Clinical Epilepsy

1. Clinical Epilepsy American Epilepsy Society

2. Definitions  Seizure: the clinical manifestation of an abnormal, excessive excitation and synchronization of a population of cortical neurons  Epilepsy: two or more recurrent seizures unprovoked by systemic or acute neurologic insults

3. Epidemiology of Seizures and Epilepsy  Seizures Incidence: 80/100,000 per year Lifetime incidence: 9% (1/3 febrile convulsions)  Epilepsy Incidence: 45/100,000 per year Point prevalence: 0.5-1% Cumulative lifetime incidence: 3%

4. ILAE Classification of Seizures

5. ILAE Classification of Seizures

6. ILAE Classification of Seizures

7. Complex Partial Seizures  Impaired consciousness  Clinical manifestations vary with site of origin and degree of spread • Presence and nature of aura • Automatisms • Other motor activity  Duration typically < 2 minutes

8. Secondarily Generalized Seizures  Begins focally, with or without focal neurological symptoms  Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases  Typical duration 1-3 minutes  Postictal confusion, somnolence, with or without transient focal deficit

9. EEG: Partial Seizure Right temporal seizure with maximal phase reversal in the right sphenoidal electrode

10. EEG: Partial Seizure Continuation of same seizure Right temporal seizure with maximal phase reversal in the right sphenoidal electrode

11. ILAE Classification of Seizures

12. Typical Absence Seizures  Brief staring spells (“petit mal”) with impairment of awareness • 3-20 seconds • Sudden onset and sudden resolution • Often provoked by hyperventilation • Onset typically between 4 and 14 years of age • Often resolve by 18 years of age  Normal development and intelligence  EEG: Generalized 3 Hz spike-wave discharges

13. EEG: Typical Absence Seizure

14. Atypical Absence Seizures  Brief staring spells with variably reduced responsiveness • 5-30 seconds • Gradual (seconds) onset and resolution • Generally not provoked by hyperventilation • Onset typically after 6 years of age  Often in children with global cognitive impairment  EEG: Generalized slow spike-wave complexes (<2.5 Hz)  Patients often also have Atonic and Tonic seizures

15. Atypical Absence Seizures

16. Myoclonic Seizures  Brief, shock-like jerk of a muscle or group of muscles  Epileptic myoclonus • Typically bilaterally synchronous • Impairment of consciousness difficult to assess (seizures <1 second) • Clonic seizure – repeated myoclonic seizures (may have impaired awareness)  Differentiate from benign, nonepileptic myoclonus (e.g., while falling asleep)  EEG: Generalized 4-6 Hz polyspike-wave discharges

17. Myoclonic Seizures

18. Tonic and Atonic Seizures Tonic seizures • Symmetric, tonic muscle contraction of extremities with tonic flexion of waist and neck • Duration - 2-20 seconds. • EEG – Sudden attenuation with generalized, low-voltage fast activity (most common) or generalized polyspike-wave. Atonic seizures • Sudden loss of postural tone • When severe often results in falls • When milder produces head nods or jaw drops. • Consciousness usually impaired • Duration - usually seconds, rarely more than 1 minute • EEG – sudden diffuse attenuation or generalized polyspike-wave

19. Tonic and Atonic Seizures

20. Generalized Tonic-Clonic Seizures • Associated with loss of consciousness and post-ictal confusion/lethargy • Duration 30-120 seconds • Tonic phase • Stiffening and fall • Often associated with ictal cry • Clonic Phase • Rhythmic extremity jerking • EEG – generalized polyspikes

21. Epilepsy Syndromes Epilepsy Syndrome Grouping of patients that share similar: • Seizure type(s) • Age of onset • Natural history/Prognosis • EEG patterns • Genetics • Response to treatment

22. Epilepsy Syndromes

23. Etiology of Seizures and Epilepsy  Infancy and childhood • Prenatal or birth injury • Inborn error of metabolism • Congenital malformation  Childhood and adolescence • Idiopathic/genetic syndrome • CNS infection • Trauma

24. Etiology of Seizures and Epilepsy  Adolescence and young adult • Head trauma • Drug intoxication and withdrawal*  Older adult • Stroke • Brain tumor • Acute metabolic disturbances* • Neurodegenerative *causes of acute symptomatic seizures, not epilepsy

25. Questions Raised by a First Seizure  Seizure or not?  Focal onset?  Evidence of interictal CNS dysfunction?  Metabolic precipitant?  Seizure type? Syndrome type?  Studies?  Start AED?

