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Managing seizures: Achieving control while minimizing risk
• Prescribe an antiepileptic drug (AED) after a first unprovoked seizure only if the seizure was prolonged or there is a risk of recurrence. C
• Use monotherapy whenever possible; if seizures continue and potential adverse effects prevent an increase in dosage, switch to a different AED and taper off the first agent. A
• Consider gradual withdrawal of AEDs from patients who have been seizure-free for 2 to 5 years. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE Joe G, a 44-year-old man who has been your patient for years, comes to your office 48 hours after having a seizure. He has no history of seizures, had no warning signs or symptoms, and felt fine all day, but simply collapsed when the seizure occurred. He was transported to the emergency department (ED), and found to be postictal, with no further seizure activity. The ED work-up included a hemogram, comprehensive metabolic panel, and computed tomography brain scan, all of which were normal. An hour later, Joe had a normal neurological exam, then underwent electroencephalography (EEG) and magnetic resonance imaging (MRI) and was discharged home without medication.
How would you treat this patient?
About 10% of Americans will experience a seizure at some point in their lives,1,2 and more than 3 million have epilepsy.3 The incidence ranges from 1% among 20-year-olds to more than 3% by the age of 75.1,2
To adequately care for such patients—whether they have had multiple seizures or only one—you need to know whether they’re at risk for recurrences, when (or if) to prescribe an AED, and which agents provide optimal seizure control with the fewest adverse effects. You also need to know when a referral to an epilepsy specialist is indicated, when or whether it’s safe for patients to stop taking antiseizure medication, and how to address lifestyle issues that patients with epilepsy often need help with.
This review addresses these and other questions.
Is it epilepsy? How to respond to a single seizure
A seizure—a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neural activity in the brain—can be either focal (partial) or generalized. In addition, seizures can be broadly divided into 2 categories, based on etiology:
Provoked seizures are caused by an acute structural, toxic, or metabolic insult to the brain, and, presumably, would not have occurred if the underlying medical condition did not exist. Treating the cause—eg, alcohol withdrawal, hyponatremia, or hypoglycemia—should prevent a recurrence.
Unprovoked seizures have no apparent underlying cause. Epilepsy is defined as a chronic condition characterized by ≥2 unprovoked seizures at least 24 hours apart, and epilepsy syndromes are classified as localization-related or generalized (TABLE 1).1,4,5
Generally, epileptologists do not recommend symptomatic treatment of a first unprovoked seizure6—a consensus based on several randomized controlled trials that found immediate treatment with an AED reduced the risk of a subsequent seizure in the short term, but did not affect long-term outcomes or the development of epilepsy.7
Treatment should begin after a single seizure, however, if the seizure was prolonged or there is an increased risk of recurrence.6 Factors that increase this risk include an abnormal EEG, particularly if the abnormality is epileptiform; the presence of a brain lesion; a localized (focal) seizure; and an abnormal neurologic exam.8 A history of status epilepticus—a single, unremitting seizure lasting ≥5 to 10 minutes or frequent seizures without a return to neurologic baseline in between—or complex febrile seizures, and a family history of epilepsy are risk factors for recurrence, as well.7
When the patient is a child. Prescribing an AED for a child after a first unprovoked seizure is not indicated to prevent the development of epilepsy, but may be considered, as for adults, in circumstances where the benefit of reducing the risk of a second seizure outweighs the risk of pharmacologic and psychosocial adverse effects.9
CASE Joe’s ED records show that his MRI was normal, but his EEG revealed an epileptogenic focus on the right temporal region—a finding that indicates that he has an elevated risk of recurrence and is a candidate for an AED. Before selecting a particular agent, you review his chart.
Joe is taking a thiazide diuretic and a calcium channel blocker for hypertension. He was a heavy drinker until he had an episode of pancreatitis 10 years ago, and has been abstinent ever since. About 5 years ago, he suffered from depression and was treated with sertraline, but the depression resolved and the drug was discontinued 3 years ago. The patient’s mother and brother have type 2 diabetes and his father had a myocardial infarction before the age of 60. Joe was laid off from his sales job 18 months ago and is actively seeking employment. At this point, you consider a broad-spectrum AED that would not interact with his current medications or adversely affect his medical conditions, and would be relatively inexpensive.
TABLE 1
Identifying seizures and types of epilepsy:1,4,5 International League Against Epilepsy classification
| Type of seizure |
Focal
Generalized
|
| Type of epilepsy syndrome* |
Localization related (partial or focal)
Generalized
|
| *This is a partial listing, with selected examples of epilepsy syndromes. |
What to consider in a first-line drug
The number of AEDs on the market has increased sharply in the past few years, giving physicians many medications to choose from. Selecting the optimal drug is particularly important for the initial treatment, as many patients remain on the first AED for years. Second-generation AEDs have been found to be as effective as, and better tolerated than, first-generation antiseizure drugs. But all AEDs carry a warning of a potential increase in suicide risk and the need to monitor patients for behavior changes.10
Before selecting an AED for a particular patient, consider the following questions:
What type of seizure? AEDs are generally classified by spectrum of activity into “narrow-spectrum” and “broad-spectrum.” Narrow-spectrum drugs are more effective for controlling partial seizures, but have the potential to exacerbate generalized seizures; broad-spectrum AEDs can be used for both. (TABLE 211-18 lists indications for first- and second-generation AEDs based on type of epilepsy.) If there’s no definitive diagnosis of the type of epilepsy a patient has, use a broad-spectrum drug.
What other drugs is the patient taking? If the AED will be added to the patient’s current medication regimen, look closely at potential pharmacodynamic drug-drug interactions, and consider whether a dosage adjustment is needed. Determine, too, whether the patient has any comorbidities that could affect his or her response to the AED.
Side effects, such as weight gain or loss, urolithiasis, and hepatic enzyme induction, are key considerations. (TABLE W1,19-24 which details dose, side effects, and costs of first- and second-generation AEDs, can be found at jfponline.com.)
Is the patient elderly? AED clearance is reduced in the elderly, so lower doses are needed. Reduction in serum albumin increases the free or active component of highly protein-bound drugs, increasing the likelihood of adverse effects.
Is the patient female? Some AEDs may have effects on women’s hormonal function, sexuality, bone health, and pregnancy.25 Hepatic enzyme inducers increase the clearance of oral contraceptives, reducing their efficacy. Vitamin D and calcium metabolism can also be affected, which can lead to osteomalacia. Valproate treatment in women is associated with higher levels of insulin, testosterone, and triglycerides.26 Cytochrome P-450-activating AEDs in general are associated with higher testosterone levels and reduced libido.27
Potential pregnancy is another consideration. Women with epilepsy are able to bear healthy children. What’s more, patients whose seizures are controlled with AEDs should be maintained on medication throughout pregnancy, as the risk of fetal harm from seizures generally outweighs the teratogenicity of the drug.28
Although large studies are limited, a study of 1532 infants exposed to AEDs in the first trimester did not find an increase in major birth defects compared with infants without such exposure.29 More recently, a large observational cohort study conducted in more than 40 countries found that the possibility of harm to a developing fetus is not only drug-specific but also dose-related.30 (To learn more, see “Pregnancy and epilepsy—when you’re managing both,” in the December 2010 issue of The Journal of Family Practice.)
Is cost a factor? Finally, consider the cost of the AED you would like to prescribe, and whether the patient has a prescription drug plan or the means to pay for his prescription.
CASE After a discussion of potential side effects, including the potential for suicidal ideation associated with AEDs, you prescribe carbamazepine for Joe as seizure prophylaxis, because it is the least expensive of the broad-spectrum AEDs and is unlikely to exacerbate his previous pancreatitis or interact with his current medications.
