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  1. 1. Seizures and Epilepsy Dr. Khalid El-Salem American Board of Neurology American Board of Clinical Neurophysiology Assistant Prof of Neurology JUST
  2. 2. Concepts Seizure: sudden temporary change in brain function caused by an abnormal rhythmic excessive electrical discharge Epilepsy: a state of recurrent seizures
  3. 3. Epidemiology of Epilepsy Lifetime risk of developing epilepsy is 3.2% 10% of population experience at least one seizure before the age of 80 years Higher prevalence at the extremes of age
  4. 4. Seizure Type Versus Epileptic Syndrome A seizure type is determined by the patient’s behavior and EEG pattern during the ictal event An epileptic syndrome is defined by - Seizure type(s) - Natural history - EEG (ictal and interictal) - Response to AEDs - Etiology
  5. 5. Classification of Seizures Partial seizures - Simple partial seizures - Complex partial seizures Impaired consciousness at outset Simple partial evolving to lost consciousness - Partial seizures evolving to general tonic-clonic seizures (GTCS)
  6. 6. Classification of Seizures (cont.) Generalized seizures - Absence seizures - Tonic-clonic seizures - Myoclonic seizures - Tonic seizures - Clonic seizures - Atonic seizures
  7. 7. Classification of Epilepsies Partial Epilepsy Syndromes  Generalized Epilepsy Syndromes - Symptomatic - Symptomatic •Lennox-Gastaut Syndrome •Lesional epilepsy •West’s Syndrome •Medial Temporal Sclerosis •Progressive Myoclonic Epilepsy •Neocortical Epilepsy - Idiopathic(Genetic) - Idiopathic(Genetic) •Juvenile myoclonic epilepsy •Benign Rolandic Epilepsy •Generalized tonic clonic •Benign occipital Epilepsy seizures upon awakening
  8. 8. Absence Seizure Simple: abrupt onset and cessation of motionless stare, with unresponsiveness and no post ictal state ( few-30 sec) Complex: typical+clonic/myoclonic activity or automatism Activated by hyperventilation
  9. 9. Generalized Tonic Clonic Seizure Prodrome: apathy, fatigue No aura Tonic phase: 10-15 sec, jaw snap shut, spasm, cyanosis Clonic phase: 1-2 min, rhythmic generalized muscle contractions apnea, increased BP Terminal phase: coma, pupils react, breathing resume Post-ictal phase: confusion, somnolence
  10. 10. Complex Partial Seizures Prodrome: Lethargy Aura: common Oral or motor automatism, alteration of consciousness, head and eye deviation, contralateral twitching or clonic movements, posturing Rt temporal often hypermobile Lt temporal often behaviour arrest
  11. 11. Frontal lobe seizures are partial seizures that can be easily confused with psychiatric disease
  12. 12. Acquired Epilepsy Trauma Infection Vascular disease Metabolic changes Tumor Age effects on brain
  13. 13. Epilepsy Risk Factors Structural brain lesions Degenerative diseases Head trauma CNS infections Perinatal insults Alcohol/drugs HIE Febrile seizures Genetic factors
  14. 14. Diagnosing Epilepsy History of recurrent seizures - Differentiate epileptic from non- epileptic fits - Classify seizure type - Determine etiology Associated clinical features Diagnostic testing • EEG • MRI
  15. 15. Epileptiform Discharges
  16. 16. Focal Discharges
  17. 17. Generalized Discharges
  18. 18. Phenytoin For partial and generalized Sz ^ Pt. bound, hepatic inducer Side effects - Dose related: ataxia, dysarthria, nystagmus - Idiosyncratic: hirsutism, gingival hypertrophy, acne, coarsening facial features
  19. 19. Valproic Acid Strong metabolic inhibitor For partial and generalized Sz Strongly Teratogenic: spina bifida Side effects: - somnolence, wt gain, tremor, hair loss - Pancreatitis, hepatotoxicity, blood dyscrasias
  20. 20. Carbamazepine Potent enzyme inducer Mainly for partial seizures Side effects: - somnolence, dizziness, blurred vision, diplopia’ nystagmus - skin rash, hepatotxicity, blood dyscrasias
  21. 21. Classic Versus Newer Anticonvulsants Classic AEDs Newer AEDs Phenobarbital  Felbamate (Felbatol®) Phenytoin (Dilantin®)  Gabapentin (Neurontin®)  Lamotrigine (Lamictal®) Primidone (Mysoline ) ®  Levetiracetam (Keppra®) Carbamazepine  Oxcarbazepine (Tegretol®) (Trileptal®) Valproate  Tiagabine (Gabitril®) (Depakote®/ Depacon®)  Topiramate (Topamax®) Ethosuximide  Vigabitrin (Sabril®) (Zarontin®)  Zonisamide (Zonegran®)
