Both types can spread, resulting in secondarily generalized tonic-clonic seizures. About 70% of adult patients with epilepsy have some type of partial-onset seizures, and approximately 50% of these have both partial seizures and generalized tonic-clonic seizures. In general, these latter seizures are easier to control (followed by complex partial seizures and then simple partial seizures) because seizure medications are typically more effective in blocking seizure spread than in preventing initiation.

Generalized seizures are those in which the first clinical changes indicate that both hemispheres are initially involved. Consciousness usually is impaired during generalized seizures, although some myoclonic seizures may be so brief that impairment of consciousness cannot be assessed.

Table 2 Causes of epilepsy

Causes and risk factors Many abnormalities of the nervous system can result in seizure activity. Seizures can also occur in the normal nervous system when its metabolic balance is disturbed (see Table 2). Certain genetic and environmental factors may be involved, including head trauma, brain tumor, stroke, medication, and infections. About 35% of all cases of epilepsy have no clearly definable cause.²

Treatment Only 15% to 20% of patients with new-onset epilepsy are initially seen by a neurologist, with primary care clinicians providing approximately 40% of the long-term management of epilepsy patients with or without initial consultation with a specialist.⁵ Thus, primary care clinicians play a vital role in the treatment of patients with epilepsy with ongoing seizures. Many patients who have a single seizure or recurrent seizures can be safely and appropriately cared for by a primary care physician, although it may be best to coordinate initial care with a neurologist and/or an epileptologist.

Once the initial evaluation is complete, the mainstay of epilepsy treatment is AEDs. Prior to 1993, the choice of an anticonvulsant was limited to 5 medications—primidone, phenytoin, carbamazepine, phenobarbital, and valproate. While these medications continue to be widely used, they continue to be problematic because of the narrow therapeutic window of dosing, frequent dose-dependent CNS side effects, and rare but severe idiosyncratic end-organ toxicities.

Table 3 Second-generation antiepileptic drugs

Since 1993, 8 AEDs have been approved by the FDA (see Table 3). While several of the newer drugs are approved for monotherapy, only one—oxcarbazepine—is approved for initial monotherapy. Although there are subtle differences in the FDA-approved indications for each of these agents, all have demonstrated efficacy as adjunctive treatment of partial seizures with or without secondary generalization. None of the new agents has a formal indication for the treatment of absence (brief loss of consciousness) and other forms of primarily generalized epilepsy, although topiramate is indicated for the treatment of generalized tonic-clonic seizures.^6,7

AEDs are selected first and foremost according to clinical efficacy, then safety, tolerability, drug interaction profile, and ease of use. Cost is a major factor in the underserved population. Most neurologists agree that monotherapy is currently the best pharmacotherapeutic option and is mandatory when first starting AED treatment. There is evidence to suggest that in people newly diagnosed with epilepsy, only a relatively small percentage of patients who do not achieve seizure control with monotherapy will do so with polytherapy. One study showed that of the 64% of patients who were newly diagnosed and who subsequently became seizure free, 61% were seizure free on monotherapy, and 3% were seizure free on a 2-drug regimen.²

An appropriate drug for the seizure type and epilepsy syndrome with low adverse event risk and expected best efficacy should be selected, using accepted dosing guidelines and appropriate titering to response. If monotherapy is poorly tolerated or ineffective, the strategy is to switch to another drug. If the first drug has partial efficacy and is well tolerated, it is worth trying another drug in combination. Add-on therapy appears to be more effective when started immediately after first-drug failure, rather than waiting until a second drug has also failed. Special issues for young women with epilepsy include contraception, pregnancy planning, teratogenicity, parenting, and breastfeeding.

Specific treatment concerns Despite a much better understanding of, and an increased ability to predict drug-drug interactions, serious drug interactions still occur. More than 30% of all new seizures occur in the elderly; because this population may be taking other medications, the addition of an AED can have profound effect on these other therapies.

Carbamazepine, oxcarbazepine, phenobarbital, primadone, and phenytoin (and topiramate to some extent) all enhance cytochrome P-450 microsomal oxidative enzyme activity, thereby increasing steroid hormone clearance. In women, these particular AEDs can cause significant alterations of sex hormones and decrease the efficacy of oral contraceptives. In children and adults, these AEDs may result in long-term endocrine effects, including bone loss and lipid, thyroid, and sex hormone abnormalities. Adults taking AEDs are at increased risk for osteopenia and osteoporosis because of abnormalities of bone metabolism associated with AEDs and may require calcium and vitamin D supplementation. Physicians should counsel these patients about good bone health practices. Evaluation of bone health by measuring bone mineral density (BMD) is advisable af-ter 5 years of AED treatment or be-fore treatment in postmenopausal women.⁸