26. Evaluation of a First Seizure • History, physical • Blood tests: CBC, electrolytes, glucose, calcium, magnesium, phosphate, hepatic and renal function • Lumbar puncture (only if meningitis or encephalitis suspected and potential for brain herniation is excluded) • Blood or urine screen for drugs • Electroencephalogram • CT or MR brain scan

27. Seizure Precipitants  Metabolic and Electrolyte Imbalance  Stimulant/other proconvulsant intoxication  Sedative or ethanol withdrawal  Sleep deprivation  Antiepileptic medication reduction or inadequate AED treatment  Hormonal variations  Stress  Fever or systemic infection  Concussion and/or closed head injury

28. Seizure Precipitants (cont.) Metabolic and Electrolyte Imbalance • Low blood glucose (or high glucose, esp. w/ hyperosmolar state) • Low sodium • Low calcium • Low magnesium

29. Seizure Precipitants (cont.) Stimulants/Other Pro-convulsant Intoxication  IV drug use  Cocaine  Ephedrine  Other herbal remedies  Medication reduction

30. EEG Abnormalities  Background abnormalities: significant asymmetries and/or degree of slowing inappropriate for clinical state or age  Interictal abnormalities associated with seizures and epilepsy • Spikes • Sharp waves • Spike-wave complexes  May be focal, lateralized, generalized

31. Medical Treatment of First Seizure Whether to treat first seizure is controversial  16-62% will recur within 5 years  Relapse rate might be reduced by antiepileptic drug treatment  Abnormal imaging, abnormal neurological exam, abnormal EEG or family history increase relapse risk  Quality of life issues are important (ie driving) Reference: First Seizure Trial Group. Randomized Clinical Trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic-clonic seizure. Neurology 1993; 43 (3, part1): 478-483. Reference: Camfield P, Camfield C, Dooley J, Smith E, Garner B. A randomized study of carbamazepine versus no medication after a first unprovoked seizure in childhood. Neurology 1989; 39: 851-852.

32. Choosing Antiepileptic Drugs  Seizure type  Epilepsy syndrome  Pharmacokinetic profile  Interactions/other medical conditions  Efficacy  Expected adverse effects  Cost

33. Choosing Antiepileptic Drugs • Limited placebo-controlled trials available, particularly of newer AEDs • In practice, several drugs are commonly used for indications other than those for which they are officially approved/recommended • Choice of AED for partial epilepsy depends largely on drug side-effect profile and patient’s preference/concerns • Choice of AED for primary generalized epilepsy depends on predominant seizure type(s) as well as drug side-effect profile and patient’s preference/concerns • ILAE and AAN recommendations indications listed in the appendix

34. Broad-Spectrum Agents Valproate Felbamate Lamotrigine Topiramate Zonisamide Levetiracetam Rufinamide* Narrow-Spectrum Agents Partial onset seizures Phenytoin Carbamazepine Oxcarbazepine Gabapentin Pregabalin Tiagabine Lacosamide* Absence Ethosuximide Choosing Antiepileptic Drugs * New AEDs (approved 2008) categorization may change

35. Choosing Antiepileptic Drugs (cont.) Choosing Antiepileptic Drugs (cont.) Monotherapy for Partial Seizures Best evidence and FDA indication: Carbamazepine, Oxcarbazepine, Phenytoin, Topiramate Similar efficacy, likely better tolerated: Lamotrigine, Gabapentin, Levetiracetam Also shown to be effective: Valproate, Phenobarbital, Felbamate, Lacosamide Limited data but commonly used: Zonisamide, Pregabalin Azar and Abou-Khalil, Seminars in Neurology, 2008 28:305-316

36. Choosing Antiepileptic Drugs (cont.) Monotherapy for Generalized-Onset Tonic-Clonic Seizures Best evidence and FDA Indication: Valproate, Topiramate Also shown to be effective: Zonisamide, Levetiracetam Phenytoin, Carbamazepine (may exacerbate absence and myoclonic sz ) Lamotrigine (may exacerbate myoclonic sz of symptomatic generalized epilepsies)

37. Choosing Antiepileptic Drugs (cont.) Absence seizures Best evidence: Ethosuximide (limited spectrum, absence only) Valproate Also shown to be effective: Lamotrigine May be considered as second-line: Zonisamide, Levetiracetam, Topiramate, Felbamate, Clonazepam

38. Choosing Antiepileptic Drugs (cont.) Myoclonic Seizures Best evidence: Valproate Levetiracetam (FDA indication as adjunctive tx) Clonazepam (FDA indication) Possibly effective: Zonisamide, Topiramate

