Epilepsy in Adults
Omkar N. Markand
I. DEFINITIONS
A.
An epileptic seizure is a transient and reversible alteration of behavior caused by a paroxysmal, abnormal, and excessive neuronal discharge.
B.
Epilepsy usually is defined as two or more recurring seizures not directly provoked by intracranial infection, drug withdrawal, acute metabolic changes, or fever.
II. CLASSIFICATIONS
There are two classifications—one of seizure types and one of epilepsy or epileptic syndromes. Accurate diagnosis of the type of epileptic seizure and the categorization of epilepsy (or epileptic syndrome) for each patient are essential for proper selection of antiepileptic drug (AED) therapy and for prognosis.
A. Classification of epileptic seizures
is based on the patient’s behavior during seizures and on the associated EEG characteristics. Epileptic seizures are classified into two main types—partial and generalized.
1. Partial (focal) seizures
arise at specific loci in the cerebral cortex and are associated with focal interictal and ictal EEG changes. Clinically, a partial seizure can range in intensity from a disorder of sensation without loss of consciousness to a generalized convulsion.
Simple partial seizures. Consciousness remains intact. Such seizures can be motor seizures (focal motor twitching or Jacksonian seizures), sensory seizures (numbness or tingling involving parts of the body), autonomic seizures, or seizures with psychic symptoms.
Complex partial seizures. Consciousness is impaired during complex partial seizures. Previously, these seizures were called psychomotor seizures. They constitute the most common type of seizure in adults. Approximately 85% have an epileptogenic focus in the temporal lobe, whereas the remaining 15% are of extratemporal origin, usually frontal.
Secondarily generalized (tonic-clonic) seizures. During any focal seizure (simple or complex partial), the epileptic excitation can spread widely to the entire brain, resulting in a generalized tonic-clonic convulsion.
2. Generalized seizures
are characterized by generalized involvement of the brain from the outset and have no consistent focal areas of ictal onset. There are many subtypes.
Absence seizures were formerly known as petit mal seizures. The dominant feature is a brief loss of consciousness with no or minimal motor manifestations (e.g., twitching of the eyelids). During the seizure, EEG shows 3-Hz generalized spike-wave discharges.
Myoclonic seizures are brief jerks involving part of the body or the entire body.
Clonic seizures are rhythmic twitching of the body.
Tonic seizures are brief attacks of stiffness in part of the body or the entire body.
Atonic seizures are losses of posture with resultant drop attacks.
Tonic-clonic seizures are generalized convulsions or grand mal seizures. It is important to emphasize that some tonic-clonic (grand mal) seizures are generalized from the outset and some are secondarily generalized (they start as focal seizures and then become generalized). The second type is the most common among adults. The presence of an aura, focal manifestations during the seizure, and postictal focal deficits favor a secondarily generalized tonic-clonic seizure.
Confusion can arise in differentiating absence seizures and complex partial seizures. Both can present with a brief loss of awareness or altered responsiveness, and in both there may be automatic activities of various kinds. Diagnosis is aided by EEG findings (generalized spike-wave discharges in absence seizures and focal epileptiform abnormalities in complex partial seizures). Correct diagnosis is critical for instituting proper AED therapy.
B. Classification of epilepsy or epileptic syndromes.
Classifying the seizure type, although useful, is of limited value because seizures usually appear as part of a cluster of other symptoms and signs that include etiologic factor, site of seizure onset, age, precipitating factors, response to medication, and prognosis. Hence, the ultimate goal is to diagnose epilepsy or an epileptic syndrome. This is very important. It helps to choose the appropriate AEDs to control seizures and to avoid using an AED, which may not only be ineffective but may even exacerbate seizures.
1. Localization-related (focal or partial) epilepsy or epileptic syndromes
are disorders in which a localized origin of the seizures can be established. The patient has focal or secondarily generalized tonic-clonic seizures. EEG shows focal epileptiform discharges overlying the epileptogenic focus.
Most localization-related forms of epilepsy are acquired or symptomatic. Temporal lobe epilepsy is the common localization-related epilepsy among adults, and it is often associated with mesial temporal sclerosis on the MRI scan.
There are age-related idiopathic or primary localization-related epileptic syndromes. The best known is benign rolandic epilepsy of childhood.