For most patients, antiepileptic monotherapy is less likely to cause unwanted side effects and more likely to control seizures. Other advantages of monotherapy include lower costs, ease of compliance, and decreased possibility of drug interactions. The older AEDs are known to have a problem with interactions among both other anticonvulsants and other therapeutic classes.⁹

Despite the array of new drugs, seizure control may not be achievable for all patients. From 60% to 70% of newly diagnosed patients will achieve remission once treatment with AEDs is initiated. The remainder—about 30% of patients—will continue to have recurrent seizures despite treatment.¹⁰ Disappointingly, these figures have remained largely static. Direct comparisons between newer and established AEDs show, that for partial seizures, there is little or no difference in efficacy between all the available drugs.¹¹

Are the new AEDs better?

One of the major differences between the older and the newer AEDs is the potential of the older drugs for significant interactions with other medications. Many of the drug-drug interactions involving the older AEDs are reciprocal, that is both drugs affect each other. In contrast, the newer AEDs have either no or limited drug interaction potential, which allows increased ease of use and perhaps greater safety, especially for patients taking multiple medications.¹²

There is some question as to whether the new AEDs are superior to their older counterparts. While there have been no head-to-head trials comparing the newer drugs with the older ones, gabapentin, lamotrigine, and oxcarbazepine have been compared with carbamazepine as monotherapy and have been found to have better tolerability, but with no difference in efficacy.^13,14

In 2004, the American Academy of Neurology (ANA) issued an evidence-based assessment of the efficacy, tolerability, and safety of 7 of the new AEDs (gabapentin, lamotrigine, topiramate, tigabine, oxcarbazepine, levetiracetam, and zonisamide).¹⁵ The ANA practice parameter states that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children.¹⁵

Because there are insufficient data for target concentration ranges for the newer AEDs, routine therapeutic drug monitoring is not required unless the patient is responding in an unexpected manner. Most of the new AEDs have not demonstrated significant interaction with other hepatically metabolized medications or potentially life-threatening adverse effects. However, they are 3 to 4 times more expensive than their older counterparts and have shown no evidence of being more effective.

Selecting an AED Selection of either an older or newer AED for first-line therapy requires careful consideration, an individualized evaluation, and should be based on the following:

• Select an AED based on seizure type and epilepsy syndrome.
• For focal-onset seizures, select an AED based on pharmacokinetics, side effect profile, dosing frequency, and cost since all available AEDs are efficacious.
• Start one AED at a time.
• If feasible, start AEDs at a low dosage and increase gradually. However, an initial therapeutic level of an anticonvulsant such as phenytoin becomes mandatory if the patient is susceptible to recurrent seizure activity. An alternative anticonvulsant can be substituted over time if clinically indicated. The dose escalation recommended in the labeling for AEDs may be well tolerated by otherwise healthy patients, but a slower dose escalation is usually necessary for patients on concomitant AEDs or psychoactive drugs or for those who have concomitant illnesses.
• Increase the dosage until either it is effective or side effects occur to define the maximum tolerated dose before deciding that it is ineffective.¹⁶

Table 4 Health and safety concerns for patients with seizures

While drug therapy is the mainstay of epilepsy treatment, it is only one part of patient management. Patients also need information about their conditions and to be reminded about the practical issues related to their safety and well-being (see Table 4). The requirements for licensed drivers to report a seizure condition varies from state to state. A summary of state driving laws can be found at the Epilepsy Foundation Web site (http://www.epilepsyfoundation.org|~www.epilepsyfoundation.org/).

When to refer When adequate seizure control is obtained, no further neurologic consultation is necessary. However, if seizures persist and cannot be brought under control within 3 months, a neurologist or epileptologist should be consulted.¹⁷ Once the seizures are fully controlled, care can be transferred back to the primary care physician. Should the initial diagnosis of epilepsy be in question, early referral to an epilepsy center is appropriate as evidence suggests that early, accurate diagnosis followed by optimal medical therapy may decrease seizure recurrence, reduce the number of drug trials, and minimize the impact of seizures.¹⁸ If 2 drugs have failed as monotherapy, the patient should also be referred to a neurologist or epileptologist. Such patients may be candidates for brain surgery; if this is not feasible, polytherapy or vagus nerve stimulation (VNS) can then be considered.

Referrals may also be required for women who become pregnant, as anesthesia requirements during delivery may have to be carefully titrated, and for patients with comorbidities such as depression, anxiety, or attention-deficit hyperactivity disorder (see "Comorbidities of epilepsy").

