Epilepsy Part 2

Brain Imaging

Because epilepsy is a symptom, particularly in adults, treatable illnesses must be excluded in the initial diagnostic evaluation. A CT scan of the brain will reveal whether the patient has lesions needing urgent treatment, but magnetic resonance imaging is the preferred method for studying brain structure in a patient with epilepsy; indeed, structural MRI is a routine part of the epilepsy workup. Patients with intractable complex partial seizures arising from temporal lobe structures have mesial temporal atrophy or sclerosis as their most common focal lesion; detecting such lesions is of prognostic value.18 MRI changes in these patients typically consist of increased signal intensity and loss of detailed hippocampal structure with atrophy [see Figure 3]. Quantitative MRI aids in identification of hippocam-pal atrophy.

Figure 2 Electroencephalogram obtained from electrodes affixed to the patient’s scalp and reformatted with analog-to-digital conversion. An isolated focal epileptiform discharge present in the lower four traces occurs 7 seconds after the beginning of this EEG epoch. This interictal EEG pattern is typical for a patient with complex partial seizures of temporal lobe origin. The darker vertical lines denote 1 second; the sensitivity is 7 V/mm.

MRI is both sensitive and specific in patients with partial seizures, allowing noninvasive diagnosis through detection of many types of lesions.20 These lesions include such neoplastic changes as low-grade glioma and ganglioglioma and specific lesions such as dysembryoplastic neuroepithelial tumors. Vascular changes include arteriovenous malformation, cavernous hemangioma, venous angioma, and telangiectasias. Developmental abnormalities include such neuronal migration disorders as lissencephaly, pachygyria, band or laminar heterotopia, and subependymal heterotopias. More restricted lesions include focal cortical dysplasia, polymicrogyria, focal subependymal heterotopia, and schizencephaly.20

Imaging techniques that show cerebral function play a growing role in the evaluation of epilepsy. Such techniques include functional MRI, magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT), and positron emission tomography (PET).21

The use of functional MRI to evaluate epilepsy is a relatively recent development. Functional MRI can detect transient focal or regional changes in cerebral blood flow associated with seizure activity. The technique shows promise in the preopera-tive assessment of candidates for surgical excision of epilepto-genic foci.21,22

MEG is a noninvasive method of imaging brain function. MEG identifies the location of activated sets of neurons, on the basis of the associated magnetic flux on the head surface, and projects the location onto an MRI for visualization of the activated region. Currently, MEG is the only imaging modality approved by the Food and Drug Administration that can provide noninvasive imaging of the motor cortex, the sensory cortex, and language function. MEG has an emerging role in the preoperative evaluation of patients with refractory epilepsy.23

MRS measures concentrations of a variety of substances within the brain, offering a way to obtain metabolic information in patients with epilepsy. It can be used to detect increased inorganic phosphate concentration, altered pH, and decreased levels of phosphomonoesters. Alterations in levels of N-acetyl-aspartate, choline, and creatine/phosphocreatine and increased lactic acid concentration postictally may aid identification of the location of onset of focal seizures.24

SPECT reveals decreased blood flow in the region of seizure origin in some patients.

Figure 3 Mesial temporal sclerosis, a cause of seizures that may be amenable to surgical correction, is visible only on MRI with a specific epilepsy sequence. This coronal view, obtained perpendicular to the hippocampus, demonstrates left mesial temporal sclerosis (the left hippocampus is on the right side of the figure). Note the smaller size and increased signal (brighter appearance) of the left hippocampus and the compensatory increased size of the adjacent temporal horn of the lateral ventricle. The patient, an adult, presented with new-onset complex partial seizures and a history of two prolonged febrile seizures in childhood. A CT scan of the brain was normal.

Use of SPECT alone between seizures is currently of little value, but ictal SPECT may be helpful with patients (especially those with temporal lobe epilepsy) in whom other imaging techniques give normal results. In the future, the most important role for SPECT may be its use in combination with MRI for presurgical evaluation. So-called ictal difference images, which are created through coregistation of interictal and ictal SPECT images, can in turn be coregistered with MRI results to provide an accurate picture of cerebral function.

