Epilepsy

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14 Epilepsy

Joel M. Oster, Jose A. Gutrecht, Ritu Bagla, Jeffrey E. Arle, G. Rees Cosgrove

Epilepsy is generally defined as an illness of recurrent seizures. The prevalence of epilepsy is estimated at 1 in 200 persons. It affects all ages and is generally a chronic problem with significant personal, social, and economic impact, often affecting the ability to hold jobs and drive. Poor epilepsy control and the seizures themselves can lead to significant cognitive and personality changes as well as chronic depression. The incidence is about 200,000 new cases yearly in the United States. The clinical manifestations are initiated by abnormal electrical discharges within the brain. The underlying pathophysiology is complex and not completely defined, but ultimately involves repetitive cortical potentials leading to altered modulation of excitatory inputs and suppression of inhibitory feedback circuits (Fig. 14-1). The diagnosis of epilepsy is primarily clinical, based on patient and witness history of the events and on the neurologic examination. An abnormal electroencephalograph (EEG) may substantiate a suspected diagnosis with specific EEG patterns, particularly focal or generalized spikes or spike-and-wave discharges, being highly associated with seizures. Many other EEG changes are not specific for seizures and are of little help in differentiating epileptic from nonepileptic events. Epilepsy is a treatable disease, often with a specific correctable medical or surgical pathology. Accurate diagnosis must be the predominant goal in approaching a patient with seizures of recent onset. Magnetic resonance imaging (MRI) and neuroimaging studies are critical to define any potentially treatable structural brain disease (Fig. 14-2). Laboratory testing may assist in the evaluation and treatment. Patients with chronic forms of epilepsy require long-term medical treatment. Failure of medical therapy or quality-of-life issues may necessitate intensive patient evaluation for potential seizure surgery. Surgical removal of carefully selected areas of diseased brain may provide improvement and often a cure.

Figure 14-1 Origin and Spread of Seizures.

Figure 14-2 Neuroimaging Studies.

Differential Diagnosis

All paroxysmal disorders of consciousness or perception may be included in the differential of seizures. Migraine with aura (classic migraine) is differentiated by generally distinct and recurrent positive visual or sensory phenomenon evolving gradually, then resolving over minutes and followed by a throbbing often unilateral headache. Transient ischemic attacks are characterized by negative (loss of function) neurologic symptoms often consistent with a single vascular territory that start maximally, then resolve gradually over seconds to minutes. Syncope is usually preceded by prodromal symptoms of lightheadedness, limpness, pale complexion, and diaphoresis. Once the patient falls or lies down and cerebral circulation is restored, full consciousness is regained with little or no persistent confusion or disorientation, unlike the postictal period following seizures. Parasomnias with stereotyped nocturnal movements and psychiatric disorders can also be confused with seizures. One disorder that continues to be difficult to classify is transient global amnesia (TGA). It is considered by most to be a distinct benign entity that does not warrant any specific long-term treatment. A brief discussion follows.

Transient Global Amnesia

Transient Global Amnesia is a term that was first used by Fisher and Adams in the 1960s to denote a syndrome of abrupt onset of severe anterograde amnesia with other elements of neurologic function remaining intact or unchanged from baseline. Retrograde amnesia may be present to a variable degree. Patients appear anxious or even agitated but are able to communicate and often ask the same exact questions repeatedly even when answered promptly. Patients recover fully without residual memory problems but have no recollection of the spell and do not normally evoke any precipitating event. Associated altered level of consciousness, ataxia, dysarthria, visual changes, headache, abnormal movements, and vomiting strongly suggest a basilar ischemic etiology or seizure and should be absent. Several etiologies have been proposed including seizure, migraine, ischemia, venous congestion, and psychogenic disturbances.

In 1985 Caplan proposed to reserve the term TGA for patients who do not have epilepsy. Case reports of documented seizures causing memory dysfunction mimicking TGA have been described. However, attacks in these cases tend to recur more frequently and are generally briefer, lasting minutes as opposed to hours with classic TGA. Unlike TGA, these attacks may be associated with EEG abnormalities and respond to antiepileptic medications. TGA cases rarely recur and there have been no consistently associated EEG epileptiform abnormalities. A theoretical concern however is that surface EEG may not detect deep mesial temporal seizures. To date, there have not been any reports of invasive or implanted electrodes monitoring during a typical spell of TGA.

A review of the TGA literature suggests associated subtle neuroimaging changes with transient intense diffusion-weighted imaging (DWI) signal seen within the hippocampus. This has led to the speculation of a vascular cause of the syndrome. However, similar DWI changes and transient hippocampal dysfunction have been seen in the perictal period and is due to excitotoxicity rather than ischemia.

Therefore, for now, the exact etiology of TGA remains unknown and without an identifiable purely vascular or an ictal mechanism; more research will be needed to settle the issue.

Partial Seizures

Simple Partial Seizures

Clinical Vignette

A 40-year-old woman experiences episodic numbness that spreads from the left thumb to the hand, arm, and then to the face over a period of about 30 seconds. These occur sporadically and are stereotypical in nature. She maintains alertness throughout the events. Since starting antiepileptic medications, these events have abated.

This history represents typical simple partial seizure (SPS). During the episodes, patients are conscious, aware of their surroundings, and able to respond appropriately. Partial seizures originate and develop within a discrete area of the cerebral cortex (Fig. 14-3). They may have a “Jacksonian march” wherein the cortical epileptic discharges spread along contiguous cortical regions. The brain area involved determines the clinical signature of the event. Symptoms may be somatosensory, as in the above vignette, when the origin is in the parietal lobe, motor when discharges arise from the frontal or motor cortex, and visual when they begin in the occipital lobe. However, the relation of focal cortical location to clinical expression is not absolute. Seizures may start in a “silent” cerebral cortical area with the manifest ictal symptoms representing the result of the discharge spreading to neighboring cortical areas. SPSs may occasionally have autonomic, psychic, or cognitive manifestations. Other seizure types may start off as SPS and then evolve into broader disruptions. By definition, these simple ictal events do not include any change in level of consciousness and it is this preserved responsiveness to the external environment that characterizes SPSs. Auras, a warning that a patient experiences prior to altered or loss of consciousness, are, in effect, SPS.

