The Treatment of Epilepsy: A Modern-Day Approach

1. The Treatment of Epilepsy: A Modern-Day Approach Jeffrey M. Politsky, MD, FRCP(C) NORHEAST REGIONAL EPILEPSY GROUP

2. Objectives • Develop a basic understanding of the approach to treatment of epilepsy • Understand the different treatment approaches to the different type of epilepsies

3. Goals of Epilepsy Therapy • Long-term seizure control • Long-term quality-of-life benefits • Safety • Assured compliance • No interactions with other medications • No side-effects or complications • There is no single treatment modality that guarantees all of these goals

4. Epilepsy Treatments • Pharmacologic Therapy • Antiepileptic drugs (AEDs) • Non-pharmacologic Therapy • Diet • Marijuana • Others • Surgical Therapy • Epilepsy surgery

5. Wide range of anti-seizure drugs to choose from Can change medications fairly easily Adjunctive (polypharmacy) often used Current AEDs have been thoroughly researched Prescribed for neonates, children, adults, & elderly Pharmacologic Treatment

6. AEDs • Usually first-line treatment • Pseudo-rational approach – first choice IS relevant • Anti-seizure drugs can be tailored for type of seizure disorder & in consideration of patient • Controls seizures in two thirds of people with epilepsy • With or without side effects • 1/3 of people with epilepsy have Drug-Resistant “Intractable” Epilepsy

7. Pharmacologic Treatment • Factors in choosing Treatment • Diagnosis • Syndrome v.s. Localization • Cost • Patient Profile • Wishes, co-morbidity, profession, resources • Drug Profile • Mechanism of action, side effects, quantitation • FDA Approval

8. New AED’s Fewer serious adverse effects i.e. many are better tolerated Class C Teratogencity in animals* Rash +/- SJS HA Sedation Visual blurring/Blindness Irritability Cognitive Disturbance glaucoma Kidney stones SIADH Hematologic d/o Hepatotoxicity, Anemia, MOF Old AED’s Sedation Hair Loss Weight gain Tremor Ginigival hyperplasia, hirsutism Hepatic Necrosis +/- MOF Hematologic d/o Rash +/- SJS, TEN SIADH Osteoporosis Known teratogenicity Cortical & Cerebellar Atrophy Cognitive Dysfunction Ataxia Pharmacologic Treatment

9. AED’s: Pharmacology

10. AED’s: Pharmacology

11. Monotherapy Partial Epilepsy Lamotrigine Topiramate Oxcarbazepine Eslicarbazepine Parampanel Lacosamide Generalized Epilepsy Lamotrigine Topiramate Adjunctive Therapy Partial Epilepsy Zonisamide Leviteracetam Gabapentin Pregabalin Generalized Epilepsy Leviteracetam Zonisamide Parampanel AED Indications

12. What Is Treatment-resistant Epilepsy? • Seizures that continue even on AEDs • Frequency • Severity • Duration • Adverse effects • Persistence of seizures despite at least 2 anti-seizure drugs that work by different mechanisms and have achieved therapeutic levels • Applies to ~1/3 of all newly treated patients • Very negative impact on quality of life

13. n % Seizure-free on first monotherapy 222 47 Seizure-free on second monotherapy 61 13 Seizure-free on third monotherapy 6 1 Seizure-free on two drugs 12 3 Total seizure-free 301 64 Intractable Epilepsy N Engl J Med 2001 Aug 2;345(5):311-8

14. Intractable Epilepsy • Response to AEDs -- % Seizure-free • First Drug 47% • Seizure free on monotherapy (44%) • Seizure free after AED withdrawal (3%) • Response to Second Drug 13% • Seizure free on monotherapy ( 9%) • Seizure free after AED withdrawal ( 4%) • Response to Third or Multiple Drugs 4% • Seizure free on monotherapy ( 1%) • Seizure free on two drugs (3%) *Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.

15. Intractable Epilepsy Seizure free with first drug Seizure free with second drug Seizure free with third ormultiple drugs Treatment-resistant epilepsy 47% 36% 4% 13% *Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.

16. Intractable Epilepsy • % Pts Seizure Free • Idiopathic Generalized Epilepsy 74% • Symptomatic or Cryptogenic Epilepsy 60% *Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.