In the past, PET with 18-fluorodeoxyglucose to image the cerebral metabolic rate was useful for detecting a seizure focus that might be amenable to surgery. With advances in MRI technology, however, the value of PET is now limited to selected patients with normal MRI results.21 In patients with complex partial seizures of temporal lobe origin, PET may reveal interictal hypometabolism, depending on the duration of epilepsy.26

Differential Diagnosis

Although sudden alterations in neurologic function are characteristic of seizures, sudden alterations also occur when in-tracranial structures are deprived of glucose or oxygen. Failure to maintain adequate cerebral perfusion will cause loss of consciousness, as in syncope of any cause. Motor activity during simple syncope is uncommon. However, prolonged interruption of cerebral perfusion may cause convulsive movements or even tonic-clonic seizures.

Sensory or motor dysfunction can be caused by transient is chemia, which may result from embolic cerebrovascular disease, extracranial carotid or basilar artery disease, and migraine. Seizures may occur with embolic strokes. Metabolic disease, particularly disease related to glucose metabolism that requires regulation of blood glucose concentration with insulin therapy, may be associated with episodes of hypoglycemia. Both focal and generalized seizures can be manifestations of hypo-glycemia or of hyperosmolar states.

All patients with initial presentation of a seizure must undergo a complete blood count and blood chemistry studies. The CBC results may suggest infection, a platelet abnormality, or anemia. The blood chemistry studies must include measurement of glucose, urea nitrogen, electrolyte, and liver enzyme levels.

Lumbar puncture with a cerebrospinal fluid study should be performed if the patient is febrile or has altered cognitive function, such as behavioral changes, that could be ascribed to an en-cephalopathic process. To prevent complications from lumbar puncture, the clinician must first exclude the presence of an in-tracranial mass or increased intracranial pressure.

Nonepileptic Seizures

Approximately 20% of patients admitted to epilepsy monitoring units for diagnostic evaluation have episodic behavioral alterations that are not caused by physiologic dysfunction of the brain.27 In the past, these alterations were described as pseudo-seizures. Although that term is still used for communication among physicians, it is not appropriate for communication with patients.28 Currently, the preferred term is nonepileptic seizures (or nonepileptic events). Use of these terms tends to help patients understand their problem and facilitates referral for behavioral therapy. Patients react angrily to the term pseudo and are less likely to believe the physician is interested in their problem.

An important clue to the diagnosis of nonepileptic seizures is that they are periodic events that tend not to be stereotyped. Both patients and observers report varied behaviors with each event. Another clue is prolonged duration. Nonepileptic seizures may last 30 minutes to several hours. Epileptic seizures, both partial and generalized, seldom continue for more than several minutes. Patients with both nonepileptic seizures and epilepsy pose a challenging clinical problem; this combination is occasionally found in patients undergoing assessment in epilepsy monitoring units. Treatment of nonepilep-tic seizures requires behavioral intervention. If both disorders are found, treatment of epilepsy needs to be continued in parallel with behavioral therapy.

Treatment of Seizures and Epilepsy

Historically, drug therapy with AEDs has been the mainstay of treatment for seizures. Nonpharmacologic options have gained greater prominence in recent years, however. Use of vagus nerve stimulation devices is growing rapidly. Some patients may be candidates for surgical treatment. In children, the keto-genic diet has reemerged.

Drug Therapy

Antiseizure medications, usually referred to as antiepileptic drugs, have been available for more than a century. However, the modern era of AED therapy began in the early 20 th century with the introduction of phenobarbital. More than two dozen agents available in the United States are classified as AEDs.

Most were introduced before 1980, but a number of new drugs were licensed for epilepsy treatment in the 1990s.