2. Generalized epilepsy or epileptic syndromes
are disorders that involve one or more types of generalized seizures. EEG shows generalized epileptiform abnormalities.
Primary (idiopathic) generalized epilepsy (PGE) is characterized by generalized seizures without any identifiable etiologic factor. EEG shows generalized spike-wave or polyspike-wave discharges with a normal background activity. Genetic factors predominate in these forms of epilepsy. Common syndromes include childhood absence epilepsy, juvenile myoclonic epilepsy, juvenile absence epilepsy, and tonicclonic seizures occurring often in the early morning (“awakening” grand mal).
Secondarily (symptomatic) generalized epilepsy is characterized by various types of generalized seizures resulting from acquired cerebral diseases (e.g., seizures secondary to ischemic-hypoxic encephalopathy or following severe cerebral trauma or intracranial infection) or from inborn errors of metabolism (e.g., lipidosis and progressive myoclonus epilepsy). EEG shows generalized, irregular spike-wave, 2.5 Hz in frequency with an abnormally slow background activity. Patients usually have varying degrees of cognitive and neurologic deficits, and the seizures are often drug resistant. Within this category are two commonly recognized age-related syndromes—West’s syndrome (infancy) and Lennox-Gastaut’s syndrome (childhood).
III. EVALUATION
It is essential to establish that the spells or episodes are indeed epileptic seizures. Nonepileptic physiologic disorders that result in transient, reversible alterations of behavior or function, such as syncope, migraine, breath-holding spells, anxiety episodes, transient ischemic attacks, hypoglycemic episodes, and narcoleptic-cataplectic attacks, must be differentiated from epileptic seizures. Moreover, there are nonepileptic psychogenic seizures or pseudoseizures that are conversion reactions characterized by episodes of motor activity and loss of consciousness but not associated with ictal EEG patterns and without an underlying physiologic basis.
A.A history
of the episodes, obtained not only from the patient but also from one or more observers, is perhaps the most essential element in making the diagnosis of epileptic seizures and differentiating them from nonepileptic disorders. The history can aid in ascertaining the type of epileptic seizures.
B. Physical and neurologic examinations
can help detect the underlying cause of the brain disorder responsible for the epilepsy by uncovering evidence of a focal cerebral lesion or another organic disorder, such as tuberous sclerosis or neurofibromatosis.
C. Neuroimaging.
Although CT of the head with and without contrast enhancement is performed on most patients believed to have epilepsy, MRI of the head is the imaging procedure of choice. MRI is particularly sensitive in detecting hamartoma, cavernous malformation, and low-grade glioma and in providing evidence of mesial temporal sclerosis in patients with temporal lobe epilepsy.
D. EEG
is the most informative test for confirmation of the diagnosis of epilepsy and proper classification of the seizure type and even the epileptic syndrome. It also aids in initiation, selection, and discontinuation of antiepileptic therapy (see Chapter 33).
Not all patients with epilepsy have interictal epileptiform abnormalities; approximately 50% have such abnormalities in a routine awake-and-asleep EEG study that includes hyperventilation and intermittent photic stimulation. The yield increases with repeated EEG studies with sleep deprivation and extra recording electrodes. On the other hand, 1% to 2% of healthy persons without clinical seizures have epileptiform abnormalities in EEG studies. Hence, an interictal EEG alone can neither prove nor exclude a diagnosis of epilepsy. Similarly, the presence of interictal epileptiform EEG abnormalities does not automatically warrant AED therapy, and the absence of such abnormalities is not sufficient grounds for discontinuing AED treatment.
E. Intensive video EEG monitoring.
Patients with drug-resistant epilepsy or poorly characterized episodes may need intensive monitoring that consists of simultaneous monitoring of the patient’s behavior and EEG to provide detailed clinical and EEG correlation of episodic events. This is an expensive and time-consuming technique and thus is left to the discretion of a consulting neurologist specialized in epilepsy. Only 5% to 10% of patients believed to have epilepsy need this technique to characterize and classify the epileptic episodes. Video EEG is mandatory in the presurgical evaluation of patients to document epileptic seizures prior to surgical resection to treat epilepsy, and even before placing a patient on vagal nerve stimulation (VNS). It is most helpful in patients who have frequent episodes that are suspected to be of the nonepileptic type. These episodes are not accompanied by the characteristic ictal pattern in the simultaneously recorded EEG.