Figure 14-3 Classification of Partial Seizures.

Clonic phases of partial motor seizures that continue uninterrupted for prolonged periods, with no progression into other body segments, are known as epilepsia partialis continua, or Kojevnikov syndrome, and are discussed below.

The clinical evaluation of patients with partial epilepsy must include an EEG, a neuroimaging test, and laboratory testing. Although routine EEG recordings may often be normal in patients with unequivocal seizure disorders, it remains of paramount importance for the correct diagnosis and classification of the ictal events. Even when the neurologist suspects a seizure disorder from the clinical description, the EEG, if positive, may serve as an important confirmatory test when the episode is not well described. It should be remembered, however, that a routine EEG represents only a limited time sample and that sporadically firing interictal discharges can, therefore, be easily missed in patients with unequivocal seizure disorders. Long-term seizure telemetry units and ambulatory EEG monitoring are now available to increase recording time and enhance detection rates. The EEG hallmark of partial epilepsy is focal spikes or spike-and-wave discharges. Because delta-wave non-REM sleep activates or disinhibits epileptiform discharges, the EEG is preferably recorded during both wakefulness and sleep to increase the probability of making the correct diagnosis and defining the focal origin (Fig. 14-4). A definitive result is often obtained only during sleep recordings. Repeated recordings may be necessary if the nature of the episode is unclear or if psychogenic nonepileptic seizures are suspected. In contrast, the EEG in patients with epilepsia partialis continua contains spike-wave discharges in a variably continuous manner, often in the contralateral frontal lobe. A small number of individuals in the healthy population have abnormal EEG containing focal spikes but do not go on to have seizures later in life. This emphasizes that an abnormal EEG can only be interpreted in light of the presenting clinical symptoms and that it does not, on its own, define a seizure syndrome or dictate treatment. At best, the EEG may capture an ongoing seizure and greatly clarify its origin. It may also help to localize the epileptogenic pathology, guiding surgery if medical treatment fails.

Figure 14-4 Electroencephalography.

Neuroimaging studies, especially MRI, are vital to the evaluation of new-onset or changing-pattern seizures. Brain computed tomography is a useful screening technique when MRI is not available. The onset of new partial seizures strongly suggests the development of a new pathologic process, including tumors (primary or metastatic) or abscess in the adult population, stroke from emboli or rarely vasculitis in older age groups, and focal encephalitis such as Rasmussen encephalitis in children, herpes simplex encephalitis in children or adults, or head trauma (Fig. 14-5). However, sometimes a patient with a lesion, for example, mesial temporal sclerosis or an AVM, does not present with partial seizures until adulthood. Rarely, acute-onset partial seizures may be caused by metabolic abnormalities, such as nonketotic hyperglycemia or hypoglycemia.

Figure 14-5 Causes of Seizures.

Complex Partial Seizures

Clinical Vignette

A 37-year-old patient experiences episodic events that start with a rising feeling in the stomach followed by a blank stare with loss of awareness. Subsequently, he has nonpurposeful movements of the hands lasting several minutes followed by somnolence.

This patient’s history represents a typical example of complex partial seizures (CPSs). The clinical manifestations of this seizure type include changes in alertness or level of consciousness, partial amnesia, and automatisms (Fig. 14-3). Patients often perform simple motor tasks and even may walk during the seizure. CPSs usually arise from mesial temporal structures but can also originate in other extralimbic temporal structures or the inferior frontal lobe and spread via the uncinate fasciculus and other pathways to the mesial temporal area.

Partial seizures of frontal lobe origin are frequently confused with a CPS of temporal origin but are distinguished by brief auras with rapid generalization or versive head and eye movements with tonic posturing of the arms. Rarely, a fall is the only clinical feature. Nocturnal frontal lobe seizures often produce odd complex behaviors suggestive of psychogenic nonepileptic seizures but should be kept in mind in those with fairly consistent patterns and no obvious secondary gain.

Because complex seizures are of focal origin, patient evaluation is similar to that undertaken for SPS. Typically, the interictal EEG (i.e., obtained between seizures) reveals spike discharges in one or both anterior temporal lobes. The ictal EEG is usually abnormal, with recurrent focal spikes or rhythmic activity. Brain MRI with special attention given to the temporal lobes shows that these patients often have mesial temporal lobe sclerosis with cell loss and atrophy (see Fig. 14-5).

Partial Seizures with Secondary Generalization

At times, an SCS or a CPS develops into a generalized tonic–clonic convulsion. Careful attention to the history is necessary to distinguish this secondarily generalized seizure from a primary generalized convulsion, especially when the event goes unwitnessed or the initial partial symptom may be brief or not recalled. Capturing a seizure with continuous EEG recordings may be the only way to differentiate them.

Generalized Seizures

Tonic–Clonic (Grand Mal) Seizures

Clinical Vignette

A 40-year-old patient experiences events in which he suddenly stiffens, cries out, loses consciousness, and progresses to have rhythmic tonic–clonic movements of all four extremities lasting several minutes. The events are associated with incontinence, tongue bites, muscle soreness, and ultimately a state of somnolence. Several hours later, the patient was awake and back to normal but had no recollection of the event.

This type of seizure represents the classic picture that the public and medical community generically perceives as epilepsy. Generalized seizure begin with simultaneous and almost equal involvement of both hemispheres from the onset and, unlike partial seizures with focal cortical abnormalities, involve the deeper thalamic, subcortical, and brainstem structures in a feedback loop to the cortices. Tonic–clonic (grand mal) seizures are often preceded by nonspecific, vaguely defined prodromes lasting at times up to hours or have no promontory symptoms at all. Seizures with specific auras, on the other hand, usually are of a focal origin with secondary generalization.