AED treatment should be directed at both controlling seizures and, when possible, correcting the underlying disease or disorder. AEDs may be used only briefly, if at all, in patients with a single seizure or a few seizures resulting from a transient disorder, such as drug intoxication, withdrawal from alcohol or sedative-hypnotic drugs, hyponatremia, or hypoglycemia. Patients who have recurrent seizures secondary to a treatable neurologic disease, such as brain tumor or intracranial infection, should be treated with AEDs; the underlying problem should also be treated. In many patients, such as those with completed cerebral infarction or brain contusion secondary to head injury, recurrent seizures result from the prior insult or from an undefined process. In these patients, AEDs are the only possible therapy. Patients with chronic recurrent seizures, regardless of etiology, should be treated with AEDs.

Whether to start AED treatment after a single unprovoked first seizure is a controversial issue. Many authorities argue that because many patients will not have a second seizure during several years of follow-up, there may be no justification for beginning AED treatment and subjecting patients to possible side effects.29 In support of this idea is a retrospective study reporting that only 60% of patients who had a single convulsion had a second one within 5 years.30 Also, the risk of seizure recurrence diminishes progressively the longer a patient remains seizure free. Because many patients have recurrent seizures, however, not all physicians accept that justification is lacking for AED treatment after single first seizures. I recommend not treating patients after a single seizure if results of the neurologic examination, EEG, and imaging study of the brain are normal. In addition, the patient must be willing to accept the risks associated with another seizure. Treatment with an AED should be initiated for most patients after a first seizure when evaluation reveals any structural or functional brain abnormality such as epilepti-form discharges on the EEG.

Treatment with AEDs should follow certain basic principles. Therapy should be started with a single suitable agent. Seizure control should be achieved, if possible, by increasing the dosage of this agent rather than by adding a second one. If seizure control cannot be achieved with the first medication, a second, alternative agent should be considered. Monotherapy—usually with the first or second agent chosen—can control seizures in about 60% of patients with newly diagnosed epilepsy. In the remainder of cases, control is often difficult from the outset.31

The use of two or more AEDs in combination should be avoided whenever possible, but rational drug combinations may be useful when monotherapy fails. Drug selection should be guided by the patient’s seizure type and epilepsy syndrome classification, in concert with the mechanisms of action and side effects of the individual agents.31 Changes in dosage should be guided by the patient’s clinical response rather than by drug levels, with inadequate seizure control indicating the need for raising the dosage and toxicity indicating the need to lower the dosage.

Monitoring of drug levels is usually not necessary for patients who tolerate their medication well and have adequate seizure control. Under some circumstances, however, monitoring drug levels may be useful to determine prescription compliance or explain changes in seizure control or drug toxicity.

Mechanisms of Action of AEDs

AEDs appear to control seizures by decreasing neuronal excitability or enhancing inhibition of neurotransmission. This is achieved by altering intrinsic membrane currents, such as sodium, potassium, and calcium conductance through ion channels, or by affecting the activity of various neurotransmitters, such as Y-aminobutyric acid (GABA), glutamate, or other neurotransmitters that may take part in seizure activity. Although several AEDs have common mechanisms, each seems to have distinct actions. Each AED has been reported to have several molecular and cellular actions, but probably only some of these individual actions are responsible for the anticonvulsant and antiepileptic effects.

The intrinsic membrane currents affected by AEDs are primarily those involving the voltage-gated sodium channel and the calcium channel. The drugs that act at sodium channels in therapeutic concentrations—phenytoin, carbamazepine, primi-done, valproate, and lamotrigine—inhibit high-frequency neuronal discharge.32 Because they block the sodium channel gradually and in proportion to the rate of firing (i.e., they are both use dependent and voltage dependent), they have little effect on normal neuronal activity. However, during high-frequency firing, which typically occurs at seizure onset, they delay reactivation of the sodium channel and produce an increasing inhibitory effect on the action potential until firing is completely blocked.

