Epilepsy Part 3

Adverse Effects of AEDs

All AEDs can produce adverse effects, which are numerous and vary considerably from patient to patient. Most of the adverse effects caused by AEDs can be tolerated. However, rare idiosyncratic effects may be life threatening [see Table 4]. Good medical practice demands that physicians obtain screening studies before starting a patient on AED treatment. However, prospective studies of the effect of routine blood and urine assessment in patients receiving long-term AEDs showed no value in asymptomatic patients.40 On the other hand, clinical moni-toring—by reviewing and reporting symptoms or by physical examination—is cost-effective and practical. Routine laboratory monitoring, as currently practiced, is not effective in anticipating life-threatening effects associated with the major AEDs, including carbamazepine, phenytoin, phenobarbital, lamotrigine, and valproate. Continuing communication with the patient and family is the best strategy for monitoring for adverse events. They must be aware of potential complications and the symptoms that might herald an adverse event. An approach that combines clinical expertise with educating patients and care-givers about the risks and benefits of treatment and enlisting their active participation is becoming the standard of care.

Table 4 Idiosyncratic Reactions to Antiepileptic Drugs^{83 84}

Agent	Agranulocytosis	Allergic Dermatitis/ Rash	Aplastic Anemia	Hepatic Failure	Pancreatitis	Serum Sickness Reaction	Stevens-Johnson Syndrome	Teratogenic Effects (FDA Pregnancy Category*)
Carbamazepine	+	+	+	+	+	+	+	Neural tube defects, facial anomalies, microcephaly (D)
Clonazepam	+	-	-	-	-	-	-	(D)
Ethosuximide	+	+	+	-	-	+	+	(C)
Felbamate	+	+	+	+	-	-	-	(C)
Gabapentin	-	+	-	-	-	-	-	(C)
Lamotrigine	-	+	-	-	-	-	+	(C)
Levetiracetam	-	+	-	-	-	-	-	(C)
Oxcarbazepine	-	+	-	-	-	-	-	(C)
Phenobarbital	+	+	-	+	-	+	+	Facial anomalies (D)
Phenytoin	+	+	+	+	+	+	+	Facial anomalies, low IQ, IUGR (D)
Primidone	+	+	-	+	-	+	+	Facial anomalies, low IQ (D)
Tiagabine	-	+	-	-	-	-	-	(C)
Topiramate	-	+	-	-	-	-	-	(C)
Valproate	+	+	+	+	+	+	+	Neural tube defects, facial anomalies (D)
Zonisamide	-	+	-	-	-	-	+	(C)

FDA Pregnancy Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. FDA—Food and Drug Administration IQ—intelligence quotient IUGR—intrauterine growth retardation

*FDA Pregnancy Category C: Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans; but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Some of the undesirable side effects of AEDs, such as neuro-toxicity, are clearly dose related. Other adverse effects, such as some forms of hepatotoxicity or aplastic anemia, seem to be idiosyncratic. Still others have other mechanisms. An efficient way to understand the adverse effects of AEDs is to define them according to the affected organ system.

Effects on the central nervous system All AEDs can cause depression of cortical function, with symptoms of sedation and lethargy. Dose-dependent neurologic toxic changes are the most common adverse effects of AEDs and limit the amount of drug that may be used. CNS symptoms are used to titrate to an acceptable dose; this is independent of AED blood levels, because the therapeutic range is statistically derived and may not apply to an individual patient. For example, carbamazepine causes diplopia or sedation; either one serves as an indication that the patient has reached the maximum tolerated dose. If AED blood levels reach the upper limit of the therapeutic range but seizures continue to be uncontrolled and the patient remains free of side effects, the dose is increased until neurotoxic-ity develops. This defines the maximum tolerable dose for that patient.

Although dose-related effects of phenytoin on the cerebellum are classic indicators of toxicity, the typical findings are often blunted or inapparent because of individual patient responses.40 The expected progression of symptoms from nystagmus to ataxia and confusion or feelings of intoxication does not always occur. Residual ataxia after prolonged phenytoin intoxication can probably occur, especially in vulnerable patients.

