Management of Epilepsy

Management of Epilepsy Robert L. Macdonald M.D., Ph.D. Department of Neurology Vanderbilt University Medical Center Nashville, TN

Epidemiology of Seizures and Epilepsy • Seizures • Incidence: approximately 80/100,000 per year • Lifetime prevalence: 9% (1/3 benign febrile convulsions) • Epilepsy • Chronic recurring, unprovoked seizures • Incidence: approximately 45/100,000 per year • Point prevalence: 0.5-1%

Seizure Classification • Partial seizures (focal or local origin) • Simple partial seizures with: • motor signs • somatosensory or special sensory symptoms • autonomic symptoms or signs • psychic symptoms (disturbance of higher cerebral function) • Complex partial seizures with: • Impaired consciousness • Presence and nature of aura (simple partial origin) • Automatisms and other motor activity • Secondary generalized seizures

Seizure Classification • Primary generalized seizures (bilateral origin) • Absence • Myoclonic • Atonic • Tonic • Tonic-clonic

Epilepsy Syndromes • Partial epilepsies • Idiopathic • Symptomatic • Cryptogenic • Generalized epilepsies • Idiopathic • Symptomatic • Cryptogenic • Undetermined epilepsies • Special syndromes

Age Dependent Etiologies of Epilepsies • Infancy and childhood • Birth injury • Inborn error of metabolism • Congenital malformation • Childhood and adolescence • Idiopathic/genetic syndrome • CNS infection

Age Dependent Etiologies of Epilepsies • Adolescence and young adult • Head trauma • Drug intoxication and withdrawal* • Older adult • Stroke • Brain tumor • Acute metabolic disturbances* *causes of acute symptomatic seizures, not epilepsy

Questions Raised by a First Seizure • Seizure or not? • Focal or generalized onset? • Evidence of CNS dysfunction? • Metabolic or other precipitant? • Seizure type? Syndrome type? • Studies? • Start an AED?

Seizure Precipitants • Metabolic and Electrolyte Imbalance • Low (occ high) blood glucose, Na, Ca, Mg • Stimulant/other proconvulsant intoxication • IV drug use, cocaine, ephedrine, herbal remedies • Sedative/medication reduction • Sleep deprivation, stress • Hormonal variations • Infection

Evaluation of a First Seizure • History, physical exam • Blood tests: CBC, electrolytes, glucose, Ca, Mg, hepatic and renal function • Lumbar puncture only if meningitis or encephalitis suspected and potential for brain herniation is ruled out • Blood or urine screen for drugs • Electroencephalogram if indicated • CT or MR brain scan if indicated

Medical Treatment of First Seizure Whether to treat first seizure is controversial. • 16-62% will recur within 5 years. • Relapse rate is reduced by antiepileptic drug treatment. • Abnormal imaging, abnormal EEG or family history increase relapse risk. • Quality of life issues are important. • Was the seizure “precipitated”?

Medical Treatment of Epilepsy • Treat with an antiepileptic drug (AED) following a first seizure if the patient has a high likelihood of developing epilepsy to prevent seizure recurrence. • Treat with an AED if the patient has recurrent, unprovoked seizures (epilepsy).

Choosing an AED • Seizure type • Epilepsy syndrome • Pharmacokinetic profile • Interactions/other medical conditions • Efficacy • Expected adverse effects • Useful as monotherapy - simplifies treatment and reduces adverse effects • Cost

Spectrum of seizure efficacy for classical AEDs AED Partial/ GAE JME GTC Phenytoin ++ - - Carbamazepine ++ - - Valproate ++++++ Primidone + - - Phenobarbital + - - Clonazepam + + + Methsuximide + + + Ethosuximide - ++ -

Monotherapy treatment of new onset epilepsy with new AEDs AED Partial\mixed Absence Gabapentin + - Lamotrigine + + Topiramate + - Tiagabine - - Levetiracetam - - Oxcarbazepine + - Zonisamide - - Neurology 62:1252, 2004

Choosing an AED • Partial onset seizures phenytoin* gabapentin carbamazepine* phenobarbital valproate primidone lamotrigine felbamate** oxcarbazepine topiramate levetiracetam tiagabine zonisamide * considered by many as drugs of choice **associated with aplastic anemia and hepatic failure

Choosing an AED • Generalized onset seizures Absence: valproate* = ethosuximide Myoclonic: valproate, clonazepam Tonic-clonic: valproate = phenytoin, carbamazepine * the risk of valproate-induced hepatic failure must be carefully weighed in young children

Preconception counseling and teratogenicity • Preconception information should be offered to all females with childbearing potential. • If changes in AED medication are to be made, they should be completed before conception. • If AED treatment is needed, a single agent is preferred. • The risk of fetal malformation is increased in women receiving treatment for epilepsy compared with the general population (3% with carbamazepine or lamotrigine, 7% with valproate sodium, and 15% with two or more AEDs).

Preconception counseling and teratogenicity • Most major malformations occur at an early stage in pregnancy, often before the woman knows she is pregnant. • Women with epilepsy who are planning a pregnancy should take folic acid 5 mg/day in the preconception period and throughout the pregnancy; vitamin K should be used in the last month of pregnancy in women on enzyme-inducing AEDs. • The use of phenytoin, valproate, carbamazepine, lamotrigine, and phenobarbital has been associated with an increased risk of major malformations and minor morphological anomalies .