Nonpharmacologic management Surgery is an option for a small number of patients whose epilepsy cannot be controlled with medication. A good candidate for surgery has seizures that always begin in the same cerebral location, assuming that the tissue can be resected without creating deficits. Neurosurgeons generally avoid performing surgery in areas of the brain responsible for speech, hearing, and other important functions. Surgical options include

Lobectomy (lesionectomy) removes a small part of the brain where seizures originate. It is appropriate only for partial seizures.

Multiple subpial transection involves a series of small incisions are made that impede the spread of nerve activity. This procedure may be used when seizures originate in a part of the brain that cannot be removed.

Corpus callosotomy is used to treat uncontrolled generalized tonic-clonic seizures, complex partial seizures with drop attacks, and other generalized seizures. In this procedure, the surgeon severs the nerve fibers that connect the hemispheres of the brain to each other. Reduced seizure activity usually continues on one side.

Hemispherectomy is a last resort in children with severe brain damage on one side and seizures that do not respond to medication. It involves removing the entire affected side of the brain. The remaining hemisphere develops language and motor areas for both sides of the body. With intense rehabilitation, many patients will lead functional lives.

Devices for epilepsy In VNS, a small, pacemaker-sized device is implanted near the collarbone and attached to the vagus nerve. It delivers small bursts of electrical energy to the nerve, and therefore the brain at regular, preprogrammed intervals. Each device is programmed for the individual patient, and the patient or a caregiver has the ability to initiate or abort stimulation with the use of a handheld magnet.

It is thought that by stimulating the vagus nerve, electrical energy is discharged upward into a wide area of the brain, disrupting the abnormal brain activity responsible for seizures.¹⁹ A second theory suggests that stimulating the vagus nerve causes the release of special brain chemicals that decrease seizure activity. In some patients, seizure frequency is reduced. Most patients remain on antiepileptic medication but may be able to reduce the dosage. Since 1997, VNS has been approved by the FDA for use as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures that are refractory to antiepileptic medications.

In deep brain stimulation (DBS), electrodes are implanted into the brain, usually the thalamus, hippocampus, or temporal lobe. The equipment includes a pulse generator similar to a pacemaker, which is implanted under the chest as well as a tiny electrode and connecting wire. The implanted electrode stimulates the specific structures deep in the brain and may actually disrupt the circuits that generate seizures. Some clinical trials are looking at the effect of placing the electrode into the hippocampus. The investigators seek to determine whether the generator can detect a seizure at its onset and then deliver a stimulation in response, which could then teach the neurostimulator the patient seizure-onset pattern. Because the electrodes are placed directly into the brain, DBS is more risky than VNS. Currently, DBS is FDA approved only for Parkinson's disease and essential tremor.

Diet, lifestyle, and alternative interventions A ketogenic diet is used in children who do not respond to standard therapy or cannot tolerate the side effects produced by AEDs. The diet is a high-fat, low-carbohydrate diet that fundamentally changes the body's metabolism from using glucose as a primary energy source to using ketones. A recent review of the results from numerous studies of the ketogenic diet found that over half of children with seizures unresponsive to AEDs have a 50% or greater decrease in seizure frequency with the ketogenic diet.²⁰

The ketogenic diet is most effective in children 10 and younger. Compliance, which is essential for controlling seizures, is difficult to maintain. The regimen often is initiated with a 12- to 24-hour fasting period. Every meal includes exact amounts of fats, proteins, carbohydrates, and beverages, and only those foods listed for the diet can be eaten. Snacking is discouraged and sugars are not allowed. Vitamin A and mineral supplementation must be given.

The diet should be undertaken only with close medical supervision. Children must be monitored for growth and nutritional deficiencies. Common complications include poor growth and poor weight gain, hypercholesterolemia, and constipation.

Yoga, acupuncture, aromatherapy, biofeedback, behavior psychotherapy, and meditation may improve the quality of life for patients with epilepsy. Patients who practice interventions that promote sleep and reduce stress may be able to abort seizure activity.

Fostering patient adherence Persons with epilepsy sometimes miss taking their medication, with many reporting that missed medication had caused problems for themselves or their families. Reasons for noncompliance include complex medication regimens, limited access to medications, adverse effects, or feeling it was not important to take medication. Demographically, teenagers and adults younger than 60 are least likely to comply.²¹

Table 5 Epilepsy treatment strategies for patients and physicians

Compliance is enhanced when clinicians work in partnership with the patient. Education, including information about drug half-lives and their importance in maintaining adequate drug levels may help, together with simple dosing schedule cues (pills placed near a toothbrush to facilitate the morning and evening dosage) and compliance reinforcement by the physician. Table 5 lists patient and physician strategies to improve as well as to identify and eliminate barriers to compliance.

This consensus article was written by Jill Shuman in consultation with Drs Karceski, Kelley, and Schachter.