17. Intractable Epilepsy • % Seizure-free (7 year follow-up of 2200 pts) • Idiopathic Generalized Epilepsy 82% • Symptomatic Partial Epilepsy 35% • Cryptogenic Partial Epilepsy 45% Seemah, 1998

18. Intractable Epilepsy • % of Seizure-free Pts with Partial Epilepsy • Temporal Lobe Epilepsy 20% • Extra-temporal Epilepsy 36% • Partial Epilepsy with MTS 11% • Partial Epilepsy with cerebral dysgenesis 24% • Partial Epilepsy with dual pathology 3% Seemah, 1998

19. Intractable Epilepsy • Reasons for evaluation and intervention: • Cognitive/memory deficits that may be associated with drug therapy • Adverse effects with long-term drug therapy • Risk of Injury • Higher depression rates • Other co-morbid conditions • Reduced lifetime income • Burden on healthcare system • Complete Lack of Response, despite AED polypharmacy

20. Intractable Epilepsy: Mortality • Underlying causes of epilepsy • Sudden unexpected death in epilepsy (SUDEP) 1,2 • (1/200 in pts with chronic epilepsy • Status epilepticus • Potential for accidental death 1Lhatoo SD, Langan Y, Sander JWAS. Postgrad Med J. 1999;75:706-709. 2Annegers JF et al. Epilepsia. 1998;39:206-212.

21. Alternative Therapeutic Options • Should be considered early • After 2 to 3 drug “failures” • When there are severe side effects • Early identification of patient enhances seizure control and quality of life • Other options include • Ketogenic Diet • Epilepsy Surgery

22. Epilepsy Treatments • Pharmacologic Therapy • Antiepileptic drugs (AEDs) • Non-pharmacologic Therapy • Diet • THC • Others • Surgical Therapy • Epilepsy surgery

23. Ketogenic Diet • Most effective in children • Not typically used in adults • High ratio of fat to protein/carbohydrate • Appears to be effective for most seizure types • More than half of patients experience 50% seizure reduction at 6 months • One out of ten have seizure freedom at 1 year • A 47% continuation rate at 1 year Vining EP et al. Arch Neurol. 1998;55:1433-1437.

24. Possible Adverse Effects Constipation & vomiting Lethargy Kidney stones Excess acid accumulation Severe dehydration Behavioral changes Increased risk of infections Other Disadvantages Initiation of diet usually requires hospitalization Food must be carefully weighted and measured Poor compliance rate Ketogenic Diet

25. Epilepsy Treatments • Pharmacologic Therapy • Antiepileptic drugs (AEDs) • Non-pharmacologic Therapy • Ketogenic diet • Surgical Therapy • Epilepsy surgery

26. Epilepsy Surgery • Minimally Invasive Surgery • Vagus Nerve Stimulation (VNS TherapyTM) • Moderately Invasive Surgery • Investigational Devices: Neuropace Responsive Neurostimulator (RNSTM); Medtronic Deep Brain Stimulator (DBSTM) • Maximally Invasive Surgery • Cortical Resection • Hemispherectomy/Hemispherotomy • Corpus Callosotomy

27. VNS • Available for patients > 12 years • Adjunctive therapy for partial sz • Device similar to a pacemaker • 1 hour procedure: • chest/axillary border incision for generator • Neck incision for lead • Small electrical pulses to brain via Left vagus nerve

28. Vagal Nerve Stimulator • Advantages • Shown to reduce seizure frequency in a randomized controlled trial (Neurology. 1998 Jul;51:48-55) • No medication-related side effects • Patient compliance much better than medications; the device is automatic • Reduction in medication dose and number of medications may be possible • Implantation is a minor medical procedure • Device programming requires only a laptop computer • Patients may turn the device on or off using a hand-held magnet

29. Vagal Nerve Stimulator • Disadvantages • Device produced only a modest 28% reduction in seizure frequency compared to the 15% reduction in the active control group (Neurology. 1998 Jul;51(1):48-55) • Device produced a median 45% reduction in seizure frequency in a longer 1 year uncontrolled study (Epilepsia. 2000 Sep;41(9):1195-200). • Most patients require continued pharmacotherapy • Patients rarely become seizure free • Battery changes require repeat surgeries

30. Vagal Nerve Stimulator Patients With 50% Seizure Frequency Reduction Patients (%) Morris GL, et al. Neurology. 1999;53:1731-1735.

31. Vagal Nerve Stimulator • Does not produce… • Depression • Confusion • Weight change • Memory loss • Fatigue • Cognitive slowing • Language dysfunction

32. Vagal Nerve Stimulator • Side effects include… • Hoarseness or dysphonia (usually temporary when device triggered) • Cough • ‘scratchy’ throat • dyspnea

33. Epilepsy Surgery • Minimally Invasive Surgery • Vagus Nerve Stimulation Therapy (VNS TherapyTM) • Moderately Invasive Surgery • Investigational Devices: Neuropace Responsive Neurostimulator (RNSTM); Medtronic Deep Brain Stimulator (DBSTM) • Maximally Invasive Surgery • Cortical Resection • Corpus Callosotomy • Hemispherotomy