TABLE 2
Choosing an AED: What to consider11-18
| Epilepsy type | |||||
| Localization-related (focal/partial) | Idiopathic (generalized) | Nonidiopathic (generalized) | |||
| Anticonvulsant* | Tonic-clonic | Absence | Myoclonic | ||
| First generation | |||||
| Carbamazepine† | √ | √ | |||
| Ethosuximide† | √ | ||||
| Phenobarbital† | √ | √ | √ | ||
| Phenytoin† | √ | √ | √ | ||
| Primidone | √ | √ | √ | ||
| Valproate† | √ | √ | √ | √ | √ |
| Second generation | |||||
| Felbamate | √ | √ | |||
| Gabapentin† | √ | ||||
| Lacosamide | √ | ||||
| Lamotrigine | √† | √ | √‡ | √ | |
| Levetiracetam | √ | √ | √ | ||
| Oxcarbazepine† | √ | ||||
| Pregabalin | √ | ||||
| Rufinamide | √ | √ | |||
| Tiagabine | √ | ||||
| Topiramate | √‡ | √ | √ | ||
| Vigabatrin | √ | √ | |||
| Zonisamide | √ | √ | |||
| *Bold type indicates broad-spectrum antiepileptic drugs. †Supported by American Academy of Neurology (AAN) evidence-based guideline level A or B recommendation for monotherapy in newly diagnosed epilepsy patients. ‡Supported by AAN evidence-based guideline level B recommendation for monotherapy in newly diagnosed absence epilepsy. | |||||
TABLE W1
A closer look at antiepileptic drugs19-24
| Drug name | Maintenance dosage | Adverse effects | Cost (30-day supply)* | |
| Common | Rare/idiosyncratic | |||
| First generation | ||||
| Carbamazepine | 800-1200 mg/d | Dizziness, drowsiness, diplopia, nausea, vomiting, diarrhea, rash, pruritus, SIADH | Aplastic anemia, agranulocytosis, hyponatremia, SJS, hepatic failure, pancreatitis, suicidal ideation | $4-$50 (XR: $200) |
| Ethosuximide | 20 mg/kg per day | Sleep disturbance, drowsiness, hyperactivity, behavior changes, headache, nausea, vomiting, hiccups | Agranulocytosis, aplastic anemia, SJS, hepatic failure, serum sickness, suicidal ideation | $40-150 |
| Phenobarbital | 1-4 mg/kg per day; 120-400 mg/d | Altered sleep cycles, sedation, ataxia, lethargy, behavior changes, hyperactivity, nausea, rash | Agranulocytosis, dermatitis, SJS, hepatic failure, serum sickness, connective tissue disorders, metabolic bone disease, intellect blunting, suicidal ideation | $4-$10 |
| Phenytoin | 300-600 mg/d | Confusion, slurred speech, double vision, ataxia, nystagmus, neuropathy, hirsutism, acne, gingival hyperplasia | Neuropathy, agranulocytosis, SJS, immune reactions/serum sickness, hepatic failure, skin thickening, metabolic bone disease, suicidal ideation | $35 |
| Valproic acid | 60-350 mg/kg per day | Tremor, weight gain, PCOS, nausea, vomiting, alopecia, easy bruising | Hepatic failure, pancreatitis, hearing loss, blood dyscrasias/thrombocytopenia, hyperammonemia, encephalopathy, osteoporosis, suicidal ideation | $40 (ER: $150) |
| Second generation | ||||
| Felbamate | 2400-3600 mg/d | Somnolence, nausea, vomiting, weight loss, anorexia | Aplastic anemia (>13 years), hepatic failure, suicidal ideation | $300-$500† |
| Gabapentin | 900-1800 mg/d | Somnolence, fatigue, weight gain, nystagmus | Pedal edema, suicidal ideation | $4-$100 |
| Lacosamide | 200-400 mg/d | Headache, dizziness, ataxia, nausea, diplopia | Euphoria, prolongation of PR interval, heart block, suicidal ideation | $420† |
| Lamotrigine | 300-500 mg/d | Dizziness, ataxia, nausea, somnolence, rash | SJS, hypersensitivity reactions (renal/hepatic failure), DIC, suicidal ideation | $30-$100 |
| Levetiracetam | 3000 mg/d | Somnolence, dizziness, aggression, agitation, anxiety, weight loss | Infection, pancytopenia, liver failure, suicidal ideation | $30-$100 (XR: $245†) |
| Oxcarbazepine | 1200 mg/d | Somnolence, fatigue, headache, ataxia, nausea, rash | Hyponatremia, SJS, TEN, angioedema | $250-$1000 |
| Pregabalin | 150-600 mg/d | Peripheral edema, dry mouth, dizziness, ataxia, diplopia, weight gain | Angioedema, CK elevation, mild PR interval prolongation, suicidal ideation | $100-$350† |
| Rufinamide | 3200 mg/d | Headache, dizziness, fatigue, nausea | Shortened QT interval, hypersensitivity rash, suicidal ideation | $400-$750† |
| Tiagabine | 32-56 mg/d | Difficulty concentrating, dizziness, headache, somnolence, nervousness | Spike-wave stupor, sudden death, suicidal ideation | $140-$650† |
| Topiramate | 200-400 mg/d | Somnolence, dizziness, fatigue, weight loss, difficulty concentrating, speech problems, paresthesias, diarrhea, nausea | Acute myopia and glaucoma, hyperthermia (children); metabolic acidosis, hyperammonemia, liver failure, oligohydrosis, SJS/TEN, kidney stones, suicidal ideation | $40 - $100 |
| Vigabatrin | 1500 mg/d | Fatigue, somnolence, nystagmus, tremor, weight gain | Vision loss (30% of patients) blurred vision, arthralgia, suicidal ideation | :$50 -$100† |
| Zonisamide | 400- 600 mg/d | Somnolence, difficulty concentrating, anorexia, nausea | SJS, TEN, aplastic anemia, agranulocytosis, nephrolithiasis/, oligohydrosis, acidosis, suicidal ideation | $50-$200 |
| CK, creatine kinase; DIC, disseminated intravascular coagulation; ER, extended release; IV, intravenous; PCOS, polycystic ovarian syndrome; SIADH, syndrome of inappropriate antidiuretic hormone hypersecretion; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis, XR, extended release. *Costs from www.drugstore.com, www.savewithgenericdrugs.com, and www.pharmacychecker.com. †No generic available. | ||||
When to add a second AED
Monotherapy is the preferred method of epilepsy treatment, and controls seizures for 70% to 90% of patients.31,32 If seizures continue and potential adverse effects prevent you from increasing the dosage, switching to a different AED, then tapering off the first agent, is recommended.33,34
If the new AED fails to provide adequate seizure control, consider combination therapy. An additional 10% to 15% of patients with epilepsy achieve control with dual therapy.33,34
Many second-generation agents are approved for adjunctive therapy. However, the use of 2 AEDs increases the risk of toxicities and drug interactions, and requires complex dosage adjustments, which should be done slowly and cautiously. Combination therapy also increases costs and may cause a decrease in compliance.33,34
Noncompliance is the single most common reason for treatment failure in patients with epilepsy, occurring at an estimated rate of up to 60%.35,36 The complexity of the drug regimen is the major cause, regardless of patient age, sex, psychomotor development, seizure type, or seizure frequency.35,36
Because of the lack of good clinical trials of combination antiepilepsy therapy, no evidence is available to indicate which AEDs are safe and effective when taken together. There is, however, evidence that certain combinations should be avoided due to the risk of increased adverse effects. These include phenobarbital/valproate, phenytoin/carbamazepine, and carbamazepine/lamotrigine.25
Managing the patient who is seizure-free
After a patient has been seizure-free for 2 to 5 years, consider a reduction in, or a discontinuation of, his or her AED. The relapse rate varies from 10% to 70%, with meta-analyses showing a rate of 25% in the first year and 29% in the second year.19,37 The American Academy of Neurology (AAN) has published an evidence-based guideline for discontinuing AEDs in seizure-free patients, available at www.aan.com/professionals/practice/pdfs/gl0007.pdf.
Withdrawal should be gradual and, for patients on combination therapy, carried out one drug at a time to prevent a recurrence of seizures or status epilepticus. The AAN recommends a 2- to- 3-month withdrawal period for AEDs (and longer for benzodiazepines), although relapse rates have been found to be lower when the medication is withdrawn more slowly, over about 6 months.19,34 If seizures recur after withdrawal, restart the AEDs at previous dosages.19,34,38
Should the patient drive?
For patients with epilepsy, loss of independence related to driving restrictions is a major source of stress. A 10-year follow-up study of Danish patients with epilepsy found a 7-fold increase in motor vehicle accidents (MVAs) in patients with seizure disorders.39 Other studies have shown that the seizure-free interval is the best predictor of involvement in an MVA.40
The risk of driving accidents decreases as the seizure-free interval increases. Unfortunately, however, a decline in patient compliance is also associated with longer seizure-free intervals—creating the potential for recurrence and driving risk. Because of this discrepancy, a consensus statement from the AAN, American Epilepsy Society, and Epilepsy Foundation of America recommends a minimum 3-month seizure-free interval before patients are allowed to drive.41
Use clinical judgment in deciding whether to extend the seizure-free period. State laws vary widely regarding the need to report patients with seizure disorders, limitations on professional drivers, and seizure-free intervals required, so it is important to be familiar with the laws in your state. The Epilepsy Foundation has a helpful online resource with a database detailing individual state statutes (http://www.epilepsyfoundation.org/living/wellness/transportation/driverlicensing.cfm).
The danger of uncontrolled seizures
Overall, AEDs effectively control 70% of 80% of cases; the remaining 20% to 30% are considered medically refractory.38 What’s more, after 2 AED failures, a patient’s chances of achieving full seizure control with additional drugs are no better than 10% to 20%.42 And, as more drugs are tried, the likelihood of full control declines even further.43
Patients with uncontrolled seizures have a cumulative risk of sudden unexpected death in epilepsy (SUDEP) of 0.5% per year.44 Cognitive decline is associated with uncontrolled epilepsy, as well. In children, frequent seizures may significantly alter neuronal networks, affecting cognitive and motor development.
Is your patient a candidate for surgery?
Patients with disabling complex partial seizures that remain uncontrolled after 2 or more AED trials (either as monotherapy or in combination) should be referred to an epilepsy specialty center for evaluation for surgery.45 This should be considered as early as possible to afford the patient the best chance of achieving seizure control.
Successful epilepsy surgery—in which the portion of the brain causing the misfiring that causes the seizures is removed—often results in a better quality of life; it is also cost effective.46 Not everyone with refractory epilepsy is a candidate for surgery, of course. Among those who are, however, 50% to 70% of patients can expect to have improved seizure control.47
Status epilepticus is a medical emergency
A patient who develops status epilepticus is at high risk and requires immediate, and simultaneous, evaluation and treatment. Status epilepticus carries nearly a 20% mortality from the first episode,48 and the 10-year mortality rate after an episode of status epilepticus is as high as 40%.49
Although most of the deaths associated with status epilepticus are due to the underlying pathology, early treatment can prevent or ameliorate complications from rhabdomyolysis and irreversible anoxic neuronal damage.50
A benzodiazepine (typically, a 10-mg IV bolus of diazepam) is the initial treatment for status epilepticus, followed by or concurrent with fosphenytoin (15-18 mg/kg). If status epilepticus remains refractory to first-line drugs (lasting >30 minutes), intubation and transfer to an intensive care setting may be required, and a neurological consult should be obtained.
Pharmacologic treatment of status epilepticus falls into 3 main classes: benzodiazepines, standard AEDs, and general anesthetics such as propofol. Benzodiazepines act very rapidly to control most prolonged seizures, and are the first-line treatment choice. Diazepam has long been the mainstay of treatment, and is usually readily available. However, in both a large systematic review and a head-to-head trial, lorazepam was found to be superior to diazepam in ending seizure activity and maintaining seizure control without the use of other medications51,52—and is now the drug of choice for initial treatment of status epilepticus.
CASE You continue to see Joe every 3 to 4 months to monitor his basic blood work and mood. A year after his seizure, he remains seizure-free and is tolerating the AED without any adverse effects.
CORRESPONDENCE
William J. Geiger, MD, FAAFP, Medical College of Wisconsin, Columbia St. Mary’s Family Medicine Residency, 1121 East North Avenue, Milwaukee, WI 53212; [email protected]
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2. Centers for Disease Control and Prevention (CDC). Prevalence and most common causes of disability among adults—United States, 2005. MMWR Morb Mortal Wkly Rep. 2009;58:421-426. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5816a2.htm. Accessed June 15, 2009.