Persistent or fluctuating ataxia appears to be related to long duration of epilepsy, use of multiple drugs, and persistently high serum drug levels. Changes in intellectual function and alterations in personality or even psychiatric effects have been reported with several AEDs. Altered IQ in children treated with phenytoin and primidone appears to be related to higher blood levels of the drugs. Assessment of cognitive function in patients treated in random fashion failed to reveal any differences among the major AEDs, although phenobarbital appears to have a greater effect than other medications.42 Drugs administered to children may have unpredictable or paradoxical effects; for example, barbiturates are well known to cause hyperactivity in children. Depression and psychosis may be caused by AEDs. Most effects on behavior appear to be dose related. Psychosis after seizure control has been reported, as have other behavioral problems; in some cases, this appears to be related to normalization of the EEG and is termed forced normalization.

Phenytoin may cause dose-related abnormal movements; carbamazepine seldom causes involuntary movements. Val-proate may cause tremor.

Mild sensory neuropathy has been reported in 8% to 15% of patients treated with older AEDs44 and seems to require long-term exposure. Prolonged exposure to high plasma levels causes loss of large myelinated fibers and clustered nonrandom distribution of segmental demyelination that suggests a pattern of ax-onal neuropathy and secondary demyelination. Use of multiple drugs also is associated with chronic neuropathy. Altered peripheral nerve function is thought to be an effect of AEDs on fo-late metabolism, with resultant mild alteration of peripheral nerve function. Usually, the clinical effect is not severe, but loss of deep tendon responses or vibratory sensibility at the ankles may occur.

Aside from these dose-dependent effects, AEDs may induce a reversible encephalopathy and even progressive mental deterioration or delirium. On rare occasions, the initial exposure of a patient to valproate causes coma; the mechanism of this effect may be related to mitochondrial metabolism.

Gastrointestinal and hepatic effects Valproate produces hepatic failure in approximately one in 10,000 patients. The highest rate of hepatic failure is observed in children younger than 2 years who are treated with multiple drugs. Older patients on monotherapy have a much lower rate: one in 45,000.46 The mechanism of valproate-induced hepatotoxicity is unknown but may involve toxic metabolites of the drug. Hepatic damage associated with phenytoin, carbamazepine, or pheno-barbital therapy is infrequent. The mechanism that causes the hepatic failure is thought to be an idiosyncratic hypersensitivity reaction.

Pancreatitis has been observed during valproate therapy, and fatalities have occurred in both children and adults.47 Reexpo-sure of affected patients has caused recurrent pancreatitis, but the mechanism of this adverse effect has not been established.

Hematologic effects Adverse hematologic reactions associated with idiosyncratic responses to AEDs range from a mild decrease in the number of blood cells to aplastic anemia. Fortunately, serious problems are infrequent. Phenytoin may alter lymphocyte function, given that 21% to 25% of patients on long-term therapy have decreased circulating levels of IgA along with depressed lymphocyte phytohemagglutinin transforma-tion.48 Phenytoin hypersensitivity may cause generalized lym-phadenopathy and in rare instances may be associated with lymphoma.49 Carbamazepine treatment commonly causes hematologic changes. Dose-related leukopenia is reported to occur in 12% of treated patients.40 In my experience, this estimate is low. The mechanisms leading to this effect on granulocytes is unknown, but the effect appears to be dose related and does not herald more serious reactions. There appears to be little need for concern until the total white blood cell count is less than 2,500/mm3 or the total granulocyte count is less than 750/mm3.

Aplastic anemia occurs infrequently with AEDs, and no single drug, with the exception of felbamate, seems to be more likely than another to produce this serious complication. Aplastic anemia associated with carbamazepine treatment seems to be related to dosing patterns and advanced patient age.40 Of 65 patients who died of aplastic anemia associated with carba-mazepine, only four were children.40 Valproate causes a dose-related decrease in the level of circulating platelets that is only occasionally symptomatic.50 Occurrence of purpura or petechial hemorrhage requires discontinuance of the drug. The mechanism is a change in platelet adhesiveness, with acceleration in the second stage of platelet consumption causing accelerated loss of circulating platelets. An IgM platelet autoantibody is occasionally detected.51 Mild macrocytosis and decreased red blood cell folate levels occur with antiepileptic drug therapy, particularly phenytoin. Megaloblastic anemia is an occasional effect of antiepileptic drug treatment that appears to be related to alterations in metabolism of folate. Folate supplementation is required in some cases.

