Epilepsy 7/28/09! Definitions. Classification of epilepsy. Epidemiology of Seizures and Epilepsy. International classification of epilepsies

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1 Definitions Epilepsy Dr.Yotin Chinvarun M.D., Ph.D. Seizure: the clinical manifestation of an abnormal and excessive excitation of a population of cortical neurons Epilepsy: a tendency toward recurrent seizures unprovoked by systemic or neurologic insults Comprehensive Epilepsy and Sleep disorder Program PMK hospital 1 2 Epidemiology of and Epilepsy Classification of epilepsy!incidence: approximately 80/100,000 per year!lifetime prevalence: 9% (1/3 benign febrile convulsions) Epilepsy!Incidence: approximately 45/100,000 per year!point prevalence: 0.5-1% Seizure classification is important, guiding the investigation, therapy, and prognosis of seizure types. The major subdivisions are Primarily generalised seizures seizures 3 4 International classification of epilepsies International classification of epilepsies 5 6 1!

2 International classification of epilepsies Simple Absence Complex Myoclonic Secondarily Atonic Tonic Tonic-Clonic 7 8 Simple Complex Secondary generalized Simple Complex Secondarily 9 10 Simple Seizure Subclassification EEG: Simple Seizure With motor signs With somatosensory or special sensory symptoms With autonomic symptoms or signs With psychic symptoms (disturbance of higher cerebral function) Left parietalposterior temporal seizure !

3 Simple! Impaired consciousness! Clinical manifestations vary with site of origin and degree of spread Presence and nature of aura Automatisms 13 Other motor activity! Duration typically < 2 minutes Complex 14 Complex Impaired consciousness Clinical manifestations vary with site of origin and degree of spread! Presence and nature of aura! Automatisms! Other motor activity Duration (15 sec. 3 min.)! 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 Secondarily Secondarily Assumed or observed to begin as simple and/or complex partial seizures Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases Usual duration sec. Postictal confusion, somnolence, with or without transient focal deficit Right temporal seizure with maximal phase reversal in the right sphenoidal electrode !

4 Continuation of same seizure Right temporal seizure with maximal phase reversal in the right sphenoidal electrode Absence Myoclonic Atonic Tonic Tonic-Clonic 19 20! 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 Simple Complex Absence Myoclonic!! Often resolve by 18 years of age! Normal development and intelligence Absence Secondarily Atonic Tonic! EEG: 3 Hz spikewave discharges Tonic-Clonic Primary generalized seizures EEG: Absence Seizure Have a bilateral symmetrical onset. The clinical manifestations are diverse, and include:- Tonic, clonic, or tonic-clonic( grand mal ) Absence Myoclonus !

5 ! 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: slow spike-wave complexes (<2.5 Hz)! Patients often also have Atonic and Tonic seizures 25 26! 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: 4-6 Hz polyspike-wave discharges Myoclonic Tonic seizures!! Symmetric, tonic muscle contraction of extremities with tonic flexion of waist and neck!! Duration 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 29 Tonic 30 5!

6 !! Associated with loss of consciousness and post-ictal confusion/lethargy!! Duration seconds!! Tonic phase!! Stiffening and fall!! Often associated with ictal cry!! Clonic Phase!! Rhythmic extremity jerking!! EEG generalized polyspikes Tonic- Clonic Epilepsy Syndrome Grouping of patients that share similar: Seizure type(s) Age of onset Natural history/prognosis EEG patterns Genetics Response to treatment Epilepsy Syndromes epilepsies!idiopathic (genetic related)!symptomatic (lesion)!cryptogenic (unknown cause) Epilepsy Syndromes (cont.) epilepsies! Idiopathic! Symptomatic! Cryptogenic Undetermined epilepsies Special syndromes Etiology of and Epilepsy Infancy and childhood! Birth injury! Inborn error of metabolism! Congenital malformation Childhood and adolescence! Idiopathic/genetic syndrome! CNS infection !

7 Etiology of and Epilepsy (cont.) 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 Seizure or not? Focal onset? Questions Raised by a First Seizure Evidence of CNS dysfunction? Metabolic precipitant? Seizure type? Syndrome type? Studies? Start AED? Seizure Precipitants Evaluation of a First Seizure Low (less often, high) blood glucose Low sodium Low calcium Low magnesium Stimulant/other proconvulsant intoxication Sedative or AEDs withdrawal Severe sleep deprivation Stress Infection, fever Concussion, closed head trauma History, physical 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 CT or MR brain scan EEG Abnormalities Background abnormalities: significant asymmetries and/or degree of slowing inappropriate for clinical state Transient abnormalities associated with seizures and epilepsy! Spikes! Sharp waves! Spike-wave complexes May be focal, lateralized, generalized 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 !

8 Choosing Antiepileptic Drugs Seizure type Epilepsy syndrome Pharmacokinetic profile Interactions/other medical conditions Efficacy Expected adverse effects Cost!! 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 Choosing Antiepileptic Drugs (cont.) Broad-Spectrum Agents Valproate Felbamate Lamotrigine Topiramate Zonisamide Levetiracetam Rufinamide* Narrow-Spectrum Agents onset seizures Phenytoin Carbamazepine Oxcarbazepine Gabapentin Pregabalin Tiagabine Lacosamide* Absence Ethosuximide onset seizures phenytoin* gabapentin carbamazepine* phenobarbital valproate primidone lamotrigine felbamate** topiramate Tiagabine Lacosamide * considered by many as drugs of choice **associated with aplastic anemia and hepatic failure Choosing Antiepileptic Drugs (cont.) Monotherapy for 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 onset seizures Absence: valproate* = ethosuximide Myoclonic: valproate, clonazepam Tonic-clonic: valproate = phenytoin in Lennox-Gastaut Syndrome: valproate, lamotrigine, felbamate** * the risk of valproate-induced hepatic failure must be carefully weighed in young children ** associated with aplastic anemia and hepatic failure !

9 Monotherapy for -Onset Tonic- Clonic 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 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 Myoclonic Lennox-Gastaut Syndrome Best evidence: Valproate Levetiracetam (FDA indication as adjunctive tx) Clonazepam (FDA indication) Possibly effective: Zonisamide, Topiramate 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 Antiepileptic Drug Monotherapy Simplifies treatment, reduces adverse effects Conversion to monotherapy from polytherapy! Eliminate sedative drugs first! Withdraw antiepileptic drugs slowly over several months!! 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) !

10 Therapeutic Range of AED Serum Concentrations 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 A guide not a goal Limited data Broad generalizations Individual differences Useful in:! Providing initial target in patients with infrequent seizures! Understanding unexpected seizures or side effects, especially with polypharmacy! Verifying compliance 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 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 57 58!! 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 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 Arif H et al. Neurology 2007! !