IV. GENERAL PRINCIPLES IN TREATING PATIENTS WITH EPILEPSY
A.
AED therapy should be initiated only when the diagnosis of epileptic seizures is wellestablished. If the patient’s episodes are yet to be clearly defined and there is reasonable doubt of their being epileptic in nature, it is prudent to wait until the diagnosis of epilepsy can be confirmed.
B. First seizure.
AED therapy usually is not initiated after the first tonic-clonic seizure and postponed until a second seizure occurs when the diagnosis of recurrent seizures or epilepsy is made. The incidence of recurrence is 25% to 65% after the first and over 75% after the second seizure. The first seizure can be an isolated episode and not necessarily the onset of epilepsy. This is particularly true if a single tonic-clonic seizure was related to sleep deprivation, physical or mental stress, drug or alcohol withdrawal, or use of prescribed (e.g., Welbutrin) or recreational drugs (e.g., cocaine). In general, 50% of patients have recurrence over a 3-year follow-up period after the first tonic-clonic seizure. The incidence is <25% among subjects with low-risk factors to 65% or more for those with two or more of the following risk factors: strong family history of seizures in siblings, history of febrile convulsions, focal-onset seizure, postictal paralysis, abnormal findings at cognitive and neurologic examinations, evidence of a structural cerebral lesion at neuroimaging, and the presence of epileptiform abnormalities at EEG. Patients with two or more of these risk factors therefore may need prompt initiation of therapy even after the first tonic-clonic seizure.
C. Monotherapy
is preferable to the use of several drugs because it has fewer toxic side effects, less likelihood of drug interactions, and better compliance. The chosen AED (Table 39.1) should be slowly increased until seizures are controlled or until clinical signs of toxicity develop. If seizures are not adequately controlled at the maximum tolerable dosage, a second AED is slowly introduced. After the second drug attains therapeutic
levels, the first drug is gradually withdrawn. Monotherapy adequately controls newonset epilepsy in about two-thirds of the patients.
levels, the first drug is gradually withdrawn. Monotherapy adequately controls newonset epilepsy in about two-thirds of the patients.
TABLE 39.1 AEDs of Choice for Specific Type of Seizures and Epilepsy Syndromes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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D. Polytherapy
with a combination of two AEDs (usually one traditional and one newer AED) becomes necessary only if monotherapy with two or more first-line AEDs has been unsuccessful. When using two AEDs, select those with different mechanism of action. Avoid using more than two AEDs simultaneously. If a combination of two AEDs in the treatment of a compliant patient with blood levels in the therapeutic range fails to provide adequate control of epileptic seizures, referral to an epileptologist or epilepsy center is indicated for further evaluation and management. After two appropriate AEDs fail to control seizures, monotherapy with a third AED or polytherapy is successful in only 4% of the patients.
E. AEDs with sedative or hypnotic side effects
need to be avoided unless first-choice AED does not work. Drugs with these effects include phenobarbital, primidone, and clonazepam. Often a patient undergoing polytherapy that includes one of the aforementioned sedative AEDs is best served by very gradual withdrawal of the sedative AED while the dosage of the other AED is maximized. Discontinuation of sedative-hypnotic AEDs is followed not only by a reduction in side effects but also by better control of seizures in many instances.
F. Simplify drug schedules.
Most AEDs have long elimination half-lives (see Tables 39.3 and 39.5), and thus can be prescribed in a single daily dose or two divided daily doses. Exceptions include the traditional AEDs, such as valproic acid and carbamazepine (extended release valproate and sustained release carbamazepine are now available), and the new AEDs such as gabapentin and tiagabine, which have to be given in two or three divided daily doses. With multiple AEDs, half-lives of some AEDs are shorter than when the same drug is given in monotherapy. Thus, larger doses and multiple dosing are required.
G. Compliance
must be emphasized. Medication is best taken at the time of meals for easy remembrance. For most AEDs, an occasional missed dose can be made up by taking an additional dose within the same 24-hour period. It is also convenient for the patient to put the medication in a plastic pillbox with divided compartments and to ensure at bedtime that the entire day’s medication has been taken.
H.
Advise the patient to maintain a seizure diary. Such a diary provides an accurate record of the frequency of seizures and assists in evaluating the effectiveness of the therapy.