Grand mal seizures start with loss of consciousness, a cry, generalized tonic muscle contraction, and a fall (Fig. 14-6). Autonomic signs are often present during the tonic phase, including tachycardia, hypertension, cyanosis, salivation, sweating, and incontinence. The tonic muscle contraction becomes interrupted relatively soon and is followed by the clonic phase of the seizure with brief relaxation periods progressively lengthening until the seizure eventually abates. Patients may remain stuporous for a moment and eventually awaken confused with postictal headaches, lethargy, disorientation, and myalgia that may persist for up to a few days.

Figure 14-6 Generalized Tonic–Clonic Seizures.

A single generalized grand mal seizure does not warrant the diagnosis of epilepsy. In the vignette above, the patient later admitted that during the previous year, he was worried about his business and had been abusing alcohol and sedatives. He had recently discontinued these and had not had alcohol or sedatives for 48 hours. EEG and neuroimaging studies were normal. The seizure described above represents a reactive type of generalized grand mal seizure secondary to drug withdrawal. Similar seizures may occur from severe sleep deprivation, withdrawal from other drugs, trauma, central nervous system (CNS) infection, and various metabolic conditions.

Absence (Petit Mal) Seizures

Clinical Vignette

A 10-year-old boy is noted to have abrupt and brief (~10-second) episodes of impaired alertness. These can be brought out particularly when he hyperventilates. Eye fluttering is often noted during the episodes and occasional lip movements. The child returns to normal right after the episodes and the neurologic examination is normal.

This is the typical history of a child with generalized absence (petit mal) seizures. Petit mal epilepsy is the classic example of benign primary generalized epilepsy, which tends to remit in adulthood. Brief lapses in consciousness without an aura or any postictal symptoms are the main features (Fig. 14-7). Automatic movements may be observed but are generally simple and brief. The neurologic examination is usually normal.

Figure 14-7 Absence (Petit Mal) Seizures.

EEG provides the best diagnostic confirmation and typically demonstrates brief generalized bilaterally synchronous 3-Hz spike-and-wave discharges. Hyperventilation may precipitate petit mal seizures and the classic EEG changes describe above. There is neither focal interictal EEG epileptic activity nor focal initiation of the spike-and-wave pattern.

Atypical Absence Seizures

Atypical absence seizures differ from typical absence seizures because motor symptoms are more prominent and sometimes have a focal preponderance. Additionally, some patients have postictal confusion. Usually beginning during childhood, atypical absence seizures tend to occur over a longer lifetime period than classic petit mal seizures. Children with atypical absence seizures tend to have multifocal or generalized cerebral pathology, clinically associated with a lag in attaining normal developmental milestones.

The EEG demonstrates a slow (1.5- to 2.5-Hz) spike-and-wave pattern. This clinical constellation with its associated seizures and EEG pattern are characteristic of the Lennox–Gastaut syndrome. Generally, these patients also have other seizure types, and treatment of the seizures is difficult, usually requiring multiple anticonvulsants.

Myoclonic Seizures

Clinical Vignette

A 20-year-old college student reports a history of muscle jerks involving either arm for the past several years, which tended to occur in the morning. She also had two recent unexplained falls, without lapse of consciousness during the falls. Her neurologic examination results were normal. On two occasions, once after staying up late studying for exams, and another after drinking alcohol to excess and missing her medications, she had a generalized tonic–clonic seizure.

One of the most frequently observed settings for myoclonus is the postanoxic syndrome (Lance–Adams syndrome) following prolonged cardiac arrest and resuscitation. Prognosis for full recovery in those who display myoclonus is generally poor. In the adult population, myoclonus is one of the classic findings in the prion-induced dementing illness or transmissible spongiform encephalopathy (Creutzfeldt–Jakob disease). This disease usually occurs in middle to late life. The EEG in Creutzfeldt–Jakob disease has a classic appearance with periodic sharp and slow wave complexes recurring usually at 1–2 Hz. The background EEG is abnormal. Myoclonus is also a nonspecific term that describes brief nonepileptic muscle jerks. They may involve a body segment or be generalized, may be single or repetitive, and may be spontaneous or provoked by sensory stimulation (reflex) or limb action. Myoclonus may be mediated by cortical, subcortical, brainstem, or spinal cord mechanisms.

The above-described patient has juvenile myoclonic epilepsy (JME), a primary generalized epilepsy syndrome that usually begins during the teenage years and is associated with morning myoclonic jerks soon after awakening. Many of these patients have occasional generalized seizures, especially under period of physiologic stress. The EEG typically demonstrates bilaterally synchronous, irregular spike-wave or polyspike discharges at variable 4- to 6-Hz repetition rates but no focal epileptic discharges. Paradoxically, the EEG discharges usually have no clinical myoclonic accompaniment. This condition responds generally well to antiepileptic medication and sometimes remits spontaneously in later years.

Myoclonic seizures also may occur in children with a variety of epileptic syndromes such as the Lennox–Gastaut syndrome, infantile spasms (West syndrome), and early myoclonic encephalopathy. Myoclonus also may be a part of CNS storage diseases. In the past, myoclonus occurred as a significant manifestation of a rare late form of measles or subacute sclerosing panencephalitis. This illness presented with poor school performance, mental changes, and myoclonus in teenagers, with periodic EEG complexes occurring regularly every several seconds.

Epileptic Syndromes

Stereotypic seizures at a particular age and associated with fairly distinct EEG abnormalities or a symptom complex constitute the epileptic syndromes. The seizures in these syndromes may be classified into reactive, the best known being benign febrile convulsions; primary or idiopathic, exemplified by childhood absence (petit mal) epilepsy; and secondary or symptomatic, for example, infantile spasms or West syndrome.