Dermatologic reactions Skin reactions to AEDs are not uncommon, but life-threatening dermatologic responses are rare.52 Drug-induced eruptions range from mild erythema, with or without pruritus, to serious exfoliative reactions or development of bullae. Dose-related exanthema is the most common skin reaction. This form of rash may respond to dose reduction. The rash may be pruritic, maculopapular, or morbilli-form, and about 50% of patients may have prodromal symptoms that include malaise and fever. Drug eruptions that begin as pruritic effects with morbilliform or scarlatiniform rashes may progress to severe exfoliative dermatitis. In such cases, the offending drug must be discontinued promptly and another AED substituted. The mechanism of skin reaction may be determined by pharmacogenetic factors related to the ability to metabolize arene compounds formed during drug metabo-lism.52 The exfoliative dermatitides produced by AEDs include erythema multiforme, Stevens-Johnson syndrome, and Lyell syndrome.52 Exfoliative dermatitis commonly occurs within 1 to 4 weeks after initiation of treatment and may be fatal. The drug responsible for the reaction must be discontinued and treatment with systemic steroids instituted. Erythema multi-forme as a drug reaction is rapid in onset, with erythematous lesions that range from a macular pattern with varied shapes to the development of vesicles or bullae. If mucosal lesions are present, the reaction has evolved to the Stevens-Johnson syndrome. In either case, dermatologic consultation is imperative. Acne is a common minor skin problem associated with pheny-toin use. Hypertrichosis is associated with both phenytoin and carbamazepine. Alopecia occurs during the first few weeks of treatment with valproate. Administration of multivitamins containing zinc appears to prevent this change in hair-shaft strength.

Connective tissue disorders AEDs may cause lupus ery-thematosus, scleroderma, Sjogren syndrome, and eosinophilic fasciitis. Lupus occurs in both a discoid and a systemic pattern. Criteria for diagnosis include malar erythema with discoid skin changes, photosensitivity, oral ulceration, nonerosive arthritis, serositis, and nephropathy. Hematologic and immunologic changes are revealed by positive lupus erythematosus cell preparations, anti-DNA (double stranded) antibodies, and anti-nuclear antibodies.53 Drugs may precipitate lupus, exacerbate existing lupus, or be associated with an isolated drug-related form. Drug-related lupus usually abates after discontinuance of the inciting drug. Further, the pattern of organ involvement usually spares skin, kidneys, and the CNS. The immunologic pattern usually does not involve the induction of antibodies to double-stranded DNA. Long-term phenytoin use has caused a syndrome of ecchymoses, gingival bleeding, and lupus anticoagulant antibodies associated with prothrombin deficiency. Carbamazepine and ethosuximide have also been associated with the development of drug-induced lupus.

Metabolic and endocrine effects Hyponatremia is a dose-related effect of carbamazepine that seems to occur only in adults. Oxcarbazepine is also associated with dose-related hy-ponatremia, primarily in adults; this occurs more commonly than with carbamazepine.54 Central effects on antidiuretic hormone and peripheral or renal effects have been considered as mechanisms, but the exact pathogenesis remains unknown. With either drug, the hyponatremia seldom causes a clinical problem. Effects of phenytoin on pituitary-adrenal function are related to the peripheral effects of induction of cytochrome P-450 hepatic enzymes, with resultant accentuation of metabolism of endogenous hormone. Accelerated metabolism of exogenously administered steroid hormone, such as birth control pills, may cause contraceptive failure. Hypothalamic function may be affected by phenytoin. Changes include altered release of antidiuretic hormone, block of thyroid-stimulating hormone effect by thyrotropin-releasing hormone, and, in women, augmentation of secretion of follicle-stimulating hormone and luteinizing hormone.55,56 Phenytoin can alter the results of thyroid function studies: it lowers total triiodothyro-nine (T3) and thyroxine (T4), so patients may have a decreased free T4 level, with a normal thyroid-stimulating hormone (TSH) level; however, phenytoin also increases free T4 and T3 by induction of displacement from thyroxine-binding globulin, which may normalize free T4 levels. Most patients remain clinically euthyroid.