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8. Berg A. Risk of recurrence after a first unprovoked seizure. Epilepsia. 2008;49(suppl 1):S13-S18.
9. Hirtz D, Ashwal S, Berg A, et al. Practice parameter: evaluating a first non-febrile seizure in children: report of the Quality Standards Subcommittee of the American Academy of Neurology, the Child Neurology Society, and the American Epilepsy Society. Neurology. 2000;55:616-623.
10. US Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm100190.htm. Updated May 5, 2009. Accessed June 28, 2009.
11. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new epilepsy, report of the therapeutic and technology assessment subcommittee and quality standards subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1252-1260.
12. French J, Smith M, Faught E, et al. Practice advisory: the use of felbamate in the treatment of patients with intractable epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 1999;52:1540-1545.
13. Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008;70:1950-1958.
14. Suzuki Y, Nagai T, Ono J, et al. Zonisamide monotherapy in newly-diagnosed infantile spasms. Epilepsia. 1997;38:1035-1038.
15. Kochak GM, Page JG, Buchanan RA, et al. Steady-state pharmacokinetics of zonisamide, an antiepileptic agent for treatment of refractory complex partial seizures. J Clin Pharmacol. 1998;38:166-171.
16. Arroyo S, Anhut H, Kugler AR, et al. Pregabalin 1008-011 International Study Group. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia. 2004;45:20-27.
17. Brodie MJ, Rosenfeld WE, Vazquez B, et al. Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial. Epilepsia. 2009;50:1899-1909.
18. Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48:1308-1317.
19. Gidal B, Garnett W. Epilepsy. In: Dipiro J, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:1023-1048.
20. Pellock JM, Treatment of epilepsy in the new millennium. Pharmacotherapy. 2000;20:129S-138S.
21. Schachter S. Pharmacology of antiepileptic drugs. Available at: http://www.utdonline.com/online/content/topic.do?topicKey=epil_eeg/5220. Accessed July 15, 2009.
22. Woelfel J. Comparison of antiepileptic drugs. Pharmacist’s Letter/Prescriber's Letter. July 2009;25:1-24.
23. Wolters Kluwer Health Inc. Anticonvulsants. Drug facts and comparisons online. Available at: http://www.efactsonline.com. Accessed July 10, 2009.
24. US Food and Drug Administration. Information for healthcare professionals. Suicidality and antiepileptic drugs [FDA alert]. Available at: http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm054709.htm. January 31, 2008. Accessed June 30, 2009.
25. French J. Treatment with antiepileptic drugs, new and old. Continuum. 2007;13:71-90.
26. Sheehan M. Polycystic ovarian syndrome: diagnosis and management. Clin Med Res. 2004;2:13-27.
27. Harden CL. Sexual dysfunction in women with epilepsy. Seizure. 2008;17:131-135.
28. Harden CL, Hopp J, Ting TY, et al. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency. Neurology. 2009;73:126-132.
29. Molgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA. 2011;305:1996-2002.
30. Tomson T, Battino D, Bonizonni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10:609-617.
31. Callaghan BC, Anand K, Hesdorffer D, et al. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann Neurol. 2007;62:382-389.
32. Luciano AL, Shorvon SD. Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol. 2007;62:375-381.
33. Abramowicz M, ed. Drugs for epilepsy [treatment guidelines]. The Medical Letter. 2008;70:1-12.
34.Stokes T, Shaw EJ, Juarez-Garcia A, et al. Clinical guidelines and evidence review for the epilepsies: diagnosis and management in adults and children in primary and secondary care. London: Royal College of General Practitioners. Available at: www.nice.org.uk/CG020fullguideline. Published October 2004. Accessed July 10, 2009.
35. Garnett WR. Antiepileptic drug treatment: outcomes and adherence. Pharmacotherapy. 2000;20:191S-199S.
36. Briesacher BA, Andrade SE, Fouayzi H, et al. Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy. 2008;28:437-443.
37. Shinnar S, Gross-Tsur V. Discontinuing antiepileptic drug therapy. In: Wyllie E, ed. The Treatment of Epilepsy. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001:811-819.
38. Kwan P, Brodie J. Refractory epilepsy: a progressive, intractable but preventable condition? Seizures. 2002;11:77-84.
39. Lings S. Increased driving accident frequency in Danish patients with epilepsy. Neurology. 2001;57:435-439.
40. Krauss GL, Krumholz A, Carter RC, et al. Risk factors for seizure-related motor vehicle crashes in patients with epilepsy. Neurology. 1999;52:1324-1329.
41. American Academy of Neurology, American Epilepsy Society, and Epilepsy Foundation of America. Consensus statements, sample statutory provisions, and model regulations regarding driver licensing and epilepsy. Epilepsia. 1994;35:696-705.
42. Thadani VM, Taylor J. Surgical treatments for epilepsy. Continuum. 2007;13:152-176.
43. Brodie MJ, Kwan P. Staged approach to epilepsy management. Neurology. 2002;58(8 suppl 5):S2-S8.
44. Sillanpaa M, Jalava M, Kaleva O, et al. Long-term prognosis of seizures with onset in childhood. N Engl J Med. 1998;338:1715-1722.
45. Engel J Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Neurology. 2003;60:538-547.
46. Boon P, D'Have M, Van Walleghen P, et al. Direct medical costs of refractory epilepsy incurred by three different treatment modalities: a prospective assessment. Epilepsia. 2002;43:96-102.
47. Passaro EA. Outcome of epilepsy surgery. Available at: http://emedicine.medscape.com/article/1185416-overview. Updated May 16, 2011. Accessed June 28, 2011.
48. DeLorenzo RJ, Pellock JM, Towne AR, et al. Epidemiology of status epilepticus. J Clin Neurophysiol. 1995;12:316-325.
49. Logroscino G, Hesdorffer DC, Cascino GD, et al. Long-term mortality after a first episode of status epilepticus. Neurology. 2002; 58:537-541.
50. Kalviaine R. Treatment of status epilepticus. Essential Evidence Plus. Wiley-Blackwell. Available at: http://www.essentialevidenceplus.com/content/ebmg_ebm/766. Accessed July 15, 2009.
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52. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med. 1998;339:792-798.
• Prescribe an antiepileptic drug (AED) after a first unprovoked seizure only if the seizure was prolonged or there is a risk of recurrence. C
• Use monotherapy whenever possible; if seizures continue and potential adverse effects prevent an increase in dosage, switch to a different AED and taper off the first agent. A
• Consider gradual withdrawal of AEDs from patients who have been seizure-free for 2 to 5 years. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE Joe G, a 44-year-old man who has been your patient for years, comes to your office 48 hours after having a seizure. He has no history of seizures, had no warning signs or symptoms, and felt fine all day, but simply collapsed when the seizure occurred. He was transported to the emergency department (ED), and found to be postictal, with no further seizure activity. The ED work-up included a hemogram, comprehensive metabolic panel, and computed tomography brain scan, all of which were normal. An hour later, Joe had a normal neurological exam, then underwent electroencephalography (EEG) and magnetic resonance imaging (MRI) and was discharged home without medication.
How would you treat this patient?
About 10% of Americans will experience a seizure at some point in their lives,1,2 and more than 3 million have epilepsy.3 The incidence ranges from 1% among 20-year-olds to more than 3% by the age of 75.1,2
To adequately care for such patients—whether they have had multiple seizures or only one—you need to know whether they’re at risk for recurrences, when (or if) to prescribe an AED, and which agents provide optimal seizure control with the fewest adverse effects. You also need to know when a referral to an epilepsy specialist is indicated, when or whether it’s safe for patients to stop taking antiseizure medication, and how to address lifestyle issues that patients with epilepsy often need help with.
This review addresses these and other questions.
Is it epilepsy? How to respond to a single seizure
A seizure—a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neural activity in the brain—can be either focal (partial) or generalized. In addition, seizures can be broadly divided into 2 categories, based on etiology:
Provoked seizures are caused by an acute structural, toxic, or metabolic insult to the brain, and, presumably, would not have occurred if the underlying medical condition did not exist. Treating the cause—eg, alcohol withdrawal, hyponatremia, or hypoglycemia—should prevent a recurrence.
Unprovoked seizures have no apparent underlying cause. Epilepsy is defined as a chronic condition characterized by ≥2 unprovoked seizures at least 24 hours apart, and epilepsy syndromes are classified as localization-related or generalized (TABLE 1).1,4,5
Generally, epileptologists do not recommend symptomatic treatment of a first unprovoked seizure6—a consensus based on several randomized controlled trials that found immediate treatment with an AED reduced the risk of a subsequent seizure in the short term, but did not affect long-term outcomes or the development of epilepsy.7
Treatment should begin after a single seizure, however, if the seizure was prolonged or there is an increased risk of recurrence.6 Factors that increase this risk include an abnormal EEG, particularly if the abnormality is epileptiform; the presence of a brain lesion; a localized (focal) seizure; and an abnormal neurologic exam.8 A history of status epilepticus—a single, unremitting seizure lasting ≥5 to 10 minutes or frequent seizures without a return to neurologic baseline in between—or complex febrile seizures, and a family history of epilepsy are risk factors for recurrence, as well.7
When the patient is a child. Prescribing an AED for a child after a first unprovoked seizure is not indicated to prevent the development of epilepsy, but may be considered, as for adults, in circumstances where the benefit of reducing the risk of a second seizure outweighs the risk of pharmacologic and psychosocial adverse effects.9
CASE Joe’s ED records show that his MRI was normal, but his EEG revealed an epileptogenic focus on the right temporal region—a finding that indicates that he has an elevated risk of recurrence and is a candidate for an AED. Before selecting a particular agent, you review his chart.
Joe is taking a thiazide diuretic and a calcium channel blocker for hypertension. He was a heavy drinker until he had an episode of pancreatitis 10 years ago, and has been abstinent ever since. About 5 years ago, he suffered from depression and was treated with sertraline, but the depression resolved and the drug was discontinued 3 years ago. The patient’s mother and brother have type 2 diabetes and his father had a myocardial infarction before the age of 60. Joe was laid off from his sales job 18 months ago and is actively seeking employment. At this point, you consider a broad-spectrum AED that would not interact with his current medications or adversely affect his medical conditions, and would be relatively inexpensive.