Dr Kelley discloses that he is on the speakers' bureau for Pfizer. Dr Schachter discloses that he is a consultant for and on the speakers' bureau for Pfizer and UCB Pharma. Dr Karceski discloses that he on the speakers' bureau for GlaxoSmithKline, Novartis, Eisai, and Cyberonics.

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4. Blume WT, Luder HO. Mizrahi E, et al. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia. 2001;42:1212-1218.

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6. LaRoche S, Helmers S. The new antiepileptic drugs. JAMA. 2004;293:605-614.

7. Cole AJ. Initial individualized selection of long-term anticonvulsant drugs by neurologists. Neurology. 2004;63(suppl 4):1-2.

8. Pack AM, Morrell MH. Epilepsy and bone health in adults. Epilepsy Behav. 2004;5(suppl 2):S24-S29.

9. Vazques B. Monotherapy in epilepsy: role of the newer antiepileptic drugs. Arch Neur. 2004;61:1361-1366.

10. Schmidt D, Gram L. Monotherapy versus polytherapy in epilepsy: a reappraisal. CNS Drugs. 1995;3:194-208.

11. Sandler JWAS. Some aspects of prognosis in the epilepsies: a review. Epilepsia. 1993;34:1007-1016.

12. Anderson G. Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs. Neurology. 2004;63(suppl 4):3-8.

13. Houtkooper MA, Lammertsma A, Meye JWA, et al. Oxcarbazepine: a possible alternative to carbamazepine? Epilepsia. 1987;28:693-698.

14. Dam M, Ekberg R, Loyning Y, et al. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res. 1989;3:70-76.

15. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1261-1273.

16. Tatum WO, Galvez R, Benbadis R, et al. New antiepileptic drugs: into the new millennium. Arch Fam Med. 2000;10:1135-1141.

17. Scheuer ML, Pedley TA. The evaluation and treatment of seizures. N Engl J Med. 1990;323:1468-1474.

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Drugs mentioned in this article

Carbamazepine (Epitol, Tegretol, Carbatrol)

Felbamate (Felbatol)

Gabapentin (Neurontin)

Lamotrigine (Lamictal)

Levetiracetam (Keppra)

Oxcarbazepine (Trileptal)

Phenobarbital

Phenytoin (Dilantin, Phenytek)

Primidone (Mysoline)

Tiagabine (Gabitril)

Topiramate (Topamax)

Valproate (Depakote)

Zonisamide (Zonegran)

Comorbidities of epilepsy Depression is the most common comorbid condition that affects people with epilepsy, and it occurs 3- to 10-fold more often in those with uncontrolled epilepsy than in the general population.¹ Depression affects up to 55% of patients with recurrent epilepsy and up to 9% of those with well-controlled seizures, although estimates vary according to the patient population studied, disease severity, and methodology used.² Furthermore, the clinical presentation of mood disorders in patients with epilepsy often differs from that in nonepileptic patients and does not always concur with standard diagnostic criteria. This may lead to underrecognition or to varying estimates of their prevalence.

Anxiety is another common comorbid disorder in epilepsy. Despite its frequent occurrence in this patient group, the relationship between anxiety and epilepsy has been less thoroughly investigated than other psychiatric conditions. Estimates of its incidence in patients with epilepsy are crude and range from 3% to 50%, although incidences of up to 66% have been identified. Like other psychiatric disorders, anxiety can occur prodromally, ictally, or postictally as an adverse consequence of antiepileptic drugs, or it may be an unrelated disorder.³

Other psychiatric comorbid conditions include psychoses and attention-deficit hyperactivity disorder (ADHD). Psychotic disorders affect 6% to 10% of patients with epilepsy.² The mechanisms of these disorders, although poorly understood, seem to be related to epileptic conditions, since their recurrence is linked to exacerbation of seizures. Children with epilepsy commonly show behavioral symptoms of inattention and hyperactivity, and some of these children have ADHD. Estimates of ADHD prevalence in children with epilepsy vary, although studies using standardized diagnostic criteria have documented ADHD in 14% to 40% of children, compared with 5% in otherwise normal school-aged children.⁴

1. Attarian H, Vahle V, Carter J, et al. Depression in epilepsy and intractability of seizures. Epilepsy Behav. 2003;4:298-301.

2. Gilliam F, Kanner AM. Treatment of depressive disorders in epilepsy patients. Epilepsy Behav. 2002; 3(5S):2-9.

3. Bazil CW. Comprehensive care of the epilepsy patient: control, comorbidity and cost. Epilepsia. 2004;45:3-12.

4. Dunn AW, Austin JK, Hareslak J, Ambrosius WT. ADHD and epilepsy in childhood. Dev Med Child Neurol. 2003;45:50-54.