Weight gain may occur with valproate or gabapentin; weight loss may occur with topiramate or zonisamide. The exact mechanisms are unknown. Other AEDs are considered weight neutral.

Discontinuing AED Therapy

Most patients treated with AEDs require treatment for several years. When a patient has remained seizure free after several years of AED therapy and the underlying epilepsy syndrome is not one that is known to require continuous treatment (e.g., juvenile myoclonic epilepsy), the question arises as to whether to discontinue treatment. A meta-analysis57 concluded that the likelihood of successful AED withdrawal was highest in patients meeting the following criteria: (1) they have been seizure free from 2 to 5 years on AED treatment, (2) they have a single type of partial seizure (simple partial, complex partial, or secondary generalized tonic-clonic seizure) or single type of primary generalized tonic-clonic seizure, (3) their neurologic examination results and IQ are normal, and (4) their EEG has normalized with treatment.

Vagus Nerve Stimulation

Electrical stimulation of the vagus nerve has both acute and chronic antiepileptic effects. The acute effects result from poly-synaptic transmission and activation of key inhibitory pathways; the chronic effects may be the result of persistent changes in neurotransmitters or changes in cortical and subcortical synaptic activity.

Vagus nerve stimulation (VNS) is now the second most common treatment for epilepsy in the United States, after AEDs. VNS devices were approved by the Food and Drug Administration in 1997, and over 16,000 of these devices have now been implanted in patients worldwide.

Implantation of a VNS device usually takes less than 1 hour and can be done as an outpatient procedure. The generator, which measures 6.9 by 52 mm and is made of titanium, is placed subcutaneously in the left upper chest. The lead wires are placed on the left cervical vagus nerve and tunneled to the generator. VNS devices have programmable settings; the intensity and duration of the pulses (e.g., 1.5 mA for 30 sec) are tailored to the individual patient. Once programmed, the device operates on its own. In addition, patients can activate the device themselves, through the use of a handheld magnet, which triggers a switch that initiates a separate program in the device. This ability to abort seizures gives patients an active role in the treatment of their epilepsy and is an important psychosocial benefit of VNS therapy.

Criteria for VNS placement include partial onset seizures that persist despite adequate trials of two or three AEDs (preferably, AEDs with differing mechanisms of action). Nonepileptic events must be excluded. The patient should not be a good candidate for focal resective surgery (see below); in patients who are good candidates, this surgery is preferred to VNS because it is more likely to render the patient seizure free. In the United States, the use of VNS is limited to patients older than 12 years; in the European Union, there is no age limit with VNS therapy, although the size of the device may limit its use in children younger than 3 or 4 years.59

Surgical Treatment

Surgical treatment is an option for patients who have failed to respond to conventional AED treatment or who have had intolerable adverse drug effects, whose seizures have a focal origin, and whose seizures originate in tissue that can be removed without causing disability.60 Epilepsy may be associated with a structural lesion in the region of seizure onset. The presence of a seizure focus in the hemisphere dominant for language and the occurrence of complex partial seizures arising in extratemporal tissue necessitate special assessment. Detection of bilateral epileptiform discharges, development of secondarily generalized seizures, and occasional onset of a seizure from contralateral tissue tend to add to the complexity of preoperative assessment.