TABLE 1
Identifying seizures and types of epilepsy:1,4,5 International League Against Epilepsy classification
| Type of seizure |
Focal
Generalized
|
| Type of epilepsy syndrome* |
Localization related (partial or focal)
Generalized
|
| *This is a partial listing, with selected examples of epilepsy syndromes. |
What to consider in a first-line drug
The number of AEDs on the market has increased sharply in the past few years, giving physicians many medications to choose from. Selecting the optimal drug is particularly important for the initial treatment, as many patients remain on the first AED for years. Second-generation AEDs have been found to be as effective as, and better tolerated than, first-generation antiseizure drugs. But all AEDs carry a warning of a potential increase in suicide risk and the need to monitor patients for behavior changes.10
Before selecting an AED for a particular patient, consider the following questions:
What type of seizure? AEDs are generally classified by spectrum of activity into “narrow-spectrum” and “broad-spectrum.” Narrow-spectrum drugs are more effective for controlling partial seizures, but have the potential to exacerbate generalized seizures; broad-spectrum AEDs can be used for both. (TABLE 211-18 lists indications for first- and second-generation AEDs based on type of epilepsy.) If there’s no definitive diagnosis of the type of epilepsy a patient has, use a broad-spectrum drug.
What other drugs is the patient taking? If the AED will be added to the patient’s current medication regimen, look closely at potential pharmacodynamic drug-drug interactions, and consider whether a dosage adjustment is needed. Determine, too, whether the patient has any comorbidities that could affect his or her response to the AED.
Side effects, such as weight gain or loss, urolithiasis, and hepatic enzyme induction, are key considerations. (TABLE W1,19-24 which details dose, side effects, and costs of first- and second-generation AEDs, can be found at jfponline.com.)
Is the patient elderly? AED clearance is reduced in the elderly, so lower doses are needed. Reduction in serum albumin increases the free or active component of highly protein-bound drugs, increasing the likelihood of adverse effects.
Is the patient female? Some AEDs may have effects on women’s hormonal function, sexuality, bone health, and pregnancy.25 Hepatic enzyme inducers increase the clearance of oral contraceptives, reducing their efficacy. Vitamin D and calcium metabolism can also be affected, which can lead to osteomalacia. Valproate treatment in women is associated with higher levels of insulin, testosterone, and triglycerides.26 Cytochrome P-450-activating AEDs in general are associated with higher testosterone levels and reduced libido.27
Potential pregnancy is another consideration. Women with epilepsy are able to bear healthy children. What’s more, patients whose seizures are controlled with AEDs should be maintained on medication throughout pregnancy, as the risk of fetal harm from seizures generally outweighs the teratogenicity of the drug.28
Although large studies are limited, a study of 1532 infants exposed to AEDs in the first trimester did not find an increase in major birth defects compared with infants without such exposure.29 More recently, a large observational cohort study conducted in more than 40 countries found that the possibility of harm to a developing fetus is not only drug-specific but also dose-related.30 (To learn more, see “Pregnancy and epilepsy—when you’re managing both,” in the December 2010 issue of The Journal of Family Practice.)
Is cost a factor? Finally, consider the cost of the AED you would like to prescribe, and whether the patient has a prescription drug plan or the means to pay for his prescription.
CASE After a discussion of potential side effects, including the potential for suicidal ideation associated with AEDs, you prescribe carbamazepine for Joe as seizure prophylaxis, because it is the least expensive of the broad-spectrum AEDs and is unlikely to exacerbate his previous pancreatitis or interact with his current medications.
TABLE 2
Choosing an AED: What to consider11-18
| Epilepsy type | |||||
| Localization-related (focal/partial) | Idiopathic (generalized) | Nonidiopathic (generalized) | |||
| Anticonvulsant* | Tonic-clonic | Absence | Myoclonic | ||
| First generation | |||||
| Carbamazepine† | √ | √ | |||
| Ethosuximide† | √ | ||||
| Phenobarbital† | √ | √ | √ | ||
| Phenytoin† | √ | √ | √ | ||
| Primidone | √ | √ | √ | ||
| Valproate† | √ | √ | √ | √ | √ |
| Second generation | |||||
| Felbamate | √ | √ | |||
| Gabapentin† | √ | ||||
| Lacosamide | √ | ||||
| Lamotrigine | √† | √ | √‡ | √ | |
| Levetiracetam | √ | √ | √ | ||
| Oxcarbazepine† | √ | ||||
| Pregabalin | √ | ||||
| Rufinamide | √ | √ | |||
| Tiagabine | √ | ||||
| Topiramate | √‡ | √ | √ | ||
| Vigabatrin | √ | √ | |||
| Zonisamide | √ | √ | |||
| *Bold type indicates broad-spectrum antiepileptic drugs. †Supported by American Academy of Neurology (AAN) evidence-based guideline level A or B recommendation for monotherapy in newly diagnosed epilepsy patients. ‡Supported by AAN evidence-based guideline level B recommendation for monotherapy in newly diagnosed absence epilepsy. | |||||
TABLE W1
A closer look at antiepileptic drugs19-24
| Drug name | Maintenance dosage | Adverse effects | Cost (30-day supply)* | |
| Common | Rare/idiosyncratic | |||
| First generation | ||||
| Carbamazepine | 800-1200 mg/d | Dizziness, drowsiness, diplopia, nausea, vomiting, diarrhea, rash, pruritus, SIADH | Aplastic anemia, agranulocytosis, hyponatremia, SJS, hepatic failure, pancreatitis, suicidal ideation | $4-$50 (XR: $200) |
| Ethosuximide | 20 mg/kg per day | Sleep disturbance, drowsiness, hyperactivity, behavior changes, headache, nausea, vomiting, hiccups | Agranulocytosis, aplastic anemia, SJS, hepatic failure, serum sickness, suicidal ideation | $40-150 |
| Phenobarbital | 1-4 mg/kg per day; 120-400 mg/d | Altered sleep cycles, sedation, ataxia, lethargy, behavior changes, hyperactivity, nausea, rash | Agranulocytosis, dermatitis, SJS, hepatic failure, serum sickness, connective tissue disorders, metabolic bone disease, intellect blunting, suicidal ideation | $4-$10 |
| Phenytoin | 300-600 mg/d | Confusion, slurred speech, double vision, ataxia, nystagmus, neuropathy, hirsutism, acne, gingival hyperplasia | Neuropathy, agranulocytosis, SJS, immune reactions/serum sickness, hepatic failure, skin thickening, metabolic bone disease, suicidal ideation | $35 |
| Valproic acid | 60-350 mg/kg per day | Tremor, weight gain, PCOS, nausea, vomiting, alopecia, easy bruising | Hepatic failure, pancreatitis, hearing loss, blood dyscrasias/thrombocytopenia, hyperammonemia, encephalopathy, osteoporosis, suicidal ideation | $40 (ER: $150) |
| Second generation | ||||
| Felbamate | 2400-3600 mg/d | Somnolence, nausea, vomiting, weight loss, anorexia | Aplastic anemia (>13 years), hepatic failure, suicidal ideation | $300-$500† |
| Gabapentin | 900-1800 mg/d | Somnolence, fatigue, weight gain, nystagmus | Pedal edema, suicidal ideation | $4-$100 |
| Lacosamide | 200-400 mg/d | Headache, dizziness, ataxia, nausea, diplopia | Euphoria, prolongation of PR interval, heart block, suicidal ideation | $420† |
| Lamotrigine | 300-500 mg/d | Dizziness, ataxia, nausea, somnolence, rash | SJS, hypersensitivity reactions (renal/hepatic failure), DIC, suicidal ideation | $30-$100 |
| Levetiracetam | 3000 mg/d | Somnolence, dizziness, aggression, agitation, anxiety, weight loss | Infection, pancytopenia, liver failure, suicidal ideation | $30-$100 (XR: $245†) |
| Oxcarbazepine | 1200 mg/d | Somnolence, fatigue, headache, ataxia, nausea, rash | Hyponatremia, SJS, TEN, angioedema | $250-$1000 |
| Pregabalin | 150-600 mg/d | Peripheral edema, dry mouth, dizziness, ataxia, diplopia, weight gain | Angioedema, CK elevation, mild PR interval prolongation, suicidal ideation | $100-$350† |
| Rufinamide | 3200 mg/d | Headache, dizziness, fatigue, nausea | Shortened QT interval, hypersensitivity rash, suicidal ideation | $400-$750† |
| Tiagabine | 32-56 mg/d | Difficulty concentrating, dizziness, headache, somnolence, nervousness | Spike-wave stupor, sudden death, suicidal ideation | $140-$650† |
| Topiramate | 200-400 mg/d | Somnolence, dizziness, fatigue, weight loss, difficulty concentrating, speech problems, paresthesias, diarrhea, nausea | Acute myopia and glaucoma, hyperthermia (children); metabolic acidosis, hyperammonemia, liver failure, oligohydrosis, SJS/TEN, kidney stones, suicidal ideation | $40 - $100 |
| Vigabatrin | 1500 mg/d | Fatigue, somnolence, nystagmus, tremor, weight gain | Vision loss (30% of patients) blurred vision, arthralgia, suicidal ideation | :$50 -$100† |
| Zonisamide | 400- 600 mg/d | Somnolence, difficulty concentrating, anorexia, nausea | SJS, TEN, aplastic anemia, agranulocytosis, nephrolithiasis/, oligohydrosis, acidosis, suicidal ideation | $50-$200 |
| CK, creatine kinase; DIC, disseminated intravascular coagulation; ER, extended release; IV, intravenous; PCOS, polycystic ovarian syndrome; SIADH, syndrome of inappropriate antidiuretic hormone hypersecretion; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis, XR, extended release. *Costs from www.drugstore.com, www.savewithgenericdrugs.com, and www.pharmacychecker.com. †No generic available. | ||||
When to add a second AED
Monotherapy is the preferred method of epilepsy treatment, and controls seizures for 70% to 90% of patients.31,32 If seizures continue and potential adverse effects prevent you from increasing the dosage, switching to a different AED, then tapering off the first agent, is recommended.33,34
If the new AED fails to provide adequate seizure control, consider combination therapy. An additional 10% to 15% of patients with epilepsy achieve control with dual therapy.33,34
Many second-generation agents are approved for adjunctive therapy. However, the use of 2 AEDs increases the risk of toxicities and drug interactions, and requires complex dosage adjustments, which should be done slowly and cautiously. Combination therapy also increases costs and may cause a decrease in compliance.33,34
Noncompliance is the single most common reason for treatment failure in patients with epilepsy, occurring at an estimated rate of up to 60%.35,36 The complexity of the drug regimen is the major cause, regardless of patient age, sex, psychomotor development, seizure type, or seizure frequency.35,36
Because of the lack of good clinical trials of combination antiepilepsy therapy, no evidence is available to indicate which AEDs are safe and effective when taken together. There is, however, evidence that certain combinations should be avoided due to the risk of increased adverse effects. These include phenobarbital/valproate, phenytoin/carbamazepine, and carbamazepine/lamotrigine.25
Managing the patient who is seizure-free
After a patient has been seizure-free for 2 to 5 years, consider a reduction in, or a discontinuation of, his or her AED. The relapse rate varies from 10% to 70%, with meta-analyses showing a rate of 25% in the first year and 29% in the second year.19,37 The American Academy of Neurology (AAN) has published an evidence-based guideline for discontinuing AEDs in seizure-free patients, available at www.aan.com/professionals/practice/pdfs/gl0007.pdf.