Preconception counseling and teratogenicity • Although valproate may the most suitable drug for some women, the risks and benefits should be carefully considered and discussed with the patient. • It is not known whether vigabatrin, gabapentin, levetiracetam, topiramate, oxcarbazepine, pregabalin, and tiagabine are associated with a risk of fetal abnormalities in humans; gabapentin, pregabalin, and tiagabine are not associated with fetal abnormalities in animal studies.

Contraception and AEDs • There are no contraindications to the use of nonhormonal methods of contraception in women with epilepsy. • For women on nonenzyme-inducing AEDs (valproate sodium, benzodiazepines, vigabatrin, gabapentin, tiagabine, levetiracetam, pregabalin), all current contraceptive methods are suitable. • Hormonal forms of contraception are affected by enzyme-inducing AEDs (phenytoin, barbiturates, carbamazepine, oxcarbazepine, topiramate [>200 mg/day], and lamotrigine); women taking these forms of contraception should be counseled on their risks and benefits.

AED Interactions • Drugs that induce metabolism of other drugs: carbamazepine, phenytoin, phenobarbital • Drugs that inhibit metabolism of other drugs: valproate, felbamate • Drugs that are highly protein bound: valproate, phenytoin, tiagabine • Other drugs may alter metabolism or protein binding of antiepileptic drugs

Dose Initiation and Monitoring • Discuss likely and unlikely but important adverse effects. • Discuss likelihood of success. • Discuss recording/reporting seizures (seizure calendar), adverse effects, potential precipitants. • Obtain appropriate “baseline” laboratory tests • CBC, platelets, LFTs • Initiate therapy with an appropriate dose. • Monitor AED levels when appropriate.

AED Serum Concentrations • In general AED serum concentrations can be used as a guide for evaluating the efficacy of medication therapy for epilepsy. Serum concentrations are useful when optimizing AED therapy, assessing compliance, or teasing out drug-drug interactions. They should be used to monitor pharmacodynamic and pharmacokinetic interactions.

AED Serum Concentrations • Serum concentrations are also useful when documenting positive or negative outcomes associated with AED therapy. Most often individual patients define their own “therapeutic range” for AEDs. The new AEDs have potential serum ranges where patients in clinical trials had optimal seizure control and minimal side-effects from the medication. For the new AEDs there is no clearly defined “therapeutic range.”

Non-Drug Treatment/Lifestyle Modifications • Adequate sleep • Avoidance of alcohol, stimulants, etc. • Avoidance of non-precipitants • Stress reduction — specific techniques • Adequate diet • Exercise

Discontinuing AEDs • Seizure free 2 years implies overall >60% chance of successful withdrawal in some epilepsy syndromes • Favorable factors • Control achieved easily on one drug at low dose • No previous unsuccessful attempts at withdrawal • Normal neurologic status and EEG? • Primarily generalized seizures except JME • “Benign” syndrome • Consider relative risks/benefits (driving, pregnancy)

Evaluation After Seizure Recurrence • Progressive pathology? • Avoidable precipitant? • If on an AED • Problem with compliance or pharmacokinetic factor? • Increase dose? • Change medication? • If on multiple AEDs • Convert to monotherapy from polytherapy? • Eliminate sedative drugs first • Withdraw antiepileptic drugs slowly over several months • If not on AED • Start therapy?

Treatment of refractory epilepsy with new AEDs AED Partial Partial Primary Symp Ped Adj Mono Gen Gen Partial Gabapentin + - - - + Lamotrigine + + - + + Topiramate + + +(GTC) + + Tiagabine + - - - - Levetiracetam + - - - - Oxcarbazepine + + - - + Zonisamide + - - - - Neurology 62:1261, 2004

AED Alternatives: Ketogenic Diet • Anti-seizure effect of ketosis, acidosis • Low carbohydrate, low protein, high fat after fasting to initiate ketosis • Main experience with children, especially with multiple seizure types • Long-term effects unknown

AED Alternatives: Vagal Nerve Stimulator • Intermittent programmed electrical stim of L vagus • Option of patient-triggered stimulation (auras) • Adverse effects related to local stimulus (hoarseness, throat discomfort, dyspnea) • Mechanism unknown • Clinical trials show 26% effective • FDA says useful for partial onset seizures

AED Alternatives: Surgery • Epilepsy syndrome not responsive to medical management • Unacceptable seizure control despite maximum tolerated doses of 2-3 appropriate drugs as monotherapy • Epilepsy syndrome amenable to surgical treatment

Evaluation for Surgery • History and Exam: consistency, localization of seizure onset and progression • MRI: 1.5 mm coronal cuts with sequences sensitive to gray-white differentiation and to gliosis • Other neuroimaging options: PET, ictal SPEC • EEG: ictal and interictal, special electrodes • Neuropsychological battery and WADA test • Psychosocial evaluation

Surgical Treatment • Potentially curative • Resection of epileptogenic region (“focus”) without causing significant new neurologic deficit • Palliative • Partial resection of epileptogenic region • Disconnection procedure to prevent seizure spread — corpus callosotomy • Vagal nerve stimulation

Epilepsy Surgery Outcomes Temporal Extra Lesional HemisphX Callosotomy Temporal Seizure Free 68 45 66 45 8 Improved 23 35 22 35 61 Not improved 9 20 12 20 31 Total 100 100 100 100 100

Management of Epilepsy