds 40°C, decrease the dose of phenytoin by only 30 to 50 mg exfoliation, mucosal lesions, facial edema, confluent per day when the plasma concentration is higher than erythema, skin pain, palpable purpura, skin necrosis, lymph-node enlargement, and asthmatic symptoms.
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If possible, a patient with a rash should be seen im- of the newer antiepileptic drugs for partial seizures mediately by a physician in order to rule out a cause (Table 3) are approved by the Food and Drug Admin- that is unrelated to the antiepileptic drug (e.g., tinea istration only as adjunctive therapy, however, there has infection or heat rash) and to check for signs that the been increased use of two-drug regimens that consist patient is at risk for a severe reaction. If the rash ap- of one first-line drug and one of the newer second- pears to be associated with the antiepileptic drug or if line drugs. These two-drug regimens have been fairly the rash cannot be observed by a physician because effective and reasonably safe.25,33-39,41 of logistic problems, the dose should be rapidly ta-pered, in the absence of signs that a severe reaction DISCONTINUING THERAPY
may occur. If such signs are present, the drug should Once antiepileptic-drug therapy has been initiated, be stopped. Gabapentin,33 divalproex sodium,34 and it is maintained for two or more years, even if the pa- levetiracetam,35 which rarely cause rashes, can be pre- tient is free of seizures. If after two years of therapy the scribed to control seizures while the drug that has patient remains free of seizures, withdrawal of the an- tiepileptic drug should be considered. The disadvan-tages of continuing treatment indefinitely include the Toxic Effects during Long-Term Therapy
risks of side effects, drug interactions, and teratogen- Neurotoxic effects are common during long-term icity, as well as the costs of the therapy.
treatment with antiepileptic drugs.22,23,31 If the seizures The risk of recurrent seizures is approximately 25 are fully controlled and neurotoxic effects are present, percent among patients without risk factors and more the dose of the antiepileptic drug can be reduced. If than 50 percent among those with risk factors.42,43 the seizures are not fully controlled and neurotoxic Approximately 80 percent of recurrences occur with- effects are present, the patient should be given anoth- in four months after a regimen of tapered doses has been initiated, and 90 percent occur within the firstyear.42,43 Driving and other potentially dangerous ac- Inadequate Seizure Control
tivities should be prohibited for at least the first four If the seizures are not controlled with the initial months after the start of drug withdrawal.43 dose of a first-line drug and if there is no evidence of Factors associated with a high risk of recurrent sei- serious toxicity, the dose of the drug should be sys- zures include a known structural lesion, electroenceph- tematically increased until the seizures are controlled alographic abnormalities, the onset of the seizure dis- or until side effects preclude further increases in the order during adolescence, neurologic abnormalities, dose. If the maximal tolerated dose of the first-line and severe epilepsy (i.e., a history of frequent seizures antiepileptic drug has been used and the seizures are or seizures that have been difficult to control, requir- still not controlled, another first-line antiepileptic drug ing more than one antiepileptic drug).42,43 Factors as- or a second-line antiepileptic drug should be added.
sociated with a low risk of recurrent seizures include A number of drugs can be used as second-line thera- idiopathic seizures, normal findings on the electroen- py for the most common types of seizure, which are cephalogram, the onset of the disorder in childhood, partial seizures (Tables 2 and 3).25,33-39 One practical the absence of neurologic abnormalities, and seizures way to deal with the large number of available drugs that have been easily controlled with one antiepileptic is to select one for maximal safety and one for max- The decision about whether to stop treatment must When starting a second antiepileptic drug, we usu- be individualized. The following factors should be ally continue to administer the first antiepileptic drug weighed: the probability of recurrent seizures, the con- to provide protection until a full dose of the second sequences of a recurrence (e.g., loss of the patient’s drug is being administered. Once the second drug is driver’s license), and the advantages of discontinuing being given at a full dose, there are strong arguments medication. If the decision is made to discontinue an- for gradually withdrawing the first drug (according tiepileptic therapy, the drug (or drugs) should be with- to the guidelines discussed in the next section). The drawn slowly in order to reduce the risk of withdrawal- advantages of this approach include reduced risks of associated seizures.42-44 One approach is to reduce the idiosyncratic reactions, drug interactions, teratogenic- daily dose by 25 percent every two to four weeks.44 ity, and other adverse events.40 However, if two-drug Rapid withdrawal of a benzodiazepine or a barbiturate therapy completely controls seizures, caution is re- is particularly likely to precipitate seizures.
quired in removing the first drug because of the riskof recurrent seizures, which can lead to loss of driv- WHEN TO SEEK NEUROLOGIC
CONSULTATION
In recent years, regimens of two or more antiepi- leptic drugs were generally used for the treatment of Refractory Status Epilepticus
partial seizures only after two or more first-line drugs Status epilepticus is a condition in which the patient given as monotherapy had been ineffective. Since most has more than one seizure and does not fully recover N Engl J Med, Vol. 344, No. 15 · April 12, 2001 · www.nejm.org · 1149
Downloaded from nejm.org on May 23, 2011. For personal use only. No other uses without permission. Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 3. ADJUNCTIVE MEDICATIONS FOR PARTIAL SEIZURES.*
INTERACTIONS
RESPONSE
WITH OTHER
FREQUENCY
TOXICITY
OF ADMINISTRATION
†The response rate denotes the percentage of patients with at least a 50 percent reduction in the frequency of partial seizures. The data are from separate studies that involved only adults and that differed in the methods used. The resultsmay therefore not be strictly comparable and may not apply to children. NA denotes not available from recent, controlledstudies.
between seizures.45,46 The most common form of this a form of epilepsy that is particularly difficult to treat, disorder is tonic–clonic status epilepticus, which be- such as the Lennox–Gastaut syndrome or infantile gins as a series of tonic–clonic seizures (phase I).46 Tonic–clonic status epilepticus is usually managedby a regimen of intravenous diazepam or lorazepam REFERENCES
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