Withdrawal should be gradual and, for patients on combination therapy, carried out one drug at a time to prevent a recurrence of seizures or status epilepticus. The AAN recommends a 2- to- 3-month withdrawal period for AEDs (and longer for benzodiazepines), although relapse rates have been found to be lower when the medication is withdrawn more slowly, over about 6 months.19,34 If seizures recur after withdrawal, restart the AEDs at previous dosages.19,34,38
Should the patient drive?
For patients with epilepsy, loss of independence related to driving restrictions is a major source of stress. A 10-year follow-up study of Danish patients with epilepsy found a 7-fold increase in motor vehicle accidents (MVAs) in patients with seizure disorders.39 Other studies have shown that the seizure-free interval is the best predictor of involvement in an MVA.40
The risk of driving accidents decreases as the seizure-free interval increases. Unfortunately, however, a decline in patient compliance is also associated with longer seizure-free intervals—creating the potential for recurrence and driving risk. Because of this discrepancy, a consensus statement from the AAN, American Epilepsy Society, and Epilepsy Foundation of America recommends a minimum 3-month seizure-free interval before patients are allowed to drive.41
Use clinical judgment in deciding whether to extend the seizure-free period. State laws vary widely regarding the need to report patients with seizure disorders, limitations on professional drivers, and seizure-free intervals required, so it is important to be familiar with the laws in your state. The Epilepsy Foundation has a helpful online resource with a database detailing individual state statutes (http://www.epilepsyfoundation.org/living/wellness/transportation/driverlicensing.cfm).
The danger of uncontrolled seizures
Overall, AEDs effectively control 70% of 80% of cases; the remaining 20% to 30% are considered medically refractory.38 What’s more, after 2 AED failures, a patient’s chances of achieving full seizure control with additional drugs are no better than 10% to 20%.42 And, as more drugs are tried, the likelihood of full control declines even further.43
Patients with uncontrolled seizures have a cumulative risk of sudden unexpected death in epilepsy (SUDEP) of 0.5% per year.44 Cognitive decline is associated with uncontrolled epilepsy, as well. In children, frequent seizures may significantly alter neuronal networks, affecting cognitive and motor development.
Is your patient a candidate for surgery?
Patients with disabling complex partial seizures that remain uncontrolled after 2 or more AED trials (either as monotherapy or in combination) should be referred to an epilepsy specialty center for evaluation for surgery.45 This should be considered as early as possible to afford the patient the best chance of achieving seizure control.
Successful epilepsy surgery—in which the portion of the brain causing the misfiring that causes the seizures is removed—often results in a better quality of life; it is also cost effective.46 Not everyone with refractory epilepsy is a candidate for surgery, of course. Among those who are, however, 50% to 70% of patients can expect to have improved seizure control.47
Status epilepticus is a medical emergency
A patient who develops status epilepticus is at high risk and requires immediate, and simultaneous, evaluation and treatment. Status epilepticus carries nearly a 20% mortality from the first episode,48 and the 10-year mortality rate after an episode of status epilepticus is as high as 40%.49
Although most of the deaths associated with status epilepticus are due to the underlying pathology, early treatment can prevent or ameliorate complications from rhabdomyolysis and irreversible anoxic neuronal damage.50
A benzodiazepine (typically, a 10-mg IV bolus of diazepam) is the initial treatment for status epilepticus, followed by or concurrent with fosphenytoin (15-18 mg/kg). If status epilepticus remains refractory to first-line drugs (lasting >30 minutes), intubation and transfer to an intensive care setting may be required, and a neurological consult should be obtained.
Pharmacologic treatment of status epilepticus falls into 3 main classes: benzodiazepines, standard AEDs, and general anesthetics such as propofol. Benzodiazepines act very rapidly to control most prolonged seizures, and are the first-line treatment choice. Diazepam has long been the mainstay of treatment, and is usually readily available. However, in both a large systematic review and a head-to-head trial, lorazepam was found to be superior to diazepam in ending seizure activity and maintaining seizure control without the use of other medications51,52—and is now the drug of choice for initial treatment of status epilepticus.
CASE You continue to see Joe every 3 to 4 months to monitor his basic blood work and mood. A year after his seizure, he remains seizure-free and is tolerating the AED without any adverse effects.
CORRESPONDENCE
William J. Geiger, MD, FAAFP, Medical College of Wisconsin, Columbia St. Mary’s Family Medicine Residency, 1121 East North Avenue, Milwaukee, WI 53212; [email protected]
• Prescribe an antiepileptic drug (AED) after a first unprovoked seizure only if the seizure was prolonged or there is a risk of recurrence. C
• Use monotherapy whenever possible; if seizures continue and potential adverse effects prevent an increase in dosage, switch to a different AED and taper off the first agent. A
• Consider gradual withdrawal of AEDs from patients who have been seizure-free for 2 to 5 years. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE Joe G, a 44-year-old man who has been your patient for years, comes to your office 48 hours after having a seizure. He has no history of seizures, had no warning signs or symptoms, and felt fine all day, but simply collapsed when the seizure occurred. He was transported to the emergency department (ED), and found to be postictal, with no further seizure activity. The ED work-up included a hemogram, comprehensive metabolic panel, and computed tomography brain scan, all of which were normal. An hour later, Joe had a normal neurological exam, then underwent electroencephalography (EEG) and magnetic resonance imaging (MRI) and was discharged home without medication.
How would you treat this patient?
About 10% of Americans will experience a seizure at some point in their lives,1,2 and more than 3 million have epilepsy.3 The incidence ranges from 1% among 20-year-olds to more than 3% by the age of 75.1,2
To adequately care for such patients—whether they have had multiple seizures or only one—you need to know whether they’re at risk for recurrences, when (or if) to prescribe an AED, and which agents provide optimal seizure control with the fewest adverse effects. You also need to know when a referral to an epilepsy specialist is indicated, when or whether it’s safe for patients to stop taking antiseizure medication, and how to address lifestyle issues that patients with epilepsy often need help with.
This review addresses these and other questions.
Is it epilepsy? How to respond to a single seizure
A seizure—a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neural activity in the brain—can be either focal (partial) or generalized. In addition, seizures can be broadly divided into 2 categories, based on etiology:
Provoked seizures are caused by an acute structural, toxic, or metabolic insult to the brain, and, presumably, would not have occurred if the underlying medical condition did not exist. Treating the cause—eg, alcohol withdrawal, hyponatremia, or hypoglycemia—should prevent a recurrence.
Unprovoked seizures have no apparent underlying cause. Epilepsy is defined as a chronic condition characterized by ≥2 unprovoked seizures at least 24 hours apart, and epilepsy syndromes are classified as localization-related or generalized (TABLE 1).1,4,5
Generally, epileptologists do not recommend symptomatic treatment of a first unprovoked seizure6—a consensus based on several randomized controlled trials that found immediate treatment with an AED reduced the risk of a subsequent seizure in the short term, but did not affect long-term outcomes or the development of epilepsy.7
Treatment should begin after a single seizure, however, if the seizure was prolonged or there is an increased risk of recurrence.6 Factors that increase this risk include an abnormal EEG, particularly if the abnormality is epileptiform; the presence of a brain lesion; a localized (focal) seizure; and an abnormal neurologic exam.8 A history of status epilepticus—a single, unremitting seizure lasting ≥5 to 10 minutes or frequent seizures without a return to neurologic baseline in between—or complex febrile seizures, and a family history of epilepsy are risk factors for recurrence, as well.7
When the patient is a child. Prescribing an AED for a child after a first unprovoked seizure is not indicated to prevent the development of epilepsy, but may be considered, as for adults, in circumstances where the benefit of reducing the risk of a second seizure outweighs the risk of pharmacologic and psychosocial adverse effects.9
CASE Joe’s ED records show that his MRI was normal, but his EEG revealed an epileptogenic focus on the right temporal region—a finding that indicates that he has an elevated risk of recurrence and is a candidate for an AED. Before selecting a particular agent, you review his chart.
Joe is taking a thiazide diuretic and a calcium channel blocker for hypertension. He was a heavy drinker until he had an episode of pancreatitis 10 years ago, and has been abstinent ever since. About 5 years ago, he suffered from depression and was treated with sertraline, but the depression resolved and the drug was discontinued 3 years ago. The patient’s mother and brother have type 2 diabetes and his father had a myocardial infarction before the age of 60. Joe was laid off from his sales job 18 months ago and is actively seeking employment. At this point, you consider a broad-spectrum AED that would not interact with his current medications or adversely affect his medical conditions, and would be relatively inexpensive.