Benign Febrile Convulsions

Benign febrile convulsions occur in otherwise healthy children at the age of 6 months to 5 years. Up to 5% of healthy children in the United States experience at least one febrile convulsion, usually early during a benign febrile illness. The seizures are brief, simple, and without localizing or lateralizing preponderance. Interictal EEGs are always normal. If not, other seizure mechanisms should be considered. The long-term prognosis is usually excellent if no seizures occur in nonfebrile settings.

Benign Childhood Epilepsy With Centrotemporal (Rolandic) Spikes

Benign childhood epilepsy with centrotemporal (rolandic) spikes is a primary (idiopathic) epileptic syndrome that develops during the first decade of life. Typically, these children have partial seizures characterized by unilateral perioral sensory or minor motor activity associated with dysarthria or speech arrest, salivation, and preserved consciousness. Nocturnal generalized convulsions may occur. Children have normal intelligence and neurologic examination.

The EEG here demonstrates distinctive high-amplitude spikes or sharp waves with maximum electronegativity in the centrotemporal regions, and positivity in the frontal regions. These epileptiform discharges, which increase during sleep, are commonly bilateral, shifting in preponderance from side to side or occur independently. Although the etiology is unknown, autosomal dominant inheritance is suggested. The prognosis is excellent for this benign type of epilepsy.

Infantile Spasms (West Syndrome)

West syndrome is an example of a secondary (symptomatic) generalized epileptic syndrome occurring during the first year of life. There is a concomitant arrest of psychomotor development. These seizures are characterized by brief jerks followed by a tonic phase and a subsequent period of generalized atonia lasting approximately 1 minute or associated with flexion–extension spasms.

The chaotic appearance of a typical EEG, called hypsarrhythmia, shows high-amplitude slow-wave activity with mixed high-amplitude sharp or spike discharges. The EEG correlate of the spasm is a sudden appearance of high-amplitude slow waves followed by an electrodecremental period with low-voltage fast activity. The prognosis is poor. The primary treatment is corticotropin administration.

Status Epilepticus

Clinical Vignette

A 60-year-old patient has a witnessed tonic–clonic seizure. 911 is called, and en-route to the local hospital, he has repeated tonic–clonic seizures, without regaining consciousness between episodes. He becomes cyanotic with labored breathing and requires emergent intubation.

Generalized convulsive status epilepticus (GCSE) is defined as recurrent seizures without recovery of consciousness lasting more than 30 minutes or when seizure activity becomes unremitting (Fig. 14-8). One of the most common and life-threatening neurologic emergencies, GCSE mandates immediate treatment because of the potential for irreversible CNS damage, that is, neuronal loss secondary to anoxia and systemic metabolic and autonomic dysfunction. Medical complications such as cardiac arrhythmias, pulmonary edema, and renal failure sometimes occur in association with GCSE. The GCSE mortality rate approaches 30%. Unfortunately, the history in the above vignette in this chapter is common in patients with partial seizures with secondary generalization who do not comply with antiepileptic therapy and progress to status epilepticus.

Figure 14-8 Status Epilepticus.

Treatment of GCSE treatment requires the maintenance of an adequate airway, ventilation, and circulatory support and the termination of seizures. Etiologic mechanisms include anticonvulsant or other medication withdrawal, illicit toxic drugs, hypoglycemia, hyponatremia, and hypocalcemia. GCSE may be the first manifestation of acute cerebral pathology.

The initial therapy, a benzodiazepine or phenytoin, often depends on whether the patient is actively seizing. Both first-line medications are frequently utilized within a short time. Intravenous lorazepam at 1–2 mg every 1–2 minutes up to 8 mg or diazepam 5 mg up to 20 mg is most often the initial therapy. An infusion of phenytoin (at 50 mg/minute) or fosphenytoin (at 150 mg /minute) up to 20 mg/kg must also be started promptly because of the short-term effect of benzodiazepines. Phenytoin is given with normal saline and not with glucose as it precipitates out of solution in this vehicle. ECG monitoring is required to monitor the effects of phenytoin on cardiac conduction, especially if infused too rapidly. Hypotension is also a serious side effect, especially in patients showing evidence of hemodynamic instability. The propylene glycol and alcohol content of the intravenous preparation is thought to be partially responsible for these effects and is dependent on the infusion rate. Fosphenytoin, a water-soluble phosphate ester rapidly converted to phenytoin, can be administered at a more rapid rate (150 mg/minute of phenytoin equivalent) while minimizing the risk of cardiovascular instability in unstable patients. Fosphenytoin also has a lower incidence of pain and burning at the infusion site but its routine use remains restricted because of its high cost. If seizures persist and serum phenytoin levels drawn 20 minutes after the initial infusion are less than 20 mg/dL then additional phenytoin or fosphenytoin (5–10 mg/kg) to control seizure and maintain the level around 20–30 mg/dL may be given. Sodium valproate IV, at a loading dose of 10–15 mg/kg, has also been used successfully to control status epilepticus, especially in patients on regular regimens of oral valproic acid.

Barbiturates have been traditionally used as second-line agents in status epilepticus. Long-acting phenobarbital (at 50–100 mg/minute, up to 20 mg/kg) or short-acting pentobarbital (3–5 mg/kg loading dose, followed by an infusion of 3–5 mg/kg/hour) may be added. Intubation for airway protection and continuous EEG monitoring are usually required at this stage. Over the years, however, many centers have shifted to using continuous infusions of other agents, such as the short-acting benzodiazepine midazolam or the hypnotic propofol (decreases excitatory effect of glutamate) for control of recurrent seizures. Many centers now use continuous infusion of benzodiazepines such as midazolam or propofol before barbiturate anesthesia is initiated.

Nonconvulsive status epilepticus or absence status epilepticus is another form of continued seizures without motor accompaniments. Typically, patients are poorly responsive with decreased alertness or obtundation. EEG reveals mostly continuous generalized spike-and-wave activity, the so-called spike–wave stupor. Intravenous benzodiazepine administration, the treatment of choice, is generally effective.

