2. Epilepsy Yitzhak Schiller MD PhD Dept of Neurology Rambam Medical Center

3. Lecture plan Definitions and pathophysiology Definitions and pathophysiology Epidemiology Epidemiology Classification Classification Seizure type Seizure type Treatment Treatment

4. Definitions and pathophysiology

5. Definitions Epileptic seizure Epileptic seizure Epilepsy Epilepsy

6. Epileptic seizure Clinical symptoms caused by increased electrical activity cortical neurons Clinical symptoms caused by increased electrical activity cortical neurons Epileptic seizures may be caused by intrinsic or extrinsic factors/causes Epileptic seizures may be caused by intrinsic or extrinsic factors/causes

7. Epilepsy-definition Recurrent unprovoked seizures Recurrent unprovoked seizures At least two seizures (with a minimal time- delay of 24 hours) At least two seizures (with a minimal time- delay of 24 hours) Without an external reversible cause Without an external reversible cause Seizures caused by an external reversible cause-Acute symptomatic seizures Seizures caused by an external reversible cause-Acute symptomatic seizures

8. Pathophysiology Increased electrical activity in individual neurons Increased electrical activity in individual neurons Synchronized activity between different neurons Synchronized activity between different neurons

9. Pathophysiological mechanisms for the development of epilepsy Hyper-excitabile neurons due to mutations in voltage- and ligand-gated channels – channelopathies Hyper-excitabile neurons due to mutations in voltage- and ligand-gated channels – channelopathies Decreased inhibition Decreased inhibition Alteration of the network-increased connections between neurons due to post-damage axonal sprouting Alteration of the network-increased connections between neurons due to post-damage axonal sprouting

10. Epidemiology Epileptic seizure Epileptic seizure Epilepsy Epilepsy

11. Epidemiology-Seizures Incidence80/100,000 Incidence80/100,000 Life time prevalence7 % (3 % F.C.) Life time prevalence7 % (3 % F.C.)

12. Prevalence of epilepsy

13. Incidence of epilepsy

14. Classification: Type of epilepsy Generalized Generalized Partial-focal Partial-focal

15. Classification: Cause of epilepsy Idiopathic Idiopathic Genetic factors Genetic factors chennelopathies chennelopathies Sympthomatic Sympthomatic CVA CVA Tumors Tumors Post traumatic Post traumatic Cryptogenic-remote symptomatic Cryptogenic-remote symptomatic

16. Types of seizures-Generalized epilepsy Generalized tonic clonic seizure Generalized tonic clonic seizure Absence seizure Absence seizure Myoclonic jerk Myoclonic jerk Tonic seizure Tonic seizure Clonic seizure Clonic seizure Atonic seizure Atonic seizure Most patients suffer from several seizure type

19. Types of seizures-Partial epilepsy Partial simple seizure Partial simple seizure Partial complex seizure Partial complex seizure Secondary generalized tonic-clonic seizure Secondary generalized tonic-clonic seizure

24. DD-Loss of consciousness with/without involuntary movements Rare etiologies Rare etiologies Migraine Migraine TIA TIA Sleep disorders Sleep disorders Genetic-metabolic disorders Genetic-metabolic disorders Epileptic seizure Cardio vascular Vaso-vagal syncope Arrhythmia Postural hypotension Psychogenic

25. Findings supporting epileptic seizures Trauma Trauma Tongue biting Tongue biting Loss of urine Loss of urine Events initiating in sleep Events initiating in sleep

26. Other presenting forms/syndromes of epilepsy Confusion and loss of awareness- starring Involuntary movements

27. Exams EEG EEG Inter ictal Inter ictal Ictal Ictal Imaging Imaging

28. EEG

29. Inter ictal EEG

31. Video-EEG monitoring

32. Ictal EEG

33. Treatment of epilepsy

34. ?Should we treat After a single seizure-not necessarily After a single seizure-not necessarily After two or more seizure-treat After two or more seizure-treat

35. How to treat First line-antiepileptic drugs. First line-antiepileptic drugs. Antiepileptic drugs are in fact anti-seizure drugs as they prevent seizures but do not treat the underline pathology Antiepileptic drugs are in fact anti-seizure drugs as they prevent seizures but do not treat the underline pathology Rarely treatment is provided to treat the underlying pathology Rarely treatment is provided to treat the underlying pathology

