1. Epilepsy Overview for 3rd year medical students SAID S. DAHBOUR,MD Associate professor of Medicine and Neurology Faculty of Medicine – Jordan University Amman - Jordan

2. Outline General Aspects New AED Epilepsy Surgery Drugs used for Status Epilepticus Conclusions

3. Seizures and Epilepsy Seizure: abnormal hypersynchronous electrical discharge form cerebral cortical neurons. Clinical seizure: the clinical manifestation of the electric seizure that depends on the site of onste and path of propagation Epilepsy =Recurrent Unprovoked Seizures

5. International classification of epileptic seizures NEJM 2002:344(15)1145-51 Partial (focal, local) seizures simple complex evolving to generalized seizures Generalized seizures absence : typicalatypical tonic clonic (grand mal) myoclonic clonic tonic atonic Unclassified neonatal infantile spasm febrile seizures

6. Modified ILAE classification of epilepsy syndromes Idiopathic : no cause identified; presumed genetic- inherited Localization relatedGeneralized BECTS Benign occipital epilepsy AD nocturnal frontal lobe epilepsy Benign familial neonatal epilepsy Benign myoclonic epilepsy of infancy Childhood absence Juvenile absence JME Epilepsy with GTC upon awakening

7. Modified ILAE classification of epilepsy syndromes Symptomatic: of underlying structural disease Localization- related generalized Temporal lobe Frontal lobe Parietal lobe Occipital lobe Early myoclonic encephalopahty Early infantile epileptic ncephalopathy with suppression- burst Cortical malformation Metabolic abnormalities West syndrome ( with pathology) LGS (with pathology)

8. Modified ILAE classification of epilepsy syndromes Cryptogenic: presumed underlying structural disease Localization-relatedGeneralized Any occurrence of partial seizures without obvious pathology (eg, MRI negative) Epilepsy with myoclonic astatic seizures Epilepsy with myoclonic absence West syndrome (unidentified pathology) LGS (unidentified pathology)

9. Modified ILAE classification of epilepsy syndromes Special syndromes or undetermined epilepsies Febrile convulsions Isolated unprovoked seizures or isolated status epilepticus Neonatal seizures of any etiology Epilepsy with continuous spike-wave during slow wave sleep (electric status epilepticus of sleep) Acquired epileptic aphasia (Landau-Kliffner syndrome)

10. a Rochester Minnesota Epilepsy Study (1935-1974)

11. Epilepsy: Diagnosis History Physical examination EEG MRI Special testing

12. RIGHT ANTERIOR TEMPORAL SHARPS.

13. INTERICTAL GENERALIZED 3 HTZ SPIKE-WAVE DISCHARGE

14. GENERALIZED SEIZURE

15. Differential diagnosis of seizures in adults Vasovagal syncope Cardiogenic syncope Migraine TIA Psychogenic pseudosizures Panic attacks Rage attacks

16. Differential diagnosis of seizures in children Tics Infantile syncope Breath holding spells Night terrors Gastroesophegeal reflux Shudder attacks Benign sleep myoclonus

17. DIFFERENCES BETWEEN SYNCOPE AND SEIZURES

18. DIFFERENCES BETWEEN SEIZURES AND PSEUDOSEIZRUES

20. ADVERSE PROGNOSTIC FACTORS IN EPILEPSY SYMPTOMATIC ETIOLOGY. PARTIAL ONSET SEIZURES. ATONIC SEIZURES. LATE ONSET OR FIRST YEAR EPILEPSY ADDITIONAL MENTAL OR MOTOR HANDICAP. LONG DURATION PRIOR TO THERAPY. POOR INITIAL RESPONSE TO THERAPY.

21. Intractable Epilepsy Impairment of quality of life due to Seizures &/ or Drugs 20-30% of epileptics are intractable Patients failing 2 drugs are likely to be intractable 30-40% newly diagnosed partial epilepsy will not attain a seizure remission with pharmacotherapy.

22. Intractable Epilepsy Treatment options New AED surgery Vagus nerve stimulation special diets in children

23. New Anti Epileptic Drugs

24. “There is scarcely a substance in the world,capable of passing through the gullet of man, that has not at one time or the other enjoyed a reputation of being an anti-epileptic “ Sieveking 1858

25. Potential benefits of AED related seizure control Reduced social stigma Reduced negative cognitive effects from frequent seizures. Reduced risk of status epilepticus ( if compliant) Reduced risk of physical injury Improve employment likelihood Helps maintain driving privileges

26. Risks of AED related adverse effects Behavioral problems Cognitive impairment Idiosyncratic reactions Systemic toxicity Teratogenicity Expense