I.
Emphasize to the patient the need for constant medical follow-up care. Once AED therapy is well-established and the seizures have been brought under satisfactory control, the patient should be examined every 6 to 12 months. During the follow-up visits, evaluate the patient for evidence of drug toxicity or development of a progressive neurologic disorder. CBC, liver function tests, and serum electrolytes may need to be performed every 6 to 12 months to detect untoward effects of AEDs on the bone marrow and liver. However, routine blood testing at periodic intervals is a controversial issue because serious side effects are rare and, when they occur, they do so over a short period to be detected by periodic monitoring.
J.
A patient who achieves good control with drug therapy may have a “breakthrough” seizure during periods of physical or mental stress, sleep deprivation, or infection. Appropriate management of such precipitants rather than increases in dose or changes in the AED is indicated.
K. Generic substitution
for brand-name AEDs can reduce the cost of medication, but the bioavailabilities of generic and proprietary AEDs are not the same. Generic preparations are required by the U.S. Food and Drug Administration (FDA) to provide bioavailabilities within ±20% of those of the corresponding proprietary formulations, but some patients may be sufficiently sensitive to these fluctuations that replacing one with the other leads to either loss of seizure control or signs of neurotoxicity. This problem applies primarily to phenytoin and carbamazepine. The proprietary phenytoin (Dilantin; Pfizer, New York, NY, USA) is more slowly absorbed than is generic phenytoin, so blood levels are maintained with less fluctuation, and no more than one or two daily doses are required. Similarly, brand-name carbamazepine (Tegretol; Novartis, East Hanover, NJ, USA) is absorbed more slowly than is the generic formulation. It is probably prudent to continue name brand AED if the patient is seizure free on
that formulation. If changed to generic AED the patient needs to be warned of the possibility of break-through seizures or drug toxicity. The patient should avoid switching between formulations of AEDs. When a generic AED is used, the formulation by the same manufacturer should be refilled.
that formulation. If changed to generic AED the patient needs to be warned of the possibility of break-through seizures or drug toxicity. The patient should avoid switching between formulations of AEDs. When a generic AED is used, the formulation by the same manufacturer should be refilled.
L. Therapeutic drug levels
are rough guides to the ranges that in most patients provide best seizure control while avoiding dose-related side effects. The blood should be drawn preferably before the morning dose of AEDs so as to obtain the lowest (trough) levels. The blood levels are not to be followed rigidly for a given patient. Some patients may attain complete seizure control at low “therapeutic” levels, and increasing the dose to attain idealized levels is not indicated. On the other hand, there are patients who need higher than “therapeutic” levels for control of their seizures and tolerate such levels without significant untoward side effects. In such patients, it is fully justified to maintain phenytoin level as high as 20 to 30 µg per ml, valproic acid level as high as 100 to 150 µg per ml, and carbamazepine level as high as 12 to 15 µg per ml. Anticonvulsant blood levels are indicated under the following circumstances:
1.
To determine the baseline plasma dose level.
2.
When the patient is believed to be noncompliant.
3.
When the patient does not respond adequately to the usual dosage of an AED.
4.
When symptoms and signs of clinical toxicity are suspected.
5.
When there is a question of drug interaction.
6.
To establish the correct dosage for a pregnant patient or a patient with diseases affecting the pharmacokinetics of the AEDs (hepatic, renal, or gastrointestinal disorders).
Total serum levels of AEDs usually are obtained. When metabolism of AEDs may be altered or serum protein levels are likely to be low (e.g., hepatic or renal disorders and pregnancy), free levels of highly protein-bound AEDs may become necessary.
M.
Emphasize the need to regularize the time and duration of sleep, because sleep deprivation tends to potentiate seizures.
N. Concomitant use of other drugs.
Alcohol in any form is best avoided or used in small amounts (e.g., one drink) because of possible interactions with most AEDs. Be aware of drugs that lower the seizure threshold (e.g., tricyclic antidepressants, Welbutrin, and phenothiazines) or those that can cause drug interactions (increasing or decreasing the levels of AEDs); they should be used with caution. Some AEDs affect the elimination kinetics of many drugs metabolized in the liver (e.g., birth control pills, corticosteroids, anticoagulants, and cyclosporine), necessitating proper dose adjustment of these comedications.