Complex partial seizures may occasionally evolve into complex partial status epilepticus, in which patients do not regain full consciousness between seizures. Prompt treatment as prescribed for GCSE is necessary. An SPS may evolve into epilepsia partialis continua, as described above. Long-term anticonvulsant therapy is usually needed in patients who have experienced status epilepticus.

Antiepileptic Therapy

The goal of antiepileptic treatment is the control of seizures. The most important step in seizure treatment is identification and treatment of the primary pathophysiologic mechanism. Examples include resection of a tumor, correction of a metabolic imbalance, and treatment of a CNS infection. Appropriate therapy may stop seizure recurrence.

Unfortunately, most seizures occur with chronic neurologic processes and are not amenable to specific curative therapy and therefore require long-term treatment. The ideal seizure medication would have high efficacy across a broad range of seizure types, with no adverse effects and little interaction with other drugs. Unfortunately, no such anticonvulsant exists, and treatment must balance seizure control with quality of life. Choosing an anticonvulsant must be done on an individual basis, considering seizure or epilepsy type, side effects, comorbidities, and psychosocial factors such as age, sex, ease of use, and cost.

There is no single approach to medication selection, and good knowledge of the available drugs and their basic properties is essential. As of 2005, phenytoin and carbamazepine are still the most commonly prescribed medications; however, seizure-free rates have recently been shown to be similar between the older and newer antiseizure medications. Newer agents are well tolerated, require less monitoring, and may be safer in the long term. With time and increasing regulatory approval, these anticonvulsants, initially approved for use as adjunctive agents, may soon replace the older ones as first-line agents in seizure management. Still, the newer medications are often more costly and may present various drug-specific side effects or issues. In addition, the therapeutic ranges are not as well established as compared to the older agents. With the exception of levetiracetam and lacosamide, the newer agents are not available in parenteral form. The variety of mechanisms of action of the newer medications has allowed these preparations to be possibly useful in other neurologic conditions such as for bipolar disease, headache, and neuropathic pain.

Phenobarbital and primidone are among the oldest antiseizure medication and are effective in all types of partial seizures and generalized tonic–clonic seizures. It binds to the beta-2 subunit of the γ-aminobutyric acid (GABAa) receptor, allowing GABA to bind to the beta-1 subunit and increase chloride conductance. It is metabolized by the hepatic cytochrome p-450 system. The half-life is about 72 hours; doses of 90–180 mg/day can be given once a day. The therapeutic blood level is between 20 and 40 µg/mL. Adverse effects are sedation and rash. Sedation is the prevalent adverse effect and has contributed to their decreased use.

Phenytoin is another long-established anticonvulsant used for more than 50 years initially as a superior less-sedating alternative to barbiturates. It is effective for partial onset seizures of all types and generalized tonic–clonic seizures. Phenytoin’s presumed mechanism of action is through the blockade of membrane voltage-dependent sodium channels to increase transmembrane potential recovery time and limit high-frequency firing. At higher concentrations, phenytoin delays efflux of potassium and prolongs neuronal refractory periods. It is metabolized by the hepatic cytochrome p-450 system and its half-life is 12–36 hours, thus allowing twice-a-day dosing (5–7 mg/kg or about 300–500 mg a day). Optimum seizure control occurs with blood levels of 10–20 mg/mL. When plasma levels are higher there is a shift from first-order to zero-order kinetics with a longer half life and with rapid increases in concentration levels and subsequent toxicity caused by small increases in the dose. Acute side effects mimic alcohol intoxication with dizziness, nystagmus, ataxia, slurred speech, and confusion. Prolonged use may produce coarsening facial features, gingival hyperplasia, acne, hirsutism, cerebellar impairment, megaloblastic anemia, and, at times, polyneuropathy. Acute idiosyncratic reactions occur in approximately 10% of patients, and vary from a mild morbilliform rash to a rare severe exfoliative dermatitis. As with other anticonvulsants, teratogenic effects may occur. Phenytoin interacts with numerous drugs of many classes and close monitoring of the levels is advised whenever such medications are prescribed.

Carbamazepine is effective for partial seizures of all types and generalized tonic–clonic seizures. It acts presumably by blocking Na channels in the brain and inhibiting depolarization of seizure foci in the brain without affecting the normal neuronal function. The usual dose is 600–1000 mg/day and the therapeutic blood serum level is between 4 and 12 mg/L. Adverse reactions relate to CNS depression and dizziness, nausea, as well as reversible and dose-dependent neutropenia and hyponatremia. Hypersensitive allergic reactions and Stevens–Johnson Syndrome can occur early on within a few weeks of treatment.

A newer agent, oxcarbazepine, has a similar mechanism of action to carbamazepine via its rapid and complete metabolism to an active 10-monohydroxy derivative. Oxcarbazepine has linear pharmacokinetics, no autoinduction, minimal interaction with other seizure medications, and does not cause neutropenia. Hyponatremia sometimes occurs. Adverse reactions include psychomotor slowing and sedation but, on the whole, it may be better tolerated than carbamazepine. The typical starting dosage is 300 mg twice daily, increased gradually to 600 mg twice daily. Occasionally, higher dosages are used but should not exceed 2400 mg daily.

Divalproex sodium is an extremely effective drug for absence, myoclonic, and generalized tonic–clonic seizures. It inhibits calcium ion influx through T-type calcium channels and inhibits sodium ion influx through voltage-gated sodium channels. The therapeutic blood level ranges from 50 to 150 µg/mL, and it is given in doses of 1000–3000 mg/day. Divalproex sodium inhibits the hepatic cytochrome p-450 system and will therefore diminish the metabolism of other drugs. Adverse effects are gastrointestinal upset, somnolence, dizziness, tremor, weight gain, and hair loss. More serious effects include hepatotoxicity, pancreatitis, thrombocytopenia, polycystic ovarian disease, and teratogenic effects (neural tube defects and lowered IQ). Ethosuximide is the first antiseizure drug used to treat absence (petit mal) seizures. It is thought to inhibit calcium ion influx through T-type calcium channels. Adverse effects are gastrointestinal and CNS related, but this drug is generally well tolerated. A common dose is 250–2000 mg/day according to age and response. The therapeutic blood level is 40–100 µg/mL.