Current standards for surgery require locating the seizure focus by several means. Although ictal and interictal scalp EEG and intraoperative electrocorticography have been used, these methods may fail to provide adequate lateralizing or localizing information. Therefore, most epilepsy centers require combined video and scalp EEG recording of at least three of a patient’s typical seizures. Additional localizing information is obtained from MRI, neuropsychology, and isotope studies of blood flow or metabolism. Location of memory function and speech lateral-ization are also important. Insertion of intracranial electrodes is required should the scalp EEG fail to provide adequate lateralizing or localizing information. However, because of the small but significant morbidity associated with invasive electrode studies, functional imaging [see Brain Imaging, above] is being explored as an alternative.21

The most commonly performed surgical procedure for epilepsy is temporal lobectomy. After this procedure, approximately 70% of patients remain seizure free, and an additional 20% show marked improvement. Histopathologic assessment shows that in at least 60% of patients, sclerotic changes occur in the resected hippocampus. Long-term follow-up studies have shown a fixed rate of recurrent seizures after temporal lobecto-my, so these patients are no longer taken off AEDs postopera-tively.62 The goal of this procedure is not to eliminate AED use; it is to eliminate seizures. Patients may be able to reduce the number of AEDs or lower the dose, but even those who remain on the same AED regimen generally enjoy significant improvement in their quality of life.

Complications associated with resective surgery remain low and generally acceptable. A superior quadrantic visual field defect may occur in patients undergoing classic temporal lobecto-my. Permanent hemiparesis is reported in up to 2.4% of patients; mortality varies from 0% to 1.7%.®

More advanced procedures (i.e., resection of extratemporal foci, sectioning of the corpus callosum, and functional hemi-spherectomy) are performed in special epilepsy centers. Corpus callosotomy is a palliative procedure for patients who sustain injuries secondary to falls during seizures.63 It has largely been supplanted by VSN device implantation, however.

The Ketogenic Diet

A diet high in fat and low in carbohydrates can prevent seizures by maintaining the patient in ketosis. The use of keto-genic diets for epilepsy was pioneered in the 1920s. Such diets remained a standard aspect of epilepsy treatment until the last decades of the 20th century, when their popularity was eclipsed by that of AEDs. However, the ketogenic diet has reemerged, and clinical studies have confirmed its efficacy in almost all seizure types.59

The classic ketogenic diet has a 4-to-1 ratio of calories derived from fats to calories derived from proteins and carbohydrates. The diet is individualized, to the extent possible, according to the patient’s food preferences and eating habits. Initiation of the diet is done with the patient in hospital. Strict adherence to the diet is necessary.

Ketogenic diets are used principally in children. Although the exact antiepileptic mechanism of ketogenic diets remains unknown, it is known that during the diet, the brain utilizes ke-tone bodies for fuel. With maturity, the brain’s ability to extract ketones from the blood decreases as much as fivefold, and this may make the ketogenic diet slightly less effective in adults. Most often, however, adults do not use the diet because they find it impractical.

Treatment of Status Epilepticus

Status epilepticus is a danger to the patient and a treatment challenge to the physician. The cardinal feature of this serious epileptic state is continuous seizures or two or more seizures occurring in sequence without recovery of consciousness between them. Status epilepticus has varied forms of clinical presentation, including repeated generalized convulsive seizures, with coma between seizures; nonconvulsive seizures, causing a change in cognitive function; and sequential focal seizures, including focal motor seizures or focal sensory complaints.

Generalized convulsive status epilepticus is the most common and most challenging form of status epilepticus. The patient has convulsive movements and is unconscious. The motor manifestations of convulsive status epilepticus may be symmetrical, with tonic and then clonic activity. If the generalized seizures arise from a focus, lateralized movements occur at the onset or during seizures.

In practical terms, any patients who are in seizure when they reach the emergency department or who are observed having a seizure for 10 minutes must be treated on the assumption that they are in status epilepticus. Treatment is divided into acute management and drug therapy [see Figure 4].

Figure 4 Treatment of convulsive status epilepticus. (D25W—25% dextrose in water; ECG—electrocardiogram; PE—phenytoin equivalents)

Acute management

Treatment begins with life support, including clearing the airway and supporting ventilation, maintaining blood pressure, and establishing intravenous access. The airway must be protected and appropriate oxygenation ensured. Although intubation may be necessary, the decision to use it must be made in parallel with selection and administration of an anticonvulsant drug. Physiologic monitoring must include assessment by electrocar-diography and measurements of blood pressure, levels of blood gases, levels of biochemical markers, and body temperature.