Some AEDs act at both the sodium and the calcium channel, such as phenytoin, carbamazepine, valproate, lamotrigine, and zonisamide.32 Other AEDs that act at calcium channels include ethosuximide and phenobarbital. Ethosuximide selectively blocks the T-type calcium current, which is not greatly affected by most of the other AEDs (except zonisamide). This current is thought to act as a pacemaker in thalamic neurons and may be important in absence seizures. Valproate and lamotrigine are also effective against absence seizures; however, it remains to be determined whether their efficacy results from action on the T-type calcium current or from some yet undefined mechanism. The blockade of other calcium currents, such as the L and N types, may be a less specific effect that affects neuronal excitability and propagation of seizure activity.33

Drugs that alter synaptic function act primarily by enhancing GABA-mediated neuronal inhibition, the brain’s main inhibitory mechanism; these drugs include phenobarbital and benzodi-azepines. Each of these drugs acts through a different mechanism to augment GABA influences in the CNS.34 Benzodi-azepines increase the frequency of GABA-mediated GABAA receptor channel openings, and barbiturates increase the duration of channel openings. A different strategy to increase extracellular GABA uses inhibition of transporters. Tiagabine delays the reuptake of GABA from the synaptic cleft, effectively enhancing the GABA effect after synaptic release. Vigabatrin, which is not available in the United States, increases GABA concentration by irreversibly binding to GABA transaminase, the enzyme that metabolizes GABA.35

The mechanisms of anticonvulsant and antiepileptic action of the major drugs used as therapy for seizure disorders are not completely understood. Some AEDs may affect ionic conductances other than those discussed, and some may directly or indirectly affect neurotransmitter processes other than the GABA system; these actions may be important for their clinical effects. For example, felbamate and topiramate may block glutamate receptors to interfere with excitation.35 Additional research is needed to completely define the molecular and cellular mechanisms and the sites of action of AEDs.

Table 3 Antiepileptic Drugs

Agent (Trade Name)	Formulations	Dosage	Principal Sites of Action	Targeted Seizure Type
Carbamazepine (Tegretol, Tegretol-XR, Carbatrol)	Tablets: 200 mg Chewable tablets: 100 mg Suspension: 100 mg/5 ml Extended-release tablets: 100, 200, and 400 mg Extended-release capsules: 200 and 300 mg	10-40 mg/kg/day in three or four divided doses (regular tablets or suspension) or two divided doses (extended-release forms)	Sodium channels	Focal and secondary GTC
Clonazepam (Klonopin)	Tablets: 0.5, 1, and 2 mg	0.01-0.30 mg/kg/day in two or three divided doses or h.s.	GABA receptors	All generalized focal and secondary GTC
Diazepam for rectal administration (Diastat)	Rectal syringe: pediatric: 2.5, 5, and 10 mg; adult, 10, 15, and 20 mg	2-5 yr: 0.5 mg/kg 6-11 yr: 0.3 mg/kg > 12 yr: 0.2 mg/kg	GABA receptors	Acute repetitive seizures
Ethosuximide (Zarontin)	Capsules: 250 mg Suspension: 250 mg/5 ml	15-40 mg/kg/day in two or three divided doses	T-type calcium channels	Absence
Felbamate (Felbatol)	Tablets: 400 and 600 mg Suspension: 600 mg/5 ml	15-45 mg/kg/day (or 1,200-3,600 mg/day) in two or three divided doses	NMDA receptors Sodium channels GABA receptors	Focal and secondary GTC Lennox-Gastaut syndrome
Fosphenytoin (Cerebyx)	Injection: 50 mg/ml (phenytoin-equivalent)	10-20 mg/kg I.V. loading dose	Sodium channels	Status epilepticus
Gabapentin (Neurontin)	Tablets: 600 and 800 mg Capsules: 100, 300, and 400 mg Suspension: 250 mg/5 ml	10-60 mg/kg/day	Increases GABA release	Focal and secondary GTC
Lamotrigine (Lamictal)	Tablets: 25, 100, 150, and 200 mg Chewable tablets: 2, 5, and 25 mg	200-500 mg/day in two divided doses Slow titration required, especially if taken with valproic acid or valproate.	Sodium channels (modulating EAA release) Calcium channels	Focal and secondary GTC
				Absence
				Tonic/atonic
				GTC
				Myoclonic
Levetiracetam (Keppra)	Tablets: 250, 500, and 750 mg	1,000-3,000 mg/day in two divided doses	Potassium channels Calcium channels	Focal and secondary GTC
Lorazepam (Ativan)	Injection: 2 or 4 mg/ml	0.05-0.1 mg/kg I.V. (total dose)	GABA receptors	Status epilepticus
Oxcarbazepine (Trileptal)	Tablets: 150, 300, and 600 mg Suspension: 300 mg/5 ml	900-2,400 mg/day in two divided doses	Sodium channels	Focal and secondary GTC