Felbamate blocks voltage-dependent sodium channels and N-methyl-D-aspartate (NMDA) receptors and was found to be more effective than divalproex sodium in partial seizures and had a significant benefit for Lennox–Gastaut syndrome. It is better tolerated than other drugs, with relatively minor gastrointestinal and cognitive adverse effects. Unfortunately, its relatively high rates of (at times fatal) hepatoxicity and aplastic anemia have severely restricted its use to those with severe epilepsy, such as Lennox–Gastaut syndrome.

Several other newer agents such as lamotrigine, gabapentin, topiramate, levetiracetam, tiagabine, and zonisamide are recommended as adjunctive to the first-line medications of carbamazepine, phenytoin, phenobarbital, primidone, or valproate. Because they have different mechanisms of action, they may complement the traditional first-line drugs.

Lamotrigine is a newer antiepileptic drug recommended as an adjunct medication for partial seizures, primary generalized tonic–clonic seizures patients of all ages and Lennox–Gastaut syndrome. It is indicated for conversion to monotherapy in adults with partial seizures treated with the older anticonvulsants, carbamazepine, phenytoin, phenobarbital, primidone, or valproate. Lamotrigine blocks voltage-gated sodium and calcium channels and inhibits the presynaptic release of glutamate and aspartate. Metabolized by glucuronidation, it is not an enzyme inducer or inhibitor. When prescribed with an enzyme-inducing antiseizure medication, lamotrigine serum concentration may decrease by up to 40%. Frequent monitoring is therefore needed when switching to lamotrigine monotherapy. It has a half-life of about 12–60 hours, and typical adult doses are 300–500 mg/day divided twice a day. It must be introduced at low doses with slow titration to the desired maintenance level over months to reduce the risk of Stevens–Johnson syndrome. Adverse effects are gastrointestinal and CNS related. There is a 10% risk of an idiosyncratic rash and a 3 in 1000 risk of Stevens–Johnson syndrome in adults, especially in those taking valproic acid. There are no known long-term effects.

Levetiracetam is another newer antiepileptic medication whose mechanism of action is not completely understood but may involve modulating neurotransmitter release at the SV2A binding receptor complex. It is indicated for partial seizures and generalized seizures. The usual adult maintenance dose is between 1000 and 2000 mg/day in divided doses. An intravenous formulation is also available. It is not an enzyme inducer or inhibitor and has few drug interactions with other medications. Levetiracetam is eliminated renally with a half-life of 6–8 hours. Adverse effects include sedation, lethargy, or ataxia. Not to be overlooked are behavioral changes seen at higher doses around 3000 mg/day with aggression, depression, suicidal ideation, and, in extreme cases, frank psychosis.

Gabapentin is usually used as adjunctive therapy for partial seizures with or without secondary generalization. There is concern that it may worsen absence and myoclonic seizure and should generally be avoided in primary generalized epilepsy syndromes. It is an analogue of GABA; however, its exact mechanism of action is unknown. It is not an enzyme inducer or inhibitor and is eliminated through the renal system with a half-life of about 5–6 hours. It is given in doses of 900–3600 mg/day in divided doses. Adverse effects are somnolence, dizziness, ataxia, fatigue, weight gain, and behavioral changes, especially in children.

Topiramate blocks voltage-gated sodium channels, enhances GABA-mediated synaptic inhibition, and antagonizes the excitatory effect of glutamate on NMDA receptors. It has limited hepatic metabolism with a half-life of about 20 hours, and typical doses are 100–400 mg/day divided twice a day. Topiramate can increase phenytoin levels. It is indicated as an adjuvant treatment or monotherapy of partial and primary generalized tonic–clonic seizures and in Lennox-Gastaut syndrome. Adverse effects are CNS related, including cognitive impairment or word-finding difficulty, weight loss, decreased sweating, glaucoma, and a 1–1.5% risk of kidney stones.

Zonisamide blocks voltage-gated sodium channels and inhibits calcium ion influx through T-type calcium channels. It is not an enzyme inducer or inhibitor, has hepatic metabolism followed by glucuronidation, and has a half-life of about 63 hours. It is given in doses of 300–400 mg once a day, or higher doses divided twice a day. Adverse effects are CNS related, rash, decreased sweating, weight loss, and a 0.6% risk of kidney stones. Tiagabine is indicated for use as adjunctive therapy for refractory partial seizures. It is a GABA uptake inhibitor, is not an enzyme inducer or inhibitor, has hepatic metabolism, and a half-life of about 7–9 hours. Adverse effects are CNS related, rash, and nonconvulsive status. Pregabalin is usually used as adjunctive therapy for partial seizures. Its exact mechanism of action is not known, is not an enzyme inducer or inhibitor, has renal metabolism, and has a half-life of about 6 hours. Adverse effects are CNS related, weight gain, and peripheral edema. Lacosamide is the newest antiseizure medication approved as adjuvant therapy for partial-onset seizures. It is available in oral and IV formulation and is thought to work by the unique mechanism of selectively modulating the slow inactivation of voltage-gate sodium channels. It is renally excreted, has few drug interactions, and is dosed at 100–400 mg/day. CNS and behavioral adverse effects have been described but are thought to be less frequent than with levetiracetam.

Ideally, a single antiepileptic drug is used. If adequate control of seizures is not achieved with one drug, another drug is substituted. Discontinuing antiseizure medications should be done gradually over 2–3 months to avoid withdrawal seizures from rebound.

Anticonvulsant Treatment Considerations

The decision to treat with antiepileptic drugs a first-time unprovoked seizure remains an individualized process that takes into account the structural integrity of the brain, the EEG findings, the circumstances surrounding the seizure, past history of provoked or unprovoked seizures, as well as the potential side effects of medications prescribed.