36. Antiepileptic drugs More than 16 available drugs More than 16 available drugs Can be divided according to: Can be divided according to: Prevention Vs aborting of prolonged seizures Prevention Vs aborting of prolonged seizures Old Vs new Old Vs new General pharmacological mechanisms General pharmacological mechanisms

37. Old antiepileptic drugs barbiturate barbiturate Hydantoin Hydantoin Carbamazepine Carbamazepine Valproic acid Valproic acid Benzodiazepins Benzodiazepins Ethosuxamide Ethosuxamide

38. New antiepileptic drugs Zonisamide (Zonigran) Zonisamide (Zonigran) (Lyrica) pregabalin (Lyrica) pregabalin Tiagabin Tiagabin Felbamate Felbamate Vigabatrin (Sabrilan) Lamotrigine (lamictal) Gabapentin (Neurontin) Oxcarbazepine (Trileptin) Topiramate (Topamax) Levetiracetam (Keppra)

39. Antiepileptic drugs- Pharmacological mechanisms Modification of voltage-gated sodium channels Modification of voltage-gated sodium channels Lamotrigine, Hydantoin Lamotrigine, Carbamazepine, Hydantoin Enhanced GABA neurotransmission Enhanced GABA neurotransmission Barbiturates, Benzodiazepines, Vigabatrin Barbiturates, Benzodiazepines, Vigabatrin Modification of voltage-gated calcium channels Modification of voltage-gated calcium channels Blockade of AMPA receptors Blockade of AMPA receptors Unknown Unknown

40. How to choose an antiepileptic drug Efficacy Efficacy Adverse events Adverse events Ease of use Ease of use Price Price

41. General principles Partial epilepsy: Carbamazepine, Lamotrigine, Topiramate, Levetiracetam Partial epilepsy: Carbamazepine, Lamotrigine, Topiramate, Levetiracetam General epilepsy: Valproic acid, Lamotrigine, Topiramate General epilepsy: Valproic acid, Lamotrigine, Topiramate Old drugs before new ? Old drugs before new ? Monotherapy when possible Monotherapy when possible Drugs available IV Valproic acid, phenytoin Drugs available IV Valproic acid, phenytoin

42. Special considerations-adverse events Women- teratogenicity Women- teratogenicity Children Children Elderly population Elderly population Patients with systemic diseases Patients with systemic diseases

43. Status epilepticus Convulsive Convulsive 30 minutes of continuous seizure or recurrent seizure without regaining consciousness Non convulsive Non convulsive Focal motor Focal motor

44. Convulsive status epilepticus Medical emergency Medical emergency IV Lorazepam or Diazepm IV Lorazepam or Diazepm IV Phenytoin or Fos Phenytoin IV Phenytoin or Fos Phenytoin IV Valproic acid IV Valproic acid IV Phenobarbital IV Phenobarbital Continuous IV administration of Midazolam Continuous IV administration of Midazolam Continuous IV administration of Propafol Continuous IV administration of Propafol Continuous IV administration of Pentotal- Pentotal coma Continuous IV administration of Pentotal- Pentotal coma

45. Discontinuation of treatment Approximately 50% of patients are cured with time Approximately 50% of patients are cured with time After 2 years of treatment AED treatment can be discontinued After 2 years of treatment AED treatment can be discontinued Under optimal conditions 1/3 of patients suffer from seizure recurrence after AED discontinuation Under optimal conditions 1/3 of patients suffer from seizure recurrence after AED discontinuation

46. Prognosis of epilepsy Fully controlled on first AED Fully controlled on AED combination Intractable Drug-resistant

47. Pharmaco-resistant epilepsy Uncontrolled seizures despite appropriate antiepileptic drug treatment Uncontrolled seizures despite appropriate antiepileptic drug treatment 30% of all patients with epilepsy 30% of all patients with epilepsy The chance of fuly controling seizures with additional medications is low The chance of fuly controling seizures with additional medications is low

48. Non pharmacological treatment for pharmaco-resistant epilepsy Epilepsy surgery Epilepsy surgery Ketogenic diet Ketogenic diet Vagal nerve stimulation Vagal nerve stimulation

49. Epilepsy surgery Existence of a well defined epileptic zone Existence of a well defined epileptic zone The epileptogenic zone was reliably localized The epileptogenic zone was reliably localized The epileptogenic zone is located in a functionally “ quit ” area The epileptogenic zone is located in a functionally “ quit ” area