O.
Encourage the patient to make the adjustments necessary for leading a normal life as much as possible. Moderate exercise does not affect seizure frequency. Encourage a regular exercise program. Participation in highly competitive sports increases the risk of physical injury. Individualize instructions to the patient by considering the risk of a particular sport against the patient’s needs. Swimming may be permitted under supervision for a patient with good control of seizures. Bathing in a bathtub is to be avoided; taking a shower is recommended instead.
P.
Most adults who have epilepsy are able to maintain competitive employment and should be encouraged to do so. This improves their self-esteem and their acceptance in the mainstream of society. There are, however, some realistic limitations on the types of work a patient with epilepsy can be permitted to do. Certain occupations, such as working with heavy machines, working above ground level, working close to water or fire, driving trucks or buses, and flying planes, may be off limits for reasons of personal and public safety. There are still scores of jobs such as secretary, lawyer, physician, accountant, and stockbroker that are acceptable.
Q.
Family members or caregivers should be educated regarding proper care of the patient when a seizure occurs. During a grand mal seizure, the patient should be helped to lie on the ground, a bed, or a couch and should be turned on one side to avoid aspiration. An object such as a spoon or a finger should never be thrust into the patient’s mouth. It is a myth that the tongue can be swallowed during a seizure. Pushing a hard object into the mouth often results in broken teeth. The patient must be closely watched and the sequence of events observed during the seizure, which can help determine the type of seizure.
R.
For a patient with a known history of seizures, an isolated self-limiting seizure does not constitute a need to call for an ambulance and have the patient rushed to an emergency department. However, if the seizure lasts longer than 5 minutes or if the patient has repeated seizures without regaining consciousness between them, prompt transfer to a nearby hospital becomes essential. Prompt medical attention must also be sought if patient had a fall and sustained bodily injury.
S. Driving.
Most states have laws denying driving privileges to patients with uncontrolled epilepsy but permit driving once the seizures have been brought under control with AEDs. In a few states, doctors are required to report cases of epilepsy. The period of time that the patient must remain seizure-free before being permitted to drive varies from 3 months to 2 years, depending on the state. Rare patients who have only nocturnal seizures or who have only simple partial seizures (no loss of consciousness) may be exempted from driving restrictions. Reinstitution of driving privileges may require reapplication, a letter from the treating physician, or a determination made by a stateappointed board. Some states require the treating physician to certify at regular intervals that the patient has continued to remain seizure-free before reissuing the driving permit. Because the laws regarding driving vary widely among different states and are frequently changing, physicians are best advised to obtain their current state registration.
In general, patients with frequent seizures with altered consciousness must be advised to refrain from driving until seizures can be satisfactorily controlled. That the patient has been properly advised must be documented in the patient’s record.
There is no consensus as to how long the patient should be advised not to drive after having a breakthrough seizure after a long seizure-free period. If such a seizure follows a known precipitant such as infection, mental or physical stress, prolonged sleep deprivation, or poor compliance, observation for at least 3 to 6 months is required before driving is again permitted.
V. SELECTION OF AED
Table 39.1 lists AEDs effective for managing various forms of epilepsy and epileptic syndromes.
A. Symptomatic partial (localization-related) epilepsy.
Several well-designed studies have shown that for simple partial, complex partial, and secondarily generalized tonicclonic seizures, several AEDs, including phenytoin, carbamazepine, valproate, phenobarbital, and primidone, have similar antiepileptic efficacy but differ greatly in toxicity. Primidone and phenobarbital are more often associated with neurotoxicity, probably less effective against simple and complex partial seizures, hence, usually avoided. Valproate is somewhat less effective against complex partial seizures than carbamazepine. There are very small differences in overall effectiveness and basic mechanism of action between carbamazepine and phenytoin. Hence, carbamazepine and phenytoin can be considered as the first-line “traditional” AEDs.