39. Choosing Antiepileptic Drugs (cont.) Lennox-Gastaut Syndrome Best evidence/FDA indication*: Topiramate, Felbamate, Clonazepam, Lamotrigine, Rufinamide * FDA approval is for adjunctive treatment for all except clonazepam Also effective: Valproate Some evidence of efficacy: Zonisamide, Levetiracetam

40. Antiepileptic Drug Monotherapy  Simplifies treatment  Reduces adverse effects  Conversion to monotherapy from polytherapy • Eliminate sedative drugs first • Withdraw antiepileptic drugs slowly over several months

41. Antiepileptic Drug Interactions • Drugs that may induce metabolism of other drugs: • carbamazepine, phenytoin, phenobarbital, primidone • Drugs that inhibit metabolism of other drugs: • valproate, felbamate • Drugs that are highly protein bound: • valproate, phenytoin, tiagabine • carbamazepine, oxcarbazepine • topiramate is moderately protein bound • Other drugs may alter metabolism or protein binding of antiepileptic drugs (especially antibiotics, chemotherapeutic agents and antidepressants)

42. Antiepileptic Drug Interactions Drugs that may decrease the efficacy of hormonal contraception • Phenytoin • Carbamazepine • Phenobarbital • Topiramate* • Oxcarbazepine* • Felbamate* *at high doses “High-dose” birth control pills are recommended for patients taking these medications. Lamotrigine levels decreased by hormonal contraception

43. AED Serum Concentrations • AED serum concentrations are to be used as a guide, not dictate clinical decision making. • Serum concentrations are useful when optimizing AED therapy, assessing compliance, monitoring during pregnancy or oral contraceptive use, or teasing out drug-drug interactions. • Individual patients define their own “therapeutic” and “toxic” ranges. Patsalos PN, et al. Epilepsia.2008. 49(7): 1239-1276

44. Adverse Effects of AEDs: Common Often dose-related: Dizziness Fatigue Ataxia Diplopia Irritability • levetiracetam Word-finding difficulty • topiramate Weight loss/anorexia • topiramate, zonisamide, felbamate Weight gain • valproate (also associated with polycystic ovarian syndrome in young women) • carbamazepine, gabapentin, pregabalin

45. Adverse Effects of AEDs: Serious Typically idiosyncratic: Renal stones • topiramate, zonisamide Hyponatremia • carbamazepine, oxcarbazepine Aplastic anemia • felbamate, zonisamide, valproate, carbamazepine Agranulocytosis • carabamazepine Hepatic Failure • valproate, felbamate, lamotrigine, phenobarbital Anhydrosis, heat stroke • topiramate Acute closed-angle glaucoma • topiramate

46. Adverse Effects of AEDs: Rash • 15.9% patients ever experienced a rash attributed to an AED • Average rate of AED-related rash for a given AED 2.8%, 2.1% causing AED discontinuation. • Predictors significant in multivariate analysis: • occurrence of another AED-rash Arif H et al. Neurology 2007

47. Adverse Effects of AEDs: Rash Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TENS) • severe life threatening allergic reaction • blisters and erosions of the skin, particularly palms/soles and mucous membranes • fever and malaise • rare: severe risk roughly 1-10/10,000 for many AEDs • rapid titration of lamotrigine especially in combination with valproate increases risk

48. Adverse Effects of AEDs: Rash Drugs rarely associated with rash • Valproate • Gabapentin • Pregabalin • Levetiracetam • Topiramate

49. AED-related rash in adult patients with epilepsy ▲▲= rash rate significantly greater than average of all other AEDs (p<0.003) ▼▼= rash rate significantly lower than average of all other AEDs (p<0.003) ▲= trend towards significantly higher than average rash rate of all other AEDs (0.003<p<0.05) ▼= trend towards significantly lower than average rash rate of all other AEDs (0.003<p<0.05)

50. AED-related rash in Asian patients with epilepsy FDA alert 12/2007 Risk of “dangerous or even fatal skin reactions” (SJS and TEN) are more common in those with HLA-B*1502 This allele is almost exclusively found in Asians • In 10-15% of population in China, Thailand, Malaysia, Indonesia, the Phillipines, and Taiwan • 2-4% in India • <1% in Japan and Korea 59/60 Asian patients w/ SJS/TEN had this allele vs 4% of cbz tolerant patients Estimated absolute risk for those with the allele: 5% Asians “should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine” These patients may also be at risk with other AEDs • Use drugs not typically associated with rash www.fda.gov