TABLE 1
Identifying seizures and types of epilepsy:1,4,5 International League Against Epilepsy classification
| Type of seizure |
Focal
Generalized
|
| Type of epilepsy syndrome* |
Localization related (partial or focal)
Generalized
|
| *This is a partial listing, with selected examples of epilepsy syndromes. |
What to consider in a first-line drug
The number of AEDs on the market has increased sharply in the past few years, giving physicians many medications to choose from. Selecting the optimal drug is particularly important for the initial treatment, as many patients remain on the first AED for years. Second-generation AEDs have been found to be as effective as, and better tolerated than, first-generation antiseizure drugs. But all AEDs carry a warning of a potential increase in suicide risk and the need to monitor patients for behavior changes.10
Before selecting an AED for a particular patient, consider the following questions:
What type of seizure? AEDs are generally classified by spectrum of activity into “narrow-spectrum” and “broad-spectrum.” Narrow-spectrum drugs are more effective for controlling partial seizures, but have the potential to exacerbate generalized seizures; broad-spectrum AEDs can be used for both. (TABLE 211-18 lists indications for first- and second-generation AEDs based on type of epilepsy.) If there’s no definitive diagnosis of the type of epilepsy a patient has, use a broad-spectrum drug.
What other drugs is the patient taking? If the AED will be added to the patient’s current medication regimen, look closely at potential pharmacodynamic drug-drug interactions, and consider whether a dosage adjustment is needed. Determine, too, whether the patient has any comorbidities that could affect his or her response to the AED.
Side effects, such as weight gain or loss, urolithiasis, and hepatic enzyme induction, are key considerations. (TABLE W1,19-24 which details dose, side effects, and costs of first- and second-generation AEDs, can be found at jfponline.com.)
Is the patient elderly? AED clearance is reduced in the elderly, so lower doses are needed. Reduction in serum albumin increases the free or active component of highly protein-bound drugs, increasing the likelihood of adverse effects.
Is the patient female? Some AEDs may have effects on women’s hormonal function, sexuality, bone health, and pregnancy.25 Hepatic enzyme inducers increase the clearance of oral contraceptives, reducing their efficacy. Vitamin D and calcium metabolism can also be affected, which can lead to osteomalacia. Valproate treatment in women is associated with higher levels of insulin, testosterone, and triglycerides.26 Cytochrome P-450-activating AEDs in general are associated with higher testosterone levels and reduced libido.27
Potential pregnancy is another consideration. Women with epilepsy are able to bear healthy children. What’s more, patients whose seizures are controlled with AEDs should be maintained on medication throughout pregnancy, as the risk of fetal harm from seizures generally outweighs the teratogenicity of the drug.28
Although large studies are limited, a study of 1532 infants exposed to AEDs in the first trimester did not find an increase in major birth defects compared with infants without such exposure.29 More recently, a large observational cohort study conducted in more than 40 countries found that the possibility of harm to a developing fetus is not only drug-specific but also dose-related.30 (To learn more, see “Pregnancy and epilepsy—when you’re managing both,” in the December 2010 issue of The Journal of Family Practice.)
Is cost a factor? Finally, consider the cost of the AED you would like to prescribe, and whether the patient has a prescription drug plan or the means to pay for his prescription.
CASE After a discussion of potential side effects, including the potential for suicidal ideation associated with AEDs, you prescribe carbamazepine for Joe as seizure prophylaxis, because it is the least expensive of the broad-spectrum AEDs and is unlikely to exacerbate his previous pancreatitis or interact with his current medications.
TABLE 2
Choosing an AED: What to consider11-18
| Epilepsy type | |||||
| Localization-related (focal/partial) | Idiopathic (generalized) | Nonidiopathic (generalized) | |||
| Anticonvulsant* | Tonic-clonic | Absence | Myoclonic | ||
| First generation | |||||
| Carbamazepine† | √ | √ | |||
| Ethosuximide† | √ | ||||
| Phenobarbital† | √ | √ | √ | ||
| Phenytoin† | √ | √ | √ | ||
| Primidone | √ | √ | √ | ||
| Valproate† | √ | √ | √ | √ | √ |
| Second generation | |||||
| Felbamate | √ | √ | |||
| Gabapentin† | √ | ||||
| Lacosamide | √ | ||||
| Lamotrigine | √† | √ | √‡ | √ | |
| Levetiracetam | √ | √ | √ | ||
| Oxcarbazepine† | √ | ||||
| Pregabalin | √ | ||||
| Rufinamide | √ | √ | |||
| Tiagabine | √ | ||||
| Topiramate | √‡ | √ | √ | ||
| Vigabatrin | √ | √ | |||
| Zonisamide | √ | √ | |||
| *Bold type indicates broad-spectrum antiepileptic drugs. †Supported by American Academy of Neurology (AAN) evidence-based guideline level A or B recommendation for monotherapy in newly diagnosed epilepsy patients. ‡Supported by AAN evidence-based guideline level B recommendation for monotherapy in newly diagnosed absence epilepsy. | |||||
TABLE W1
A closer look at antiepileptic drugs19-24
| Drug name | Maintenance dosage | Adverse effects | Cost (30-day supply)* | |
| Common | Rare/idiosyncratic | |||
| First generation | ||||
| Carbamazepine | 800-1200 mg/d | Dizziness, drowsiness, diplopia, nausea, vomiting, diarrhea, rash, pruritus, SIADH | Aplastic anemia, agranulocytosis, hyponatremia, SJS, hepatic failure, pancreatitis, suicidal ideation | $4-$50 (XR: $200) |
| Ethosuximide | 20 mg/kg per day | Sleep disturbance, drowsiness, hyperactivity, behavior changes, headache, nausea, vomiting, hiccups | Agranulocytosis, aplastic anemia, SJS, hepatic failure, serum sickness, suicidal ideation | $40-150 |
| Phenobarbital | 1-4 mg/kg per day; 120-400 mg/d | Altered sleep cycles, sedation, ataxia, lethargy, behavior changes, hyperactivity, nausea, rash | Agranulocytosis, dermatitis, SJS, hepatic failure, serum sickness, connective tissue disorders, metabolic bone disease, intellect blunting, suicidal ideation | $4-$10 |
| Phenytoin | 300-600 mg/d | Confusion, slurred speech, double vision, ataxia, nystagmus, neuropathy, hirsutism, acne, gingival hyperplasia | Neuropathy, agranulocytosis, SJS, immune reactions/serum sickness, hepatic failure, skin thickening, metabolic bone disease, suicidal ideation | $35 |
| Valproic acid | 60-350 mg/kg per day | Tremor, weight gain, PCOS, nausea, vomiting, alopecia, easy bruising | Hepatic failure, pancreatitis, hearing loss, blood dyscrasias/thrombocytopenia, hyperammonemia, encephalopathy, osteoporosis, suicidal ideation | $40 (ER: $150) |
| Second generation | ||||
| Felbamate | 2400-3600 mg/d | Somnolence, nausea, vomiting, weight loss, anorexia | Aplastic anemia (>13 years), hepatic failure, suicidal ideation | $300-$500† |
| Gabapentin | 900-1800 mg/d | Somnolence, fatigue, weight gain, nystagmus | Pedal edema, suicidal ideation | $4-$100 |
| Lacosamide | 200-400 mg/d | Headache, dizziness, ataxia, nausea, diplopia | Euphoria, prolongation of PR interval, heart block, suicidal ideation | $420† |
| Lamotrigine | 300-500 mg/d | Dizziness, ataxia, nausea, somnolence, rash | SJS, hypersensitivity reactions (renal/hepatic failure), DIC, suicidal ideation | $30-$100 |
| Levetiracetam | 3000 mg/d | Somnolence, dizziness, aggression, agitation, anxiety, weight loss | Infection, pancytopenia, liver failure, suicidal ideation | $30-$100 (XR: $245†) |
| Oxcarbazepine | 1200 mg/d | Somnolence, fatigue, headache, ataxia, nausea, rash | Hyponatremia, SJS, TEN, angioedema | $250-$1000 |
| Pregabalin | 150-600 mg/d | Peripheral edema, dry mouth, dizziness, ataxia, diplopia, weight gain | Angioedema, CK elevation, mild PR interval prolongation, suicidal ideation | $100-$350† |
| Rufinamide | 3200 mg/d | Headache, dizziness, fatigue, nausea | Shortened QT interval, hypersensitivity rash, suicidal ideation | $400-$750† |
| Tiagabine | 32-56 mg/d | Difficulty concentrating, dizziness, headache, somnolence, nervousness | Spike-wave stupor, sudden death, suicidal ideation | $140-$650† |
| Topiramate | 200-400 mg/d | Somnolence, dizziness, fatigue, weight loss, difficulty concentrating, speech problems, paresthesias, diarrhea, nausea | Acute myopia and glaucoma, hyperthermia (children); metabolic acidosis, hyperammonemia, liver failure, oligohydrosis, SJS/TEN, kidney stones, suicidal ideation | $40 - $100 |
| Vigabatrin | 1500 mg/d | Fatigue, somnolence, nystagmus, tremor, weight gain | Vision loss (30% of patients) blurred vision, arthralgia, suicidal ideation | :$50 -$100† |
| Zonisamide | 400- 600 mg/d | Somnolence, difficulty concentrating, anorexia, nausea | SJS, TEN, aplastic anemia, agranulocytosis, nephrolithiasis/, oligohydrosis, acidosis, suicidal ideation | $50-$200 |
| CK, creatine kinase; DIC, disseminated intravascular coagulation; ER, extended release; IV, intravenous; PCOS, polycystic ovarian syndrome; SIADH, syndrome of inappropriate antidiuretic hormone hypersecretion; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis, XR, extended release. *Costs from www.drugstore.com, www.savewithgenericdrugs.com, and www.pharmacychecker.com. †No generic available. | ||||
When to add a second AED
Monotherapy is the preferred method of epilepsy treatment, and controls seizures for 70% to 90% of patients.31,32 If seizures continue and potential adverse effects prevent you from increasing the dosage, switching to a different AED, then tapering off the first agent, is recommended.33,34
If the new AED fails to provide adequate seizure control, consider combination therapy. An additional 10% to 15% of patients with epilepsy achieve control with dual therapy.33,34
Many second-generation agents are approved for adjunctive therapy. However, the use of 2 AEDs increases the risk of toxicities and drug interactions, and requires complex dosage adjustments, which should be done slowly and cautiously. Combination therapy also increases costs and may cause a decrease in compliance.33,34
Noncompliance is the single most common reason for treatment failure in patients with epilepsy, occurring at an estimated rate of up to 60%.35,36 The complexity of the drug regimen is the major cause, regardless of patient age, sex, psychomotor development, seizure type, or seizure frequency.35,36
Because of the lack of good clinical trials of combination antiepilepsy therapy, no evidence is available to indicate which AEDs are safe and effective when taken together. There is, however, evidence that certain combinations should be avoided due to the risk of increased adverse effects. These include phenobarbital/valproate, phenytoin/carbamazepine, and carbamazepine/lamotrigine.25
Managing the patient who is seizure-free
After a patient has been seizure-free for 2 to 5 years, consider a reduction in, or a discontinuation of, his or her AED. The relapse rate varies from 10% to 70%, with meta-analyses showing a rate of 25% in the first year and 29% in the second year.19,37 The American Academy of Neurology (AAN) has published an evidence-based guideline for discontinuing AEDs in seizure-free patients, available at www.aan.com/professionals/practice/pdfs/gl0007.pdf.