  22. 22. Applications of New AEDs in EpilepsyMedication Application in Epilepsy Felbamate Some efficacy in all seizure types Gabapentin Partial and sec generalized tonic clonic seizures only Lamotrigine Some efficacy in all seizure typesLevetiracetam Partial and sec generalized tonic clonic seizuresOxcarbazepine Partial and sec generalized tonic clonic seizures Tiagabine Partial and sec generalized tonic clonic seizures only Topiramate Some efficacy in all seizure types Vigabatrin Infantile spasms, Partial seizures Zonisamide Some efficacy in all seizure types
  23. 23. Choice and Use of Drugs Partial Generalized Simple ComplexSecondarygeneralized Tonic- Infantile clonic Tonic Myoclonic Atonic Spasms Absence PHT, CBZ, PB, GBP, TGB, ACTH LVT, OCBZ TPM? ESX TGB? VGB? VPA, LTG, TPM, ZNS FBM
  24. 24. Newer ADE Mechanisms of ActionMedication Na Channel GABA R NMDA Channel T Calcium Channel ChannelFelbamate +/? +/? +/? ?Gabapentin +/? +/? +/? ?Lamotrigine ++ -/? +/? -/?Levetiracetam - - - -Oxcarbazepine +/? ? - -Tiagabine - ++ - -Topiramate +/? ? ? ?Vigabatrin + - - -Zonisamide + - - +
  25. 25. New AEDs Dosing Medication Starting dose Incrementation mg Maintenance dose mg mgFelbamate 600 tid 600-1200 / wk 1200-1600 tidGabapentin 300-400 qd 300-400 / day 600-1200 tidLamotrigine 50 qd 100 / wk 100-300 bidLevetiracetam 500 bid 500 bid / 2 wks 500-1000 bidOxcarbazepine 300 bid 300 bid / wk 600-1200 bidTiagabine 4 qd 4-8 qd / wk 32-56 in 2-4 dosesTopiramate 50 qd 50 / wk 100-200 bidVigabatrin 40/kg/d 80-150 /kg/dZonisamide 100 qd-bid 100 / wk 100-300 bid
  26. 26. Elimination of classic AEDsValproate Hepatic Ethosux RenalPhenobarb 0 20 40 60 80 100
  27. 27. Elimination of Newer AEDs Zonisamide LevitiracetamOxcarbazepine Tiagabine Lamotrigine hepatic Felbamate Renal Topiramate Vigabatrin Gabapentin 0 20 40 60 80 100
  28. 28. Hepatic Enzyme Effects Of AEDs Inducers Inhibitors No or Min Phenytoin Valproate GabapentinPhenobarbital Felbamate Lamotrigine Primidone TopiramateCarbamazepine Tiagabine Oxcarbazepine Levitiracetam Zonisamide
  29. 29. Drug-Drug Interaction Potential of AEDs High Intermediate Minimal-None Phenytoin Topiramate GabapentinCarbamazepine Lamotrigine Ethosuximide Valproate Tiagabine LevitiracetamPhenobarbital Oxcarbazepine Vigabatril Primidone Zonisamide Felbamate
  30. 30. Main Inhibitory Interactions of AED’s
  31. 31. Effect of Inducer AED’s on Other AED’s
  32. 32. Serious Side EffectsMedication Serious side effects Felbamate Aplastic anemia, Liver failure Gabapentin None Lamotrigine Stevens Johnson SyndromeLevetiracetam NoneOxcarbazepine Hyponatremia Tiagabine Stupor Topiramate Nephrolithiasis, glucoma Vigabatrin Optic nerve demyelination Zonisamide Renal calculi
  33. 33. Cognetive Effects of AEDs Minimal- some Significant None Gabapentin Phenytoin Phenobarbital Tiagabine Carbamazepine Primidone Lamotrigine Valproate TopiramateOxcarbazepine ZonisamideLevitiracetam
  34. 34. Therapeutic Drug Monitoring for Newer AEDs• Not widely practiced• No generally accepted target ranges• A wide range is associated with clinical efficacy.• Considerable overlap in drug concentrations related to toxicity and non response.
  35. 35. Tentative Target Concentration Ranges Medication Range Felbamate 40-100 mic g/ml Gabapentin >2 mic g/ml Lamotrigine 1-4 mic g/ml Levetiracetam 35-120 mic m/L Oxcarbazepine 4-12 mic g/ ml Tiagabine 50-250 nmol/L Topiramate 2-4 mic g/ml Vigabatrin 6-278 mic m/L Zonisamide 10-30 mic g/ml
  36. 36. AAN Evidence Based Guidelines Level A or B Recommendations Newly Diagnosed Epilepsy Medication Monotherapy for newly Newly diagnosed absence diagnosed partial/mixedFelbamateGabapentin Yes NoLamotrigine Yes YesLevetiracetam No NoOxcarbazepine Yes NoTiagabine No NoTopiramate Yes NoVigabatrinZonisamide No No
  37. 37. AAN Evidence Based Guidelines Level A or B Recommendations Refractory EpilepsyMedication Partial Partial Primary Symptomatic Peds Add on/adult Monotherapy Generalized Generalized PartialFelbamateGabapentin Yes No No No YesLamotrigine Yes Yes No Yes YesLevetiracetam Yes No No No NoOxcarbazepine Yes Yes No No YesTiagabine Yes No No No NoTopiramate Yes Yes Yes Yes YesVigabatrinZonisamide Yes No No No No
  38. 38. Conclusions New AED’s are not more effective than classical ones Classical AEDs remain first line of treatment Pharmacokinetics and dynamics are more determinent than efficacy.