Hypoglycemia must be excluded or if present, corrected. Blood glucose levels must be measured promptly. If this is not possible, the patient should be treated empirically with intravenous glucose. Adults should first receive thiamine, 100 mg intravenously, to avoid precipitating Wernicke disease in thi-amine-deficient alcoholic patients. The dose of glucose for adults is a bolus of 50 ml of 50% glucose; for children, the dose is 2 ml/kg of 25% glucose solution.

Drug therapy

Clinical and electrical seizures must be terminated rapidly because total duration of convulsive status epilepticus correlates with response to treatment and with outcome.64 Physicians treating patients with convulsive status epilepticus must be familiar with the drugs available, including methods of administration, dosages, and acute side effects. Best outcomes are associated with having a treatment plan, using effective drugs administered by the appropriate route and in adequate doses, and anticipating apnea. A protocol should be followed, and drugs should be administered intravenously (except for diazepam gel per rectum [see below]). Currently, intramuscular administration has no role in treatment. The clinical situation determines which drug should be administered. If a patient is having a seizure at the time of assessment, a benzodiazepine is needed. If the patient has a history of serial seizures but convulsive seizures have abated, administration of a long-acting AED is the best choice.65 In the only randomized, controlled trial comparing initial intravenous treatments for status epilepticus (which was conducted at Veterans Affairs hospitals), lorazepam was found to be more effective than phenytoin and easier to use, although no more effective than phenobarbital alone or diazepam followed by phenytoin.66

Benzodiazepines

The benzodiazepines are effective and highly potent. Di-azepam and lorazepam are commonly used. A rectal gel formulation of diazepam is currently available, packaged in predosed syringes. Because it can be administered to a patient with no intravenous access, it is suited for use in the home, in the field, and in the emergency department while intravenous access is being obtained. Diazepam is highly lipid soluble and penetrates the brain rapidly. However, redistribution into nonneural fatty tissue causes rapid decline in both brain and blood concentrations of the drug. If diazepam is used to terminate seizures, a long-acting AED such as fosphenytoin must be administered. Lorazepam has a longer duration of action than diazepam but is associated with a prolonged time to full recovery.65 Both of these drugs cause depression of breathing and even apnea, so ventilation must be supported, and intubation may be necessary.

Fosphenytoin

Convulsive status epilepticus can be terminated by intravenous loading of fosphenytoin, a water-soluble prodrug form of phenytoin. Fosphenytoin is administered in phenytoin equivalents of up to 150 mg/min, or 3 mg/kg/min in children weighing less than 50 kg. It is rapidly converted by phos-phatases into phenytoin, leading to blood levels equivalent to those achieved with phenytoin itself, but without the difficulties of administration and risk of tissue injury.

During fosphenytoin treatment, the elderly and patients with cardiac disease or with difficulty maintaining blood pressure require careful monitoring of cardiac rhythm and rate along with blood pressure. Those with hypotension require a slower rate of infusion. Electrocardiographic monitoring may show widening of the QT interval or even induction of arrhythmia. These changes signal the need to slow the rate of infusion even further.

Phenobarbital

Phenobarbital is highly effective and is known to many physicians. The adult dose is 10 to 20 mg/kg. Sedation may result, and apnea is a risk, particularly if the patient has taken ben-zodiazepines. Blood pressure monitoring is critical; hypotension responds to slowing the rate of administration.

Treatment of refractory status epilepticus

If a patient fails to regain consciousness or continues to have seizures after first-line therapy, neurologic consultation is required. Such a patient requires urgent EEG recording,67 and anesthesia must be considered. An effective anesthetic drug is pentobarbital, although some authors suggest use of propofol or midazolam.65,68 Midazolam (0.2 mg/kg administered by slow I.V. bolus injection followed by 0.75 to 10 ^g/kg/min) and propofol (1 to 2 mg/kg with 2 to 10 mg/kg/hr) appear to be replacing pentobarbital as the drugs of choice.65 The patient must be intubated and appropriate intensive care monitoring established. Patients are maintained in anesthetic coma for variable periods. Continued management requires gradual tapering of the maintenance dose at 4 hours, again at 8 hours, and on a regular schedule thereafter, with observation to determine whether seizures have abated and the EEG remains free of seizure discharges. Vasopressors may be needed during pentobarbital coma. Subtle convulsive status epilepticus occasionally develops. EEG assessment is required, particularly when motor changes are not obvious.67