AED Selection

The principal AEDs used to treat patients with epilepsy in the United States are carbamazepine, ethosuximide, gaba-pentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbi-tal, phenytoin, primidone, topiramate, tiagabine, valproate, and zonisamide [see Table 3]. Some benzodiazepines, including clon-azepam, diazepam, and lorazepam, are also used to treat seizures. With the exception of clonazepam, the benzodi-azepines are used for short-term treatment of acute seizures or status epilepticus and are usually administered parenterally. Clonazepam can be used to treat epilepsy but is not recommended, because most patients develop tolerance to its antiepileptic effect. Felbamate should be reserved for use in selected patients with uncontrolled seizures. Because of the high incidence of serious adverse effects associated with felbamate, treatment with this drug should be managed by experienced clinicians in established epilepsy centers.36 Several additional drugs, including methsuximide and acetazolamide, are used occasionally; none of these drugs will be considered in this subsection.

Partial seizures Most epileptologists agree that the drugs of choice for partial seizures are carbamazepine and phenytoin, which are highly effective and have acceptable adverse effects.

Valproate also has been demonstrated to be effective in the treatment of partial seizures.38,39 Both phenobarbital and primidone are probably as effective as carbamazepine or phenytoin, but the two barbiturates are associated with a much higher incidence of adverse effects, particularly sedation and impaired cognition.37 Gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiaga-bine, topiramate, and zonisamide are effective against partial seizures; each is usually used in combination with one of the older agents. However, of the newer AEDs, oxcarbazepine is approved as monotherapy, lamotrigine is approved as monothera-py after initial adjunctive use, and topiramate has a monothera-py application pending. Partial seizures that secondarily generalize respond to these same AEDs.

Generalized convulsive seizures Valproate, lamotrigine, and topiramate are the AEDs of choice for patients with primary generalized convulsions, because some of these patients may also have other generalized seizures that can be controlled with one of these agents. Carbamazepine and phenytoin were used historically to treat generalized convulsive seizures. The barbiturates are not favored in the treatment of generalized convulsive seizures, primarily because of their sedative effects. Zon-isamide and levetiracetam may benefit some patients with generalized convulsive seizures.