34. Neuropace Responsive Neurostimulator • Implantable components include the RNS plus depth and cortical strip leads • External components include a laptop computer with (proprietary) software with a wand and telemetry interface to communicate with RNS

35. Epilepsy Surgery • Minimally Invasive Surgery • Vagus Nerve Stimulation Therapy (VNS TherapyTM) • Moderately Invasive Surgery • Investigational Devices: Neuropace Responsive Neurostimulator (RNSTM); Medtronic Deep Brain Stimulator (DBSTM) • Maximally Invasive Surgery • Cortical Resection • Corpus Callosotomy • Hemispherotomy

36. Comprehensive Epilepsy Program • Epileptic focus refers to area responsible generating epileptiform discharges • Epileptogenic zone refers to the area to which epileptiform activity is conducted • Eventually, may be able to generate epileptiform discharges independently

37. Comprehensive Epilepsy Program • Epilepsy Surgery • Approximately 1/3 to ½ of intractable epilepsy surgery patients are good surgical candidates • Various pathologic circumstances can result in seizures: • brain tumors • vascular malformation • Hemorrhages • Strokes • Abscesses • Trauma (bullet and missile-type wounds, blunt trauma) • Scarring/Gliosis (mesial temporal sclerosis, previous stroke or surgery or hemorrhage, for e.g) • Abnormally formed brain tissue (cerebral dysgenesis)

38. Epilepsy Surgery Procedures Anterior Temporal Resections ExtraTemporal Resections Callosotomies Hemispherectomies Vagal Nerve Stimulation Depth Electrodes Subdural Electrodes

40. Epilepsy Surgery Temporal lobectomy • About 1/3 of people with treatment-resistant epilepsy are candidates for brain surgery • ~70% of people seizure free 2 years after surgery, following withdrawal of AEDs • Extratemporal resections • Similar statistics • Non-lesional cases • Results not as promising

41. Benefits of Epilepsy Surgery • Success rates can be predicted after test results are available • Following epilepsy surgery, those who are seizure free for > 1 year post-surgery have an excellent prognosis for remaining free of recurrent seizures • Serious complications occur in about 3-4 out of 100 temporal lobectomies • About 2/3 will remain seizure free after a 3 year interval following epilepsy surgery (J epilepsy 1991;4:39-42).

42. Benefits of Epilepsy Surgery • Randomized controlled trial of 80 temporal lobe epilepsy patients (N Engl J Med 2001 Aug 2;345(5):311-8) • Medical therapy: 8% seizure free • Surgical therapy: 58% seizure free • Quality of life significantly better for surgically treated patients (p<0.001) Van Ness PC. Arch Neurol. 2002;59:732-735. Engel J JR. Surgery for seizures. N Engl J Med. 1996;334:647-652 Wiebe S et al. N Engl J Med. 2001;345:311-318.

43. Anterior Temporal Lobectomy (Hippocampal Atrophy)

44. Anterior Temporal Lesional

45. ExtraTemporal Lesional

46. ExtraTemporal NonLesional

47. Depth Electrodes

48. Subdural Electrodes

49. Age ChildrenAdults Primarily children Children Adults 12 and older Indication Specific AEDs for specific seizure types All seizure types Pharmacoresistant or localization-related epilepsy Pharmacoresistant epilepsy, partial seizures Efficacy 64% sz freedom1 54% pts >50% sz reduction at 3 months2 70% sz free TLE surgery3 43% of pts >50% sz reduction at 3 years4 Side Effects Vary by AED Lipid disorders, ketoacidosis, Cognitive effects, surgery-related risks Voice alteration, cough, pharyngitis, dyspnea Epilepsy Treatments Treatment AEDs Ketogenic Diet Epilepsy Surgery VNS Therapy 1Brodie MJ, Kwan P. Neurology. 2002;58(suppl 5):S2-S8. 2Vining EP, et al. Arch Neurol. 1998;55:1433-1437. 3Van Ness PC. Arch Neurol. 2002;59:732-735. 4Morris GL III, Mueller WM. Neurology. 1999;53:1731-1735. 5Renfroe JB, Wheless JW. Neurology. 2002;59(suppl 4):S26-S30.

50. Summary - Objectives • Understand terminology specific to seizures & epilepsy • Distinguish partial onset from generalized seizures • Simple v. Complex • Secondarily v. Primary • Differentiate clinical from syndromic epilepsies • Appreciate variability of seizure disorders wrt clinical appearance and cause • Understand the diagnostic approach to seizure disorders • not all seizures represent epilepsy; not all spells are seizures • Develop a basic understanding of the approach to treatment of epilepsy