Withdrawal should be gradual and, for patients on combination therapy, carried out one drug at a time to prevent a recurrence of seizures or status epilepticus. The AAN recommends a 2- to- 3-month withdrawal period for AEDs (and longer for benzodiazepines), although relapse rates have been found to be lower when the medication is withdrawn more slowly, over about 6 months.19,34 If seizures recur after withdrawal, restart the AEDs at previous dosages.19,34,38
Should the patient drive?
For patients with epilepsy, loss of independence related to driving restrictions is a major source of stress. A 10-year follow-up study of Danish patients with epilepsy found a 7-fold increase in motor vehicle accidents (MVAs) in patients with seizure disorders.39 Other studies have shown that the seizure-free interval is the best predictor of involvement in an MVA.40
The risk of driving accidents decreases as the seizure-free interval increases. Unfortunately, however, a decline in patient compliance is also associated with longer seizure-free intervals—creating the potential for recurrence and driving risk. Because of this discrepancy, a consensus statement from the AAN, American Epilepsy Society, and Epilepsy Foundation of America recommends a minimum 3-month seizure-free interval before patients are allowed to drive.41
Use clinical judgment in deciding whether to extend the seizure-free period. State laws vary widely regarding the need to report patients with seizure disorders, limitations on professional drivers, and seizure-free intervals required, so it is important to be familiar with the laws in your state. The Epilepsy Foundation has a helpful online resource with a database detailing individual state statutes (http://www.epilepsyfoundation.org/living/wellness/transportation/driverlicensing.cfm).
The danger of uncontrolled seizures
Overall, AEDs effectively control 70% of 80% of cases; the remaining 20% to 30% are considered medically refractory.38 What’s more, after 2 AED failures, a patient’s chances of achieving full seizure control with additional drugs are no better than 10% to 20%.42 And, as more drugs are tried, the likelihood of full control declines even further.43
Patients with uncontrolled seizures have a cumulative risk of sudden unexpected death in epilepsy (SUDEP) of 0.5% per year.44 Cognitive decline is associated with uncontrolled epilepsy, as well. In children, frequent seizures may significantly alter neuronal networks, affecting cognitive and motor development.
Is your patient a candidate for surgery?
Patients with disabling complex partial seizures that remain uncontrolled after 2 or more AED trials (either as monotherapy or in combination) should be referred to an epilepsy specialty center for evaluation for surgery.45 This should be considered as early as possible to afford the patient the best chance of achieving seizure control.
Successful epilepsy surgery—in which the portion of the brain causing the misfiring that causes the seizures is removed—often results in a better quality of life; it is also cost effective.46 Not everyone with refractory epilepsy is a candidate for surgery, of course. Among those who are, however, 50% to 70% of patients can expect to have improved seizure control.47
Status epilepticus is a medical emergency
A patient who develops status epilepticus is at high risk and requires immediate, and simultaneous, evaluation and treatment. Status epilepticus carries nearly a 20% mortality from the first episode,48 and the 10-year mortality rate after an episode of status epilepticus is as high as 40%.49
Although most of the deaths associated with status epilepticus are due to the underlying pathology, early treatment can prevent or ameliorate complications from rhabdomyolysis and irreversible anoxic neuronal damage.50
A benzodiazepine (typically, a 10-mg IV bolus of diazepam) is the initial treatment for status epilepticus, followed by or concurrent with fosphenytoin (15-18 mg/kg). If status epilepticus remains refractory to first-line drugs (lasting >30 minutes), intubation and transfer to an intensive care setting may be required, and a neurological consult should be obtained.
Pharmacologic treatment of status epilepticus falls into 3 main classes: benzodiazepines, standard AEDs, and general anesthetics such as propofol. Benzodiazepines act very rapidly to control most prolonged seizures, and are the first-line treatment choice. Diazepam has long been the mainstay of treatment, and is usually readily available. However, in both a large systematic review and a head-to-head trial, lorazepam was found to be superior to diazepam in ending seizure activity and maintaining seizure control without the use of other medications51,52—and is now the drug of choice for initial treatment of status epilepticus.
CASE You continue to see Joe every 3 to 4 months to monitor his basic blood work and mood. A year after his seizure, he remains seizure-free and is tolerating the AED without any adverse effects.
CORRESPONDENCE
William J. Geiger, MD, FAAFP, Medical College of Wisconsin, Columbia St. Mary’s Family Medicine Residency, 1121 East North Avenue, Milwaukee, WI 53212; [email protected]
1. Epilepsy Foundation of America. Epilepsy and seizure statistics. Available at: http://www.epilepsyfoundation.org/about/statistics.cfm. Accessed June 15, 2009.
2. Centers for Disease Control and Prevention (CDC). Prevalence and most common causes of disability among adults—United States, 2005. MMWR Morb Mortal Wkly Rep. 2009;58:421-426. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5816a2.htm. Accessed June 15, 2009.
3. Hirtz D, Thurman DJ, Gwinn-Hardy K, et al. How common are the “common” neurologic disorders? Neurology. 2007;68:326-337.
4. Engel J Jr. ILAE classification of epilepsy syndromes. Epilepsy Res. 2006;70(suppl 1):S5-S10.
5. Rudzinski LA, Shih JJ. Continuum: lifelong learning in neurology. Epilepsia. 2010;16:15-35.
6. Chaves J, Sander JW. Seizure aggravation in idiopathic generalized epilepsies. Epilepsia. 2005;46(suppl 9):S133-S139.
7. Beghi E. Management of first seizure. General conclusions and recommendations. Epilepsia. 2008;49(suppl 1):S58-S61.
8. Berg A. Risk of recurrence after a first unprovoked seizure. Epilepsia. 2008;49(suppl 1):S13-S18.
9. Hirtz D, Ashwal S, Berg A, et al. Practice parameter: evaluating a first non-febrile seizure in children: report of the Quality Standards Subcommittee of the American Academy of Neurology, the Child Neurology Society, and the American Epilepsy Society. Neurology. 2000;55:616-623.
10. US Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm100190.htm. Updated May 5, 2009. Accessed June 28, 2009.
11. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new epilepsy, report of the therapeutic and technology assessment subcommittee and quality standards subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1252-1260.
12. French J, Smith M, Faught E, et al. Practice advisory: the use of felbamate in the treatment of patients with intractable epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 1999;52:1540-1545.
13. Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008;70:1950-1958.
14. Suzuki Y, Nagai T, Ono J, et al. Zonisamide monotherapy in newly-diagnosed infantile spasms. Epilepsia. 1997;38:1035-1038.
15. Kochak GM, Page JG, Buchanan RA, et al. Steady-state pharmacokinetics of zonisamide, an antiepileptic agent for treatment of refractory complex partial seizures. J Clin Pharmacol. 1998;38:166-171.
16. Arroyo S, Anhut H, Kugler AR, et al. Pregabalin 1008-011 International Study Group. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia. 2004;45:20-27.
17. Brodie MJ, Rosenfeld WE, Vazquez B, et al. Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial. Epilepsia. 2009;50:1899-1909.
18. Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48:1308-1317.
19. Gidal B, Garnett W. Epilepsy. In: Dipiro J, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:1023-1048.
20. Pellock JM, Treatment of epilepsy in the new millennium. Pharmacotherapy. 2000;20:129S-138S.
21. Schachter S. Pharmacology of antiepileptic drugs. Available at: http://www.utdonline.com/online/content/topic.do?topicKey=epil_eeg/5220. Accessed July 15, 2009.
22. Woelfel J. Comparison of antiepileptic drugs. Pharmacist’s Letter/Prescriber's Letter. July 2009;25:1-24.
23. Wolters Kluwer Health Inc. Anticonvulsants. Drug facts and comparisons online. Available at: http://www.efactsonline.com. Accessed July 10, 2009.
24. US Food and Drug Administration. Information for healthcare professionals. Suicidality and antiepileptic drugs [FDA alert]. Available at: http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm054709.htm. January 31, 2008. Accessed June 30, 2009.
25. French J. Treatment with antiepileptic drugs, new and old. Continuum. 2007;13:71-90.
26. Sheehan M. Polycystic ovarian syndrome: diagnosis and management. Clin Med Res. 2004;2:13-27.
27. Harden CL. Sexual dysfunction in women with epilepsy. Seizure. 2008;17:131-135.
28. Harden CL, Hopp J, Ting TY, et al. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency. Neurology. 2009;73:126-132.
29. Molgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA. 2011;305:1996-2002.
30. Tomson T, Battino D, Bonizonni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10:609-617.
31. Callaghan BC, Anand K, Hesdorffer D, et al. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann Neurol. 2007;62:382-389.
32. Luciano AL, Shorvon SD. Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol. 2007;62:375-381.
33. Abramowicz M, ed. Drugs for epilepsy [treatment guidelines]. The Medical Letter. 2008;70:1-12.
34.Stokes T, Shaw EJ, Juarez-Garcia A, et al. Clinical guidelines and evidence review for the epilepsies: diagnosis and management in adults and children in primary and secondary care. London: Royal College of General Practitioners. Available at: www.nice.org.uk/CG020fullguideline. Published October 2004. Accessed July 10, 2009.