50. Anterior temporal lobectomy and amygdalo-hippocampectomy

51. :Surgical outcome Good correlation between imaging and video-EEG findings Seizure free Seizures none memory severe

53. גורמים לאפילפסיה סימפטומטית אוטמים מוחיים אוטמים מוחיים 5% פרכוסים מוקדמים, שכיח יותר בדימומים לוברים ( 15%) 5% פרכוסים מוקדמים, שכיח יותר בדימומים לוברים ( 15%) 10% מפתחים אפילפסיה לאחר מאורע מוחי. 10% מפתחים אפילפסיה לאחר מאורע מוחי. חבלת ראש חבלת ראש סיכוי לאפילפסיה עולה פי 17 לאחר חבלת ראש חמורה סיכוי לאפילפסיה עולה פי 17 לאחר חבלת ראש חמורה פציעה חודרת 50% פציעה חודרת 50% דימום סוב דורלי 20% דימום סוב דורלי 20%

54. Epileptic syndromes Juvenial myoclonic epilepsy Strong genetic factors Strong genetic factors Probably AD with partial penetrance Probably AD with partial penetrance Myoclonic jerks-post sleep Myoclonic jerks-post sleep GTC Sz. GTC Sz. Absence Sz. In a third of patients Absence Sz. In a third of patients Age of onset 12-18 years Age of onset 12-18 years Sensitive to precipitating factors to seizures Sensitive to precipitating factors to seizures Life time treatment is necessary Life time treatment is necessary

55. Epileptic syndromes Lennox Gastuat Age of onset 1-8 (3-5) years Age of onset 1-8 (3-5) years Generalized seizures-multiple subtypes Generalized seizures-multiple subtypes EEG Slow spike & SW EEG Slow spike & SW Cognitive impairment Cognitive impairment

56. Epileptic syndromes-Absence epilepsy Childhood absence epilepsy Childhood absence epilepsy Multifactorial genetic (10 % in siblings) Multifactorial genetic (10 % in siblings) Age of onset 4-8 years Age of onset 4-8 years 40 % of patients with GTC Sz. 40 % of patients with GTC Sz. Myoclonic jerks ar infrequent Myoclonic jerks ar infrequent Almost all patients are cured with age Almost all patients are cured with age Juvenial absence epilepsy Juvenial absence epilepsy Age of onset 7-17 Age of onset 7-17 Genetic factors Genetic factors Less frequent absence seizures than in CAE Less frequent absence seizures than in CAE 80 % of patients with GTC Sz. 80 % of patients with GTC Sz. 15 % with myoclonic jerks 15 % with myoclonic jerks Many are cured but the prognosis is worst than CAE Many are cured but the prognosis is worst than CAE

57. Epileptic syndromes Benign focal epilepsy of childhood Benign centro-temporal epilepsy of childhood Benign centro-temporal epilepsy of childhood 25 % of epilepsy at ages of 5-14 years 25 % of epilepsy at ages of 5-14 years Focal seizures facial-mouth movements/jerks, speech arrest, hyper-salivation. Jerks in arm or arm+leg is less frequent Focal seizures facial-mouth movements/jerks, speech arrest, hyper-salivation. Jerks in arm or arm+leg is less frequent Secondary GTC seizures Secondary GTC seizures Typical EEG findings Typical EEG findings Usually spontaneously cure Usually spontaneously cure

58. Epileptic syndromes - West syndrome Infantile spasm Infantile spasm Other seizures may also occur especially generalized and focal convulsions Other seizures may also occur especially generalized and focal convulsions Hyps-arrhythmia on EEG Hyps-arrhythmia on EEG May be associated with a developmental delay May be associated with a developmental delay May be accompanied by focal neurological deficits May be accompanied by focal neurological deficits Age of onset 0-2 years. Age of onset 0-2 years. IS usually disappear up 5 years IS usually disappear up 5 years 60 % symptomatic 60 % symptomatic Prognosis 60 % continue to suffer from epilepsy, and 70 % develop MR. Prognosis 60 % continue to suffer from epilepsy, and 70 % develop MR.

59. Epileptic syndromes Reflex epilepsy Visual trigger most common-photosensitive epilepsy Visual trigger most common-photosensitive epilepsy Generalized Generalized Partial-occipital Partial-occipital TV TV Video games Video games computer computer