Phenytoin is relatively inexpensive, which can be titrated rapidly in 2 to 3 days, is better tolerated in the initial period of therapy, and can be given in one to two divided daily doses. However, it has a high incidence of chronic dysmorphic side effects, such as hirsutism, coarsening of facial features, and acneiform eruptions, which makes its use rather unacceptable in women. Its nonlinear kinetics makes the dose adjustment difficult during maintenance therapy. Carbamazepine has no dysmorphic effects and hence is better accepted by adolescent and young adult female patients. Its short half-life usually necessitates using it in three or four divided doses, but sustained-release preparations are now available and given in two daily doses. It needs to be slowly titrated over 3- to 4-week period due to autoinduction. Cognitive side effects with long-term use of phenytoin or carbamazepine have been found to be equally frequent in recent studies and both require periodic blood monitoring for bone marrow and liver functions. Oxcarbazepine, which has lesser side effects, rapid titration, and no requirement for blood monitoring, is emerging as a more favored newer AED alternative to carbamazepine since its approval by the FDA for monotherapy in adults with focal epilepsy.
Most physicians now recommend using oxcarbazepine or carbamazepine be used initially as monotherapy. If one of the two is ineffective, it can be replaced with the other. If monotherapy with carbamazepine or oxcarbazepine fails to achieve satisfactory control, a combination therapy with valproic acid is tried—carbamazepine plus valproic acid, or oxcarbazepine with valproic acid. Alternatively, adjunctive therapy with newer AEDs should be strongly considered by adding levetiracetam, lamotrigine, topiramate, zonisamide or lacosamide to carbamazepine, or oxcarbazepine, based on the lesser risk of toxicity and drug interaction of these newer AEDs. Combination therapy is more likely to produce cognitive and other side effects.
Even with adequate AED therapy, only 40% to 60% of patients with symptomatic partial epilepsy, particularly those with complex partial seizures (the most common type of seizures among adults) attain full control of seizures. In one study of new onset epileptic seizures, initial monotherapy was effective in 47% of patients. Changing to a second drug controlled another 13% of patients. Use of a third AED or combined therapy with two or more AEDs controlled only 4% of additional patients. Most experts believe that, if an adequate trial with two or three AEDs (including at least one newer AED) either as monotherapy or combined therapy fails, the patient has medically refractory epilepsy. Such a patient will need a referral to a comprehensive epilepsy center for further management.
B. Primary (idiopathic) generalized epilepsy.
Most patients with PGE have either absence, myoclonic, or tonic-clonic seizures, and most have more than one type of seizure, although one type may dominate. Depending on seizure type, several epileptic syndromes are identified under the heading PGE. The best example is juvenile myoclonic epilepsy, which is characterized by myoclonic seizures in the early hours after waking, but most patients also have occasional tonic-clonic seizures. Less often, even absence seizures may occur. Other syndromes include primary tonic-clonic seizures (contrasted to secondarily generalized tonic-clonic seizures, which are part of focal epilepsy), which commonly occur in the morning hours and hence are called “awakening” grand mal seizures. Absence seizures as the dominant manifestation of PGE commonly occur in childhood (childhood absence epilepsy), but in rare cases start in adolescence or early adulthood (juvenile absence epilepsy).
1. For absences,
both ethosuximide and valproic acid are equal and very effective in controlling these seizures in over 80% of patients. Patients with childhood or juvenile absence epilepsy who have absence seizures only can, therefore, be treated with either ethosuximide or valproic acid. Ethosuximide is preferred because of its lesser toxicity and longer half-life allowing it to be taken in only one or two divided daily doses. But those patients who have additional myoclonic and/or tonic-clonic seizures do need valproic acid for treatment of both absence and motor seizures because ethosuximide is ineffective against motor events.
2. Valproic acid
has clearly been the drug of choice for PGE where multiple seizure types are likely to be present, including the syndrome of juvenile myoclonic epilepsy, primary grand mal seizures, or combined absence-grand mal epilepsy. The advantage of valproic acid is that it is effective against all seizure types comprising PGE.
3.
Appropriate AED therapy is very effective, and good seizure control is possible for as many as 80% to 90% of patients with PGE.
4. Clonazepam
is an effective AED for myoclonic and absence seizures but has certain disadvantages. It has a high incidence of sedative and cognitive side effects, and patients develop a tolerance to its antiepileptic potency after several months of therapy. Furthermore, its use may start or exacerbate tonic-clonic seizures in juvenile myoclonic epilepsy. Use of clonazepam has, therefore, declined since the introduction of newer AEDs. If used for myoclonic or absence seizures, clonazepam can be added to valproic acid if the latter by itself fails to be fully effective.
5.
