1. Neuromodulation for Epilepsy

2. Vagus nerve stimulation

3. 3

4.  MRI/diathermy safety recommendations  Head or extremity scan only; coil = transmit/receive  Set output + magnet to zero mA before scan  No MRIs on patients with lead breaks  No diathermy (shortwave, microwave, ultrasound) on VNS patients 4 Physician’s Manual. Houston, TX: Cyberonics, Inc.

5. Vagus nerve stimulation

8. 8

9. 9 Krahl S, et al. Epilepsia. 1998;39:709-714.

10. 11 partial epilepsy patients received VNS Upon initial VNS activation, each had 015- H20-PET cerebral blood flow scans Increased thalamic blood flow bilaterally upon initial VNS activation correlated with subsequent decreased seizures during 3 months of treatment (p<0.01) (Henry et al. 1999)

11. 108.9 ms 169.6 ms VNS OFF VNS ON VNS activation prolongs transcranial magnetic stimulation cortical silent period Dean et al. 2001

12. Vagus nerve stimulation

13. Handforth A, et al. Neurology. 1998;51:48-55 P=0.04 0 10 20 30 Mean Decrease in Seizure Frequency Versus Baseline Low (n=102) High (n=94) Reduction (%) 15% 28%

14. 0 10 20 30 40 50 Last Visit Carried Forward (n=440) 3 months1 year2 years3 years Morris et al., Neurology. 1999;53:1731-1735. Patients with >50% Reduction in Seizures Patients (%) 23.0% 42.7% 43.2% 36.8%

15. 15 * Last visit carried forward (LVCF) † Simple partial seizures, complex partial seizures, and secondarily generalized tonic clonic seizures Uthman BM, et al. Neurology. 2004;63:1124-1126. -22% -26% -28% -25% -30% -42% -49% -52% -55 -50 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 6 Months (n=47) 1 Year (n=47) 2 Years (n=38) 3 Years (n=35) 5 Years (n=30) 7 Years (n=17) 10 Years (n=17) 12 Years (n=12) Time Mean % Change in Seizure Frequency*

16. Vagus nerve stimulation

17. 0 10 20 30 40 50 60 70 HoarsenessCoughParesthesiaDyspnea * 3-month results (high stimulation only, n=152). Physician’s Manual, VNS Therapy Pulse Model 102 Generator, Cyberonics, Inc.; June 2002. † Year 1, 2, and 3 results (all study patients, n=440). Morris GL III, Mueller WM. Neurology. 1999;53:1731-1735. Patients (%) Month 3 * Year 1 † Year 2 † Year 3 †

18.  84 implants, patients < 19 years old  3 infections requiring explant  3 superficial infections which resolved with antibiotics  2 revision surgeries due to lead fractures (Smyth et al., 2003)

19.  VNS SUDEP rate=4.1/1000 patient years  Resective surgery candidates SUDEP rate=9.3/1000 patient years (Annegers et al., 2000; Dasheiff et al., 1986)

20.  8 cases of asystole during intraoperative lead test  2 completed surgery, 6 surgery stopped  No morbidity or mortality  All with lead test current 1.0 mA  Now 103 and 104 lead test current is 0.25 mA; no recurrence ( Ali et al., 2004; Tatum et al., 1999; Asconape et al.,1999)

21.  PSGs on 4 VNS patients (1 with OSA)  More apnea and hypopnea during “on” phase of duty cycle  1 OSA patient, VNS increased AHI from 4 to 11.3/hour  3 non-OSA patients, all AHI < 5/hour  No apnea/hypopnea with VNS at 20 Hz

22. Vagus nerve stimulation

24. Patient categoryVNSCase-matched control Total number of patients21 AED dose reduced10 (48%)2 (10%) AED number reduced9 (43%)0 (0%) Failed additional AED4 (19%)12 (57%) Mean follow-up=13.2 months (Tatum et al., 2001)

25. Vagus nerve stimulation

26. Programmable functions [initial]

27. Duty cycle change, 3 mo vs. 12 mo Number of patients Median % change szs @ 3 months Median % change szs @ 12 months Off > 3.0 min/Off > 3.0 min 174-45%-63% Off > 3.0 min/Off 3.0 min/Off < 1.8 min71-40%-50% Off < 1.8 min/Off < 1.8 min 21-67%-80%

28. Treatment ATreatment BTreatment C On/Off time7 sec/18 sec30 sec/30 sec30 sec/3 min # Patients19 23 Mean current, mA 0.870.800.93 50% responder rate 31.6%31.7%26.1%

29. Seizure changesImprovedNot Improved Treatment group 52.5% of seizures47.5% of seizures Control group 40.7% of seizures59.3% of seizures (Morris 2003)

30. Vagus nerve stimulation

31.  Epi. duration  Age  Epi. onset age  Prior epi. surgery  # prior AEDs  Concomitant AEDs  Epi. syndrome  Gender  Seizure rate  # current AEDs  # seizure types Labar 2002

32. 32 Reduction in Seizure Frequency, % Renfroe JB and Wheless JW. Neurology. 2002;59(suppl 4):S26-S30. % of Patients * † *P=.001 ; † P<.001  50  75  90 100 EA (n = 120) Control (n = 2785) 0 10 20 30 40 50 60 51% 50% 35% 28% 26% 14% 15% 4%

33. Figure 1. Vagus nerve stimulation (VNS) efficacy in the mature adult. Sirven J et al. Neurology 2000;54:1179-1182 45 patients > 50 years of age A=3 months, all patients B=12 months, study patients ©2000 by Lippincott Williams & Wilkins

34. Should I recommend VNS? Yes-for patients with…

35. Should I recommend VNS? Yes-for patients with…

36. Should I recommend VNS? No-for patients with…

37. How do I manage VNS settings? No specific stimulation is superior

38. How do I manage VNS settings? No specific stimulation is superior

39. Video: A vagus nerve stimulator patient’s experiences

40. Neuromodulation for Epilepsy

42.  Transcutaneous VNS for 1 hour three times per day  5/7 patients had less seizures in months 7-9 compared with baseline  2/7 patients had more seizures in months 7-9 compared with baseline

43. Epilepsia Volume 47, Issue 7, pages 1213-1215, 19 JUL 2006 DOI: 10.1111/j.1528-1167.2006.00594.x http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2006.00594.x/full#f1 Volume 47, Issue 7, http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2006.00594.x/full#f1

44. ©2009 American Academy of Neurology. Published by LWW_American Academy of Neurology.2 Figure TRIGEMINAL NERVE STIMULATION FOR EPILEPSY: LONG-TERM FEASIBILITY AND EFFICACY. DeGiorgio, Christopher; Murray, Diana; Markovic, Daniela; Whitehurst, Todd Neurology. 72(10):936-938, March 10, 2009. DOI: 10.1212/01.wnl.0000344181.97126.b4 Figure Adjusted mean daily seizure rate across timeBars indicate standard error = 0.64.

45. Responsive Neurostimulator (Morell 2011)(Neuropace)

47. Deep Brain Stimulation for Epilepsy (Fisher et al., 2010)(Medtronic)

48. 48 Includes subjects with at least 70 days of diary in each 3-month period (ie, Mo 1-4, Mo 4-7, Mo 7-10, and Mo 10-13)(Fisher et al., 2010)

49. Thanks for your attention.