35. Garnett WR. Antiepileptic drug treatment: outcomes and adherence. Pharmacotherapy. 2000;20:191S-199S.
36. Briesacher BA, Andrade SE, Fouayzi H, et al. Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy. 2008;28:437-443.
37. Shinnar S, Gross-Tsur V. Discontinuing antiepileptic drug therapy. In: Wyllie E, ed. The Treatment of Epilepsy. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001:811-819.
38. Kwan P, Brodie J. Refractory epilepsy: a progressive, intractable but preventable condition? Seizures. 2002;11:77-84.
39. Lings S. Increased driving accident frequency in Danish patients with epilepsy. Neurology. 2001;57:435-439.
40. Krauss GL, Krumholz A, Carter RC, et al. Risk factors for seizure-related motor vehicle crashes in patients with epilepsy. Neurology. 1999;52:1324-1329.
41. American Academy of Neurology, American Epilepsy Society, and Epilepsy Foundation of America. Consensus statements, sample statutory provisions, and model regulations regarding driver licensing and epilepsy. Epilepsia. 1994;35:696-705.
42. Thadani VM, Taylor J. Surgical treatments for epilepsy. Continuum. 2007;13:152-176.
43. Brodie MJ, Kwan P. Staged approach to epilepsy management. Neurology. 2002;58(8 suppl 5):S2-S8.
44. Sillanpaa M, Jalava M, Kaleva O, et al. Long-term prognosis of seizures with onset in childhood. N Engl J Med. 1998;338:1715-1722.
45. Engel J Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Neurology. 2003;60:538-547.
46. Boon P, D'Have M, Van Walleghen P, et al. Direct medical costs of refractory epilepsy incurred by three different treatment modalities: a prospective assessment. Epilepsia. 2002;43:96-102.
47. Passaro EA. Outcome of epilepsy surgery. Available at: http://emedicine.medscape.com/article/1185416-overview. Updated May 16, 2011. Accessed June 28, 2011.
48. DeLorenzo RJ, Pellock JM, Towne AR, et al. Epidemiology of status epilepticus. J Clin Neurophysiol. 1995;12:316-325.
49. Logroscino G, Hesdorffer DC, Cascino GD, et al. Long-term mortality after a first episode of status epilepticus. Neurology. 2002; 58:537-541.
50. Kalviaine R. Treatment of status epilepticus. Essential Evidence Plus. Wiley-Blackwell. Available at: http://www.essentialevidenceplus.com/content/ebmg_ebm/766. Accessed July 15, 2009.
51. Prasad K, Al-Roomi K, Krishnan PR, et al. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev. 2005;(4):CD003723.
52. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med. 1998;339:792-798.
1. Epilepsy Foundation of America. Epilepsy and seizure statistics. Available at: http://www.epilepsyfoundation.org/about/statistics.cfm. Accessed June 15, 2009.
2. Centers for Disease Control and Prevention (CDC). Prevalence and most common causes of disability among adults—United States, 2005. MMWR Morb Mortal Wkly Rep. 2009;58:421-426. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5816a2.htm. Accessed June 15, 2009.
3. Hirtz D, Thurman DJ, Gwinn-Hardy K, et al. How common are the “common” neurologic disorders? Neurology. 2007;68:326-337.
4. Engel J Jr. ILAE classification of epilepsy syndromes. Epilepsy Res. 2006;70(suppl 1):S5-S10.
5. Rudzinski LA, Shih JJ. Continuum: lifelong learning in neurology. Epilepsia. 2010;16:15-35.
6. Chaves J, Sander JW. Seizure aggravation in idiopathic generalized epilepsies. Epilepsia. 2005;46(suppl 9):S133-S139.
7. Beghi E. Management of first seizure. General conclusions and recommendations. Epilepsia. 2008;49(suppl 1):S58-S61.
8. Berg A. Risk of recurrence after a first unprovoked seizure. Epilepsia. 2008;49(suppl 1):S13-S18.
9. Hirtz D, Ashwal S, Berg A, et al. Practice parameter: evaluating a first non-febrile seizure in children: report of the Quality Standards Subcommittee of the American Academy of Neurology, the Child Neurology Society, and the American Epilepsy Society. Neurology. 2000;55:616-623.
10. US Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm100190.htm. Updated May 5, 2009. Accessed June 28, 2009.
11. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new epilepsy, report of the therapeutic and technology assessment subcommittee and quality standards subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1252-1260.
12. French J, Smith M, Faught E, et al. Practice advisory: the use of felbamate in the treatment of patients with intractable epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 1999;52:1540-1545.
13. Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008;70:1950-1958.
14. Suzuki Y, Nagai T, Ono J, et al. Zonisamide monotherapy in newly-diagnosed infantile spasms. Epilepsia. 1997;38:1035-1038.
15. Kochak GM, Page JG, Buchanan RA, et al. Steady-state pharmacokinetics of zonisamide, an antiepileptic agent for treatment of refractory complex partial seizures. J Clin Pharmacol. 1998;38:166-171.
16. Arroyo S, Anhut H, Kugler AR, et al. Pregabalin 1008-011 International Study Group. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia. 2004;45:20-27.
17. Brodie MJ, Rosenfeld WE, Vazquez B, et al. Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial. Epilepsia. 2009;50:1899-1909.
18. Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48:1308-1317.
19. Gidal B, Garnett W. Epilepsy. In: Dipiro J, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:1023-1048.
20. Pellock JM, Treatment of epilepsy in the new millennium. Pharmacotherapy. 2000;20:129S-138S.
21. Schachter S. Pharmacology of antiepileptic drugs. Available at: http://www.utdonline.com/online/content/topic.do?topicKey=epil_eeg/5220. Accessed July 15, 2009.
22. Woelfel J. Comparison of antiepileptic drugs. Pharmacist’s Letter/Prescriber's Letter. July 2009;25:1-24.
23. Wolters Kluwer Health Inc. Anticonvulsants. Drug facts and comparisons online. Available at: http://www.efactsonline.com. Accessed July 10, 2009.
24. US Food and Drug Administration. Information for healthcare professionals. Suicidality and antiepileptic drugs [FDA alert]. Available at: http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm054709.htm. January 31, 2008. Accessed June 30, 2009.
25. French J. Treatment with antiepileptic drugs, new and old. Continuum. 2007;13:71-90.
26. Sheehan M. Polycystic ovarian syndrome: diagnosis and management. Clin Med Res. 2004;2:13-27.
27. Harden CL. Sexual dysfunction in women with epilepsy. Seizure. 2008;17:131-135.
28. Harden CL, Hopp J, Ting TY, et al. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency. Neurology. 2009;73:126-132.
29. Molgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA. 2011;305:1996-2002.
30. Tomson T, Battino D, Bonizonni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10:609-617.
31. Callaghan BC, Anand K, Hesdorffer D, et al. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann Neurol. 2007;62:382-389.
32. Luciano AL, Shorvon SD. Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol. 2007;62:375-381.
33. Abramowicz M, ed. Drugs for epilepsy [treatment guidelines]. The Medical Letter. 2008;70:1-12.
34.Stokes T, Shaw EJ, Juarez-Garcia A, et al. Clinical guidelines and evidence review for the epilepsies: diagnosis and management in adults and children in primary and secondary care. London: Royal College of General Practitioners. Available at: www.nice.org.uk/CG020fullguideline. Published October 2004. Accessed July 10, 2009.
35. Garnett WR. Antiepileptic drug treatment: outcomes and adherence. Pharmacotherapy. 2000;20:191S-199S.
36. Briesacher BA, Andrade SE, Fouayzi H, et al. Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy. 2008;28:437-443.
37. Shinnar S, Gross-Tsur V. Discontinuing antiepileptic drug therapy. In: Wyllie E, ed. The Treatment of Epilepsy. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001:811-819.
38. Kwan P, Brodie J. Refractory epilepsy: a progressive, intractable but preventable condition? Seizures. 2002;11:77-84.
39. Lings S. Increased driving accident frequency in Danish patients with epilepsy. Neurology. 2001;57:435-439.
40. Krauss GL, Krumholz A, Carter RC, et al. Risk factors for seizure-related motor vehicle crashes in patients with epilepsy. Neurology. 1999;52:1324-1329.
41. American Academy of Neurology, American Epilepsy Society, and Epilepsy Foundation of America. Consensus statements, sample statutory provisions, and model regulations regarding driver licensing and epilepsy. Epilepsia. 1994;35:696-705.
42. Thadani VM, Taylor J. Surgical treatments for epilepsy. Continuum. 2007;13:152-176.
43. Brodie MJ, Kwan P. Staged approach to epilepsy management. Neurology. 2002;58(8 suppl 5):S2-S8.
44. Sillanpaa M, Jalava M, Kaleva O, et al. Long-term prognosis of seizures with onset in childhood. N Engl J Med. 1998;338:1715-1722.
45. Engel J Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Neurology. 2003;60:538-547.
46. Boon P, D'Have M, Van Walleghen P, et al. Direct medical costs of refractory epilepsy incurred by three different treatment modalities: a prospective assessment. Epilepsia. 2002;43:96-102.
47. Passaro EA. Outcome of epilepsy surgery. Available at: http://emedicine.medscape.com/article/1185416-overview. Updated May 16, 2011. Accessed June 28, 2011.
48. DeLorenzo RJ, Pellock JM, Towne AR, et al. Epidemiology of status epilepticus. J Clin Neurophysiol. 1995;12:316-325.
49. Logroscino G, Hesdorffer DC, Cascino GD, et al. Long-term mortality after a first episode of status epilepticus. Neurology. 2002; 58:537-541.
50. Kalviaine R. Treatment of status epilepticus. Essential Evidence Plus. Wiley-Blackwell. Available at: http://www.essentialevidenceplus.com/content/ebmg_ebm/766. Accessed July 15, 2009.
51. Prasad K, Al-Roomi K, Krishnan PR, et al. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev. 2005;(4):CD003723.
52. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med. 1998;339:792-798.