The incidence of recurrence after a single unprovoked seizure varies widely from 10% to 70%. Predictors of recurrent seizures are an abnormal EEG demonstrating epileptiform discharges (especially generalized patterns), focal spikes or sharp waves, abnormal MRI scans, and an abnormal neurologic examination. Although only about 30% or fewer of EEGs done in adults will yield significant abnormalities, these have a strong predictive power of recurrent seizures in up to 50–60% of patients within 2–3 years. Any patient presenting with a first-time seizure will require, in addition to a detailed neurologic history and examination, imaging of the brain (preferably an MRI) and an EEG in the awake and sleep state (preferably within the first 24–48 hours). Other studies such as a toxic screen and lumbar puncture have a low general yield but may be helpful in specific clinical situations.

Immediate short-term anticonvulsant treatment reduces the likelihood of recurrent seizures by half to two thirds but does not affect the long-term recurrence rate over 1–2 years. Patients who are younger than 16, and those with partial onset seizures, either witnessed or inferred from a postictal Todd paralysis, have a significantly higher risk of recurrence. Other factors that may increase the likelihood of developing recurrent seizure or epilepsy after a first-time unprovoked seizure included a history of perinatal or congenital neurologic difficulties, a family history of epilepsy, and previous unprovoked seizures.

Women with Epilepsy

There are special considerations regarding management of women with epilepsy. Seizures and AEDs may impact menstruation, contraception, bone health, menopause, pregnancy, and breast feeding. The majority of women with epilepsy have routine pregnancies and deliver healthy babies. However, detailed discussions with patients about the potential teratogenic effects and the risks of seizures must begin prior to conception. About 25% of women experience an increase in seizures during pregnancy because of poor compliance, lowered anticonvulsant levels and protein binding, hormonal changes, or sleep deprivation. The incidence of preeclampsia (pregnancy-induced hypertension), preterm delivery, intrauterine bleeding, hyperemesis gravidarum, and abruptio placenta is increased twofold in women with epilepsy.

Generalized tonic–clonic seizures are harmful to a developing fetus and can cause seizure-related trauma, intrauterine death, and miscarriage. The risk of major fetal malformations for women with epilepsy is 4–6% compared to 2–3% in the healthy population. The major congenital anomalies include cleft lip or palate and urogenital, cardiac, and neural tube defects. Most antiseizure medications have potential teratogenic effects caused by varying degrees of folate deficiency. The risk is highest with valproic acid and increases with polypharmacy as well as higher concentration levels of antiseizure medication. The risk of major malformations, particularly neural tube defects, with valproic acid is 10.7%; phenobarbital, 6.5%; and with lamotrigine monotherapy, 2.6%. The newer antiseizure medications have pharmacokinetic advantages over the older agents and may be safer, but data are limited.

Some women with medically refractory epilepsy consider epilepsy surgery in order to attain seizure freedom before planning pregnancy. In many circumstances, seizure-free women may be tapered off their antiseizure medication before conception. Women may choose not to take antiepileptic medications in the first trimester during organogenesis, especially if the seizure type is minor and infrequent. Not all patients can do this safely and there is evidence to suggest adverse effects of recurrent complex partial seizures on fetal growth and development. The goal throughout pregnancy is to remain seizure free while exposing the fetus to the least number of drugs and the lowest possible levels of antiseizure medication.

The neural tube closes between the 24th and the 27th day after conception. Folate reduces the risk of neural tube defects in the general population. Because neural tube closure defects occur early, before many women may realize they are pregnant, prophylaxis with folic acid is recommended in all epileptic women of childbearing age. The optimal dose of folic acid is not known but ranges from 0.4 to 5 mg/day. Tests to assess for neural tube and other anticonvulsant-induced congenital defects should be considered routine prenatal care.

Antiepileptic medications during pregnancy require close monitoring and often frequent adjustments to maintain the desired therapeutic levels. Serum levels decrease during pregnancy because of accelerated hepatic metabolism, changes in plasma volume, absorption, and protein binding. With the exception of lamotrigine, the newer antiseizure medications are less prone to fluctuating levels during pregnancy. Pregnant women with epilepsy should be under the care of a high-risk obstetrician. Maternal serum alpha fetoprotein and a high-level ultrasound is recommended at 14–18 weeks and may be repeated at 22–24 weeks to screen for anomalies. About 3–4% of epileptic women experience a seizure around delivery. The risk is highest in women with subtherapeutic drug levels, idiopathic generalized epilepsy, or a history of seizures during pregnancy.

Mothers taking enzyme-inducing antiseizure medications are prescribed vitamin K 10 mg/day orally in the last month of pregnancy, and their infants should be given 1 mg of vitamin K intramuscularly at birth to prevent maternal and fetal hemorrhage. Antiseizure levels need to be monitored postpartum because levels will gradually return to baseline 8–10 weeks after delivery. Lamotrigine levels decrease markedly during pregnancy because of increased clearance and need to be monitored closely after delivery to avoid postpartum toxicity. The concern of exposing nursing infants to antiseizure medication should be discussed with the mother. Most antiseizure medications have a milk-to-plasma ratio of less than one, but the serum level below which there are no clinical effects on the neonate is unknown. Other than congenital malformations, children exposed in utero to phenobarbital and valproic acid may be at increased risk of cognitive deficits with lower verbal IQ and greater need for special education. The Neurodevelopmental Effects of Antiepileptic Drugs study is currently underway to assess children’s neurobehavioral outcomes in mothers with epilepsy and those exposed to antiseizure medications.