27. Ideal Antiepileptic Drug Antiepileptogenic Complete Seizure Suppression Minimal Side Effects

28. FACTS: 50 % of patients fail to achieve the goal of treatment. (1985) NEJM 1/3 of patients treated 1984-1997 failed to become seizure free in the first year of treatment. (2000) NEJM

29. Possible Advantages of New AED More effective Better tolerated Safer Better for women Less interaction Broader spectrum

30. New AED Label Indications FelbamateMonotherapy and add-on partial and generalized SZ GabapentinAdd-on for partial SZ LamotrigineMonotherapy and add-on partial and generalized SZ OxacarbazineMonotherapy and add-on partial SZ TiagabineAdd-on partial SZ TopiramateAdd-on and monotherapy partial and generalized SZ LevetiracetamAdd-on partial SZ ZonisamideAdd-on partial SZ

31. New AED: common concern High cost Dose related toxicity Pharmacodynamic interactions Drug levels of limited use

32. New AED : how they compare Similar in : Responder rate  40% Seizure free rate < 10% Differ in : Adverse effects Pharmacokinetic profile Efficacy for seizure type(s)

33. AED: Future Development Actions at NMDA receptors Actions at AMPA receptors GABA B receptors and absence seizures GABA and Glutamate transporters Metabotropic glutamate receptors Seretonin Neurosteroids Genetic studies and the nicotinic acetylcholenergic system

34. Epilepsy Surgery

35. Surgical Candidates Medically refractory seizures Physically, socially disabled Localization-related epilepsy Low risk of morbidity Potential for rehabilitation

36. Response to AED in newly diagnosed epileptics. Kwan et al NEJM, 2000

37. Epilepsy Surgery: Types Medial temporal lobe epilepsy: MTS Most common Most successful Lesionectomy: Tumor Vascular anomaly Cortical malformation Hemispherectomy: Rausmusen’s encephalitis Corpus callosotomy: LGS Vagal nerve stimulation: intractable, not surgical candidates Multiple subpial transection: elequent areas

38. CONTRAINDICATIONS TO EPILEPSY SURGERY Absolute: Primary generalized epilepsy Minor seizures that do not impair quality of life Relative: Progressive medical or neurological disorders Behavioral problems that impair post op rehabilitation Serious medical disorder that may increase surgical mortality Poor memory function in the opposite hemisphere Active psychosis not related to peri-ictal period

39. Pre surgical evaluation Routine EEG Brain MRI (seizure protocol) Long term video EEG monitoring Visual perimetry Neuropsychometry Sodium amobarbital test

40. Epilepsy surgery : Risks Visual field loss < 10% (temporal lobectomy) Any surgical complication < 5% Death or serious complication <0.5% Memory or cognitive deterioration ( predictable) Aphasia 1% ( reversible) Psychosis or depression 5% ( treatable) Most serious adverse outcomes occur when surgery is unsuccessful controlling seizures

41. Temporal lobectomy efficacy Sperling et al, JAMA 1996: 276:470-75 % Long term (5 yr) operative outcome of 89 patients

42. Vagus nerve stimulation Indicated for patients with intractable epilepsy who are not surgical candidates

43. Status Epilepticus Continuous or recurrent seizures without recovery of consciousness for 30 minutes or more ( tendency now to use shorter time definition like 5 minutes and more.

44. AED in Status Epilepticus DrugLoading dose Maintenance dose Adverse effect Diazepam10-20 mgNoneRespiratory depression Hypotension Sialorrhea Lorazepam4 mgNoneAs above Phenytoin20mg/kg5mg/kg/dayCardiac depression Hypotension Phosphenytoin30mg/kgNoneHypotension Parasthesia

45. AED in Status Epilepticus DrugLoading dose Maintenance dose Adverse effect Phenobarbital20mg/kg1-4 mg/kg/hrRespiratory suppression Pentobarbital2-8mg/kg0.5-5 mg/kg/hrRespiratory suppression Hypotension Midazolam0.2 mg/kg0.75-10 micgm/kg//min Hypotension Respiratory suppression Propafol2 mg/ kg5-10 mg/kg/hr initial then 1-3 mg/kg/hr Respiratory depression Hypotension Lipemia Acidosis Valproic acid25-40mg/kg @ 3-5 mg/kg/min None or oral 500-2000 mg / day ? Hepatic encephalopathy ? Coagulopathy Safe in unstable patients

46. CONCLUSIONS: Epilepsy is still a challenge New AED improved our treatment Need for more understanding of basic mechanism of epilepsy and its genesis Need to develop specific and target specific treatment Surgery is quite effective in properly selected patients but quite underused Intravenous benzodiazepines, phenytoin, phenbarb and valproic acid are available, effective and safe Rx for status epilepticus

47. THANK YOU