Because of the high incidence of fetal malformations, polycystic ovarian syndrome (PCOS), and weight gain, the use of valproic acid in women with PGE needs to be restricted because recent well-designed studies have demonstrated effectiveness of the newer AEDs, several of which are broad spectrum in their efficacy.
Lamotrigine is effective against absences, has low teratogenicity, and is a weight neutral AED. It is a good alternative for treating absences associated with childhood and juvenile absence epilepsy. Very recent studies, however, have shown it to be somewhat less effective compared with ethosuximide or valproic acid.
Lamotrigine is also found to be effective in juvenile myoclonic epilepsy, although it can occasionally exacerbate myoclonic seizures.
Topiramate is effective in PGE manifesting with generalized tonic-clonic seizures and approved by the FDA for this indication.
Levetiracetam is effective in all seizure types accompanying PGE and particularly against myoclonic seizures.
Zonisamide is probably effective, also, against all seizure types of PGE, but has more sedative side-effects than lamotrigine and levetiracetam.
6.
Although most patients with PGE can be well-controlled with appropriate AEDs, some 15% are medically refractory. Some are pseudo-refractory because they are on wrong AEDs. In recent years, sodium-channel blocking and gamma-aminobutric acid (GABA)-enhancing AEDs have been recognized to exacerbate certain seizure types in patients with PGE. Carbamazepine, oxcarbazepine, phenytoin, vigabatrin, tiagabine, gabapentin, and pregabalin commonly exacerbate absence seizures, myoclonic jerks, or both, and should not be used in the treatment of PGE. It is, therefore, critical that the patient needs to have the syndromic diagnosis of PGE established even though the precise subtype of PGE may not be identified. This will prevent iatrogenic exacerbation of seizures.
In truly refractory cases, combination therapy using Depakote with either levetiracetam, lamotrigine (but be aware of markedly decreased elimination of lamotrigine by valproic acid), topiramate, or zonisamide may be more effective. Combination of Depakote and ethosuximide may control absences more effectively than either drug alone.
C. Secondarily (symptomatic) generalized epilepsy,
which is secondary to multifocal or diffuse cerebral disorders (static or progressive), occurs mostly among children and less often among adults. Patients have multiple seizure types, including atypical absence seizures, myoclonic seizures, tonic seizures, tonic-clonic seizures, and drop attacks.
In general, response to any AED is poor, only 20% to 40% of patients attaining acceptable seizure control. Such patients commonly end up being treated with polypharmacy, which not only fails to provide better seizure control than do one or two AEDs but may even exacerbate certain types of seizures (absence seizures, myoclonic seizures, and drop attacks).
Valproic acid is the AED of first choice for secondarily generalized epilepsy and may be started as monotherapy. However, most patients need an addition of newer AEDs. Of these, lamotrigine, topiramate, zonisamide, and levetirecetam have been found useful in clinical trials. Felbamate and rufinamide have been approved by FDA for the control of seizures associated with secondary generalized epilepsy of the Lennox-Gastaut’s type but felbamate has potentially serious hepatic and bone marrow toxicity. When drug combinations are prescribed, appropriate dosages should be used to avoid sedation, which tends to exacerbate minor seizures as well as precipitate statuses in such patients.
VI. TRADITIONAL AEDS
Mechanism of action, indications, and common side effects of traditional AEDs are listed in Table 39.2, and their pharmacokinetic characteristics and adult dosages in Table 39.3.
A. Efficacy.
In general, the traditional AEDs have limited efficacy against epileptic seizures especially those associated with focal or partial epilepsy.
1.
The first landmark VA study in 1985 compared carbamazepine, phenytoin, primidone, and phenobarbital in the treatment of partial epilepsy. All four of those AEDs were shown to be equally effective as monotherapy for secondarily generalized tonic-clonic seizures, whereas carbamazepine and phenytoin were more effective and better tolerated than primidone and phenobarbital in the treatment of complex partial seizures.
2.
The second VA study in 1992 demonstrated that carbamazepine was superior to valproic acid in the treatment of complex partial seizures but both were equivalent for secondarily generalized tonic-clonic seizures.
TABLE 39.2 Mechanism of Action, Indications and Undesirable Side Effects of Traditional AEDs | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TABLE 39.3 Pharmacokinetics and Adult Dosages of Traditional AEDs | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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