Aftercare

After initial diagnostic studies are performed and the seizures controlled, the cause of status epilepticus must be sought. Medical and neurologic evaluations are important. When the patient is known to have epilepsy and the chart is available for review, further evaluation may be unnecessary. Brain-imaging studies are appropriate after seizures are under control. A history of head trauma, focal seizures, or signs of systemic illness should guide evaluation. If the patient is febrile, a lumbar puncture with examination of the CSF is needed, but only after mass lesions and ventricular obstruction are excluded by CT or MRI. An EEG is indicated in all patients with new-onset status epilepticus or those with treated status epilepticus who are not recovering their previous neurologic baseline. The clinical situation must determine decisions.

Prognosis of Epilepsy with Treatment

The likelihood of control or remission of epilepsy varies ac-cording to the particular epilepsy syndrome, as well as factors specific to the individual case. Control, when applied to epilepsy, means lack of seizures with use of medication. Remission means lack of seizures without medication.

Internet Resources on Epilepsy

Web Sites for Patients

British Epilepsy Association http://www.epilepsy.org.uk

Cyberonics (vagus nerve stimulation) http://www.cyberonics.com

Epilepsy Canada (English and French) http://www.epilepsy.ca/

Epilepsy Foundation of America http://www.epilepsyfoundation.org

Epilepsy Information Service http://www.bgsm.edu/neuro/disease/epilinfo.shtml

The Epilepsy Research Foundation http://www.erf.org.uk

University of Washington Regional Epilepsy Center http://faculty.washington.edu/chudler/epi.html

Web Sites for Physicians

American Epilepsy Society http://www.aesnet.org

University of Washington Regional Epilepsy Center— Antiepileptic Drugs http://elliott.hmc.washington.edu/EpiInfo/antiepileptic.htm

Prognosis with medical control of generalized and partial seizures has improved with better methods for assessment, introduction of new drugs, and more rational use of older agents.69 The simultaneous use of EEG and video monitoring has improved diagnostic accuracy. Of patients with new-onset seizures, 60% to 65% achieve good control with a single drug.70 Some studies show a 5-year absence of seizures in at least 70% of patients who were followed for 20 years. Of these patients, 50% were in remission—that is, they were not taking any medication.29

Control is difficult to achieve in patients with epilepsy of longer duration, with partial seizures, with more seizures before the start of treatment, with seizures that are of known cause, and with epileptiform patterns on EEG.69 Poor seizure control also is associated with various types of seizures with abnormalities on EEG, delay in the start of treatment for more than 1 year, and frequent seizures; poor control may result in impaired social adjustment.69

The prognosis for control is less favorable with complex partial seizures than with generalized seizures. Of patients with complex partial seizures, the outcome tends to be better in those who have normal mentation, short duration of illness, and low seizure frequency.29,69 However, if complex partial seizures are complicated by generalized tonic-clonic seizures, complete control is difficult to achieve. Patients at high risk for development of intractable complex partial seizures are those with clusters of seizures, more than one seizure a day, aura at the onset of seizures, and psychiatric disease.69 In drug trials using high-dose carbamazepine, phenytoin, and barbiturates to the point of clinical toxicity in patients with intractable seizures, high-dose therapy resulted in complete control in 22% of patients; 38% had either an increase or no change in seizure frequency, and approximately 30% were not affected by any drug.71

Epilepsy may affect life span. Review of coroners’ cases reveals common factors in sudden death in epileptic patients. Most deaths occurred when patients were in bed, with 6% to 30% occurring during sleep. At autopsy, few patients had therapeutic blood levels of prescribed AEDs; 50% had no detectable levels. Seizures are not always immediately associated with death72; cardiac arrhythmia has been implicated.72,73 The prevalence of sudden death is between one in 2,000 and one in 900 patients with epilepsy, with higher rates occurring in patients with refractory epilepsy and nocturnal convulsive seizures.