Table 3 Antiepileptic Drugs

Agent (Trade Name)	Formulations	Dosage	Principal Sites of Action	Targeted Seizure Type
Phenobarbital (Solfoton, Luminal)	Tablets: 8, 15, 16, 30, 32, 60, 65, and 100 mg Injection: 30, 60, 65, and 130 mg/ml Solution: 20 mg/5 ml	2-5 mg/kg/day q.d. or in two divided doses	Chloride channels	Focal Primary and secondary GTC
Phenytoin (Dilantin, Phenytek)	Chewable tablets: 50 mg Extended-release capsules: 30, 100, and 300 mg Suspension: 125 mg/5 ml Injection: 50 mg/ml	Maintenance: 3-7 mg/kg/day in three divided doses; single dose or two divided doses for extended-release forms	Sodium channels Calcium channels NMDA receptors	Focal Primary and secondary GTC
Primidone (Mysoline)	Tablets: 50 and 250 mg Suspension: 250 mg/5 ml	500-1,500 mg/day in two or three divided doses	Chloride channels GABAuptake	Focal Primary and secondary GTC
Tiagabine (Gabitril)	Tablets: 2, 4, 12, 16, and 20 mg	32-56 mg/day in two to four divided doses	Sodium channels Potassium channels Glutamate receptors Carbonic anhydrase inhibition	Partial Focal and secondary GTC Tonic/atonic GTC Myoclonic
Topiramate (Topamax) Valproic acid/val-proate sodium (Depakene/ Depacon)	Tablets: 25, 100, and 200 mg Capsules: 15 and 25 mg Capsules: 125, 250, and 500 mg Extended-release capsules: 250 and 500 mg Syrup: 250 mg/ml Injection: 100 mg/ml	500-3,000 mg/day in two to four divided doses	Sodium channels Calcium channels	Focal and secondary GTC Absence Tonic/atonic GTC Myoclonic
Vigabatrin (Sabril)+	Tablets: 500 mg	2-4 g/day	GABA transaminase	Focal and secondary GTC Infantile spasms Lennox-Gastaut syndrome
Zonisamide (Zonegran)	Capsules: 100 mg	200-600 mg/day in two divided doses	Sodium channels Calcium channels Carbonic anhydrase inhibition	Focal Primary and secondary GTC Poor or none

*Rarely, lamotrigine may exacerbate myoclonic seizures +Not available in the United States

EAA—excitatory amino acids

GABA—y-aminobutyric acid

GTC—generalized tonic-clonic

NMDA—N-methyl-D-aspartate

Generalized nonconvulsive seizures Generalized noncon-vulsive seizures, particularly absence seizures, can be treated with ethosuximide, lamotrigine, or valproate. For patients who have only absence seizures, ethosuximide is satisfactory. However, for patients who have absence seizures in conjunction with other types of seizures, such as generalized convulsions or myoclonic seizures, valproate is the drug of choice; lamotrigine may also be effective. Some patients may respond to therapy with topiramate or zonisamide.

AED Pharmacokinetics

All AEDs are given orally once daily or more frequently [see Table 3]. Absorption of most AEDs usually occurs slowly over a period of hours and may be incomplete, especially in the case of gabapentin. Protein binding varies considerably among the drugs, ranging from 0% for gabapentin to 90% or more for phenytoin. Except for gabapentin, levetiracetam, and vigaba-trin, all AEDs are metabolized in the liver before renal excretion. Additionally, zonisamide and topiramate have significant renal excretion.

AED clearance and half-life vary from hours to days. The half-lives of carbamazepine, valproate, primidone, and gaba-pentin are relatively short, ranging from 4 to 8 hours, which necessitates administering these agents at least three times daily (although extended-release formulations of valproate and car-bamazepine allow twice-daily dosing). Phenytoin, lamotrigine,phenobarbital, and zonisamide have half-lives of a day or longer and may be administered once or twice daily. Phenytoin, carbamazepine, and the barbiturates cause enzyme induction, and long-term treatment with these drugs can affect their own rates of metabolism. Perhaps as important, these agents may affect metabolism of other medications the patient is taking. All AEDs that are metabolized in the liver can compete with other drugs that also undergo hepatic metabolism and so can delay clearance of those drugs. Because of their ability to induce or block drug metabolism, all of the AEDs except gabapentin, lev-etiracetam, and vigabatrin may be associated with pharmacoki-netic drug interactions in which drug levels and effects can be markedly altered by the concomitant administration of two or more drugs. This kind of interaction should be anticipated in all patients. It can be detected from clinical symptoms and levels of AED in the blood, especially free drug levels, and can be corrected by adjustment of dosages. Pharmacodynamic drug interaction may also occur. In this situation, the combination of two or more drugs with similar or antagonistic mechanisms causes their clinical effects to be enhanced or diminished, and these changes may necessitate adjustment of dosages. Pharmacody-namic drug interactions can be anticipated when drug mechanisms of action are known.