Estrogen may have proconvulsant effects by reducing GABAa inhibition, whereas progesterone may have anticonvulsant effects by increasing GABAa inhibition. Women are prone to seizures during ovulation because of the rapid decline of progesterone that triggers menstruation. Seizures may increase a few days before or occur during the first days of menses. Seizures can also increase in midcycle as a result of increased estrogen midcycle. Women with anovulatory cycles fail to form a progesterone-secreting corpus luteum and can experience an increase in seizures during the second half of their cycle because of low progesterone levels. If a pattern can be documented, an increase in the daily dose of medication at the expected time of seizures may help control seizures. Use of acetazolamide, around the time of expected increase in seizures, has had some limited success.

Contraceptive pills are less effective in women taking hepatic enzyme–inducing antiseizure medications (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone) with a 6% failure rate. Topiramate in doses of >200 mg/day increases the clearance of estradiol and thus reduces its effectiveness. The American Academy of Neurology suggests that women on the above-mentioned antiseizure medication take higher doses of estradiol, but the lower progesterone dose may still lead to hormonal failure. Depo-Provera may be an alternative if given every 10 weeks instead of 12 weeks. Patients should be referred to their gynecologist to discuss and manage these issues long term. On the other hand, oral contraceptives in their turn may reduce lamotrigine and valproic acid levels. Levels should be monitored when oral contraceptives are initiated or discontinued. Intrauterine devices are effective in patients taking enzyme-inducing drugs and may be a safer alternative to oral contraceptives in preventing pregnancy.

Women with epilepsy may experience early menopause. There is some concern that estrogen replacement therapy might be associated with increased seizures. Although estrogen is not strictly contraindicated in women with epilepsy, selective estrogen receptor modulators may be a better alternative.

Patients with epilepsy are at increased risk for osteoporosis and fractures. Bone loss is caused by virtually all the anticonvulsants and is not restricted to the hepatic enzyme–inducing drugs. The mechanism remains obscure and no clear data exists as to which agent may be preferable. A dual-energy x-ray absorptiometry (DEXA) scan is generally recommended after 2 years of treatment with an anticonvulsant. Patients with osteopenia are advised calcium 1200 mg/day and vitamin D 800 IU/day, and lifestyle changes that include weight-bearing exercise, decreased alcohol consumption, and smoking cessation. Patients with osteoporosis should be referred to a specialist and followed closely.

All pregnant women with epilepsy, whether or not taking any antiseizure medication, should be encouraged to enroll in the North American Pregnancy Registry (www.aedpregnancyregistry.org), a prospective study to assess the risk of major fetal malformations. These data may provide the comparative teratogenic risk for individual antiseizure drugs and will help make more rational treatment decisions for pregnant women with epilepsy.

Surgical Treatments for Epilepsy

Surgical treatment may be an option for individuals whose seizures are unresponsive to medical therapy or those who cannot take medications because of significant adverse effects or quality-of-life issues. Some of the first craniotomies on record were performed to treat refractory seizure disorders. Cerebral localization was grossly defined by the specific characteristics of a seizure, and cerebral tumors were localized and removed based on these techniques. Many aspects of cortical mapping and function were derived from work related to surgery for epileptic activity.

Surgical Candidates

Clinical Vignette

A 36-year-old woman had febrile seizures as an infant followed by a latent period of about 12 years. Complex partial seizures characterized by a rising epigastric sensation and staring with oral automatisms and unresponsiveness returned at menarche, and continued 2–4 times monthly despite several medication trials. The patient could not drive, experienced medication side effects, and worsening short-term memory. MRI identified right mesial temporal sclerosis without any other overt structural abnormality.

Inpatient video EEG monitoring revealed interictal right temporal spikes and concordant complex partial seizures. Positron emission tomographic imaging revealed right temporal lobe hypometabolism.

The above vignette identifies the typical clinical scenario of a patient with medically refractory mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures are not fully controlled by medical therapy in about 30–40% of patients with epilepsy. Once a patient fails to respond to two antiseizure drugs, the chance of achieving control on a third drug is small. The initial response to medication seen in the above vignette does not mean permanent seizure control. In a randomized controlled study of patients with refractory temporal lobe epilepsy, patients that underwent temporal lobectomy were more likely to be seizure free than the patients randomized to AED therapy (58% vs 8%). Patients who underwent surgery had a significant improvement in their quality of life. Successful surgery not only can provide seizure control in patients, but also can arrest or reverse cognitive decline, lower the mortality, and relieve psychiatric disorders. Any patient in whom seizures persist after trials of two appropriate AEDs should be referred to a tertiary epilepsy center for surgical evaluation. Surgical evaluation consists of confirming a diagnosis of epilepsy and defining the location and extent of the epileptogenic zone. The above vignette represents a patient who is likely a candidate for an anterior temporal lobectomy that can often stop or completely cure the epilepsy.

Preoperative Assessments

Video EEG analysis is one of the mainstays of preoperative evaluations and is used to localize the ictal onset zone. The video is used to determine if the ictal semiology represents seizure origin or propagation. Often, seizures cannot be localized to one region of the brain but can be lateralized to one hemisphere, requiring invasive monitoring prior to surgical resection (Fig. 14-9). Invasive monitoring can also be utilized for functional mapping to define the boundaries of the epileptogenic zone in relation to eloquent cortex or key somatomotor regions that may be close to the potential resective zone. MRI is one of the most important structural neuroimaging tool in the presurgical evaluation of patients with medically refractory epilepsy. The presence of a structural abnormality may suggest site of seizure origin and surgical pathology. It can suggest a more favorable surgical outcome and help tailor the resection. The most common imaging finding in patients undergoing surgical evaluations is hippocampal atrophy best seen using T1-weighted coronal images and an increased mesial temporal signal intensity on T2-weighted or FLAIR coronal images. Magnetic resonance spectroscopy, positron emission tomography, single photon emission computed tomography, functional MRI, and magnetoencephalography are functional imaging tests that could better define the epileptogenic zone. In select cases, a Wada test can be performed for language and memory lateralization. Neuropsychological testing is performed to determine a patient’s risk for postoperative memory decline. Ultimately, a decision regarding surgical treatment is based on a convergence of all these neurodiagnostic tests.