Treatment of Epilepsy with Implanted Devices: What Are Indications and Benefits? 11/30/2012

Transcription

1 Treatment of Epilepsy with Implanted Devices: What Are Indications and Benefits? 11/30/2012 Barbara C. Jobst, MD Dartmouth-Hitchcock Epilepsy Center Geisel School of Medicine at Dartmouth American Epilepsy Society Annual Meeting 1

2 Disclosure Name of Commercial Interest Neuropace, Inc Pfizer, Inc Lundbeck Inc UCB, Inc NIH, CDC Type of Financial Relationship Research Support Fellowship Support Research / Advisory committee Research Support Research Support The use of unapproved devices will be discussed American Epilepsy Society Annual Meeting

3 Esther 30 yo woman with intractable seizures since age 15 History of treated Hodgkin disease after the onset of seizures Tried all available AEDs including progesterone osteoporosis: during a seizure fell down the stairs and acquired a C4 fracture, previously three clavicular fractures due to seizures 3

4 Esther seizure #1 4

5 Esther seizure #2 5

6 Esther seizure #3 6

7 Interictal EEG 7

8 MRI 8

9 Questions about Esther Is it a focal or generalized syndrome? When to go to a device? Which device? What are realistic expectations about a device? What is the role of a callosotomy versus a device? 9

10 Learning Objectives Know the indications for implanted devices for epilepsy Know about the efficiency of implanted devices such as the VNS, DBS and RNS Weigh the risks and benefits of devices in bilateral epilepsy syndromes Know about principles of stimulator programming Assess the benefits of VNS and callosotomy in generalized epilepsies Inform about future developments and plot a visionary path for the future American Epilepsy Society Annual Meeting

11 Algorithm Algorithm = a procedure for solving a problem or accomplishing some end especially in a finite number of steps (Merriam- Webster dictionary) 11

12 Epilepsy surgery Efficacy Medical treatment Epilepsy surgery overall Frontal lobe surgery TLE retrospective 10 years TLE retrospective 3 years early TLE controlled TLE controlled 8.0% 66.0% 57.0% 56.0% 73.0% 58.0% 83.0% 0% 20% 40% 60% 80% 100% seizure free (Wiebe 2001, Engel 2012, Yoon 2003, Lazow 2012, Spencer 2005) 12

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14 Devices : Electrical Stimulation Amplitude Pulse width Frequency Intermittent Continuous Responsive 14

15 Vagus Nerve Stimulation (VNS) 7-60 seconds ON, Up to 180 min OFF 0.25mA-3.5mA 1 Hz-30 Hz pulse width µs Typical settings: 30 sec ON, 5 min OFF ma, 20 Hz, 250 µsec, Rapid cycling 21 sec on, 1.8 min off Battery life 5-10 years Magnet for extra stimulus, usually at higher current 15

16 Device versus another medication? (double blind evidence) Efficacy Tolerability VNS EO5 1.0% 27.9% VNS EO5 1.0% VNS EO3 0.0% 25.4% VNS EO3 1.7% eslicarbazepine 8.0% 32.6% eslicarbazepine 18.8% ezogabine 2.0% 44.3% ezogabine 26.8% lacosamide 2.0% 39.0% lacosamide 17.0% levetiracetam 6.0% 37.1% levitiracetam 6.1% median sz reduction 0% 20% 40% 60% 80% seizure free 0% 20% 40% 60% 80% discontinued (AEs) (Ben-Menachem 1994, 2007, 2010, French 2011, The Vagus Nerve Stimulation Group 1995, Handforth 1998) 16

17 Device versus another medication? (observational studies) Efficacy Tolerability VNS mixed VNS > 1 year 8.3% 9.0% 63.8% 59.2% 59.0% 51.0% pain vocal cord paralysis dysphagia 1.9% 0.2% 0.5% VNS 1 year VNS 4 years levetiracetam Not reported Not reported 11.7% 35.0% 46.0% 38.6% 39.6% 64.0% hoarseness infection lead fracture removal 3.7% 2.5% 4.5% 17.0% 0% 20% 40% 60% 80% 0% 20% 40% 60% seizure free Responders > 50% median sz reduction 50% of patients have 50% less seizures (Ben-Menachem 2003, De Giorgio 2000, De Herdt 2007, Elliot 2011,) 17

18 Device versus another medication? (Clinical Reality or The Art of Medicine) Side effects: cognition, sedation vs hoarseness Psychiatric considerations: depression, memory Patient preference Seizure severity or frequency Health care system The magic of a device 18

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20 The magic of a device VNS 2 VNS 03 eslicarbazepine ezogabine lacosamide levitiracetam Placebo response 0.0% 11.3% 0.0% 15.2% 1.0% 0.8% 0.0% 17.5% 0.0% 10.0% 0.0% 6.8% 0% 20% 40% 60% 80% Expectation determines the therapeutic response as well as the brain physiology (single neuron firing and dopamin release) Sham surgery is thought to have an even greater response seizure free mean sz reduction 20

21 The magic of a device II: Neuromodulation Efficacy increases with prolonged use Cave: Enriched population (Elliot 2011) 21

22 VNS Long-Term Adverse Effects 70% 60% 50% 40% 30% 20% 10% 0% 60% Month 3 Year 1 Year 2 29% 38% Year 3 19% 21% 21% 8% 12% 6% 2% 2% 4% 0% 8% 3% 3% Hoarseness Cough Paresthesia Dyspnea (Morris 1999). 22

23 VNS in different populations Efficacy Postsurgical 5.1% 55.1% 50.5% Children 10.1% 60.0% 68.7% Generalized 43.8% 43.3% Epileptic encephalopathies 0.0% 17.0% 26.0% Lennox-Gastaut 5.0% 21.0% 20.6% medical refractory 7.0% 50.0% 55.0% 0% 20% 40% 60% 80% seizure free Responders > 50% median sz reduction (Jobst 2010, Majoie 2005, Holmes 2004, Alexopoulos 2006, Amar 2004 ) 23

24 Trends in VNS response Children of younger age seem to respond more favorably Epilepsy duration seems to have a inverse relationship with favorable response Possibly tuberous sclerosis and trauma respond more favorably than other pathologies Generalized tonic-clonic seizures may be a negative predictor of a favorable response Simple partial seizures tend to respond the best Engelot

25 ? Future: transcutaneous stimulation Auricular branch of the vagus nerve Trigeminal stimulation (TNS) Nemos N=10 data in 7 Safety in psychiatric trial for tinnitus 5/7 decreased seizure frequency No patient >50% seizure reduction Monarch N=13 data in 12 66% mean seizures reduction 5/12 responders (Stefan 2012, DeGiorgio 2009 ) 25

26 Seizure reduction Seizure reduction Seizure reduction 26

27 DBS principle Intermittent or continuous Amplitude V Pulse width µs Frequency Hz Battery life ~ 3 years Modulation of limbic circuits Target: anterior nucleus of the thalamus 27

28 SANTE Amplitude 5V Pulse width 90 µs Frequency 140 Hz 1 min ON - 5 min OFF Implantation effect N=108 GEE: mean percent difference -17%, (p=0.038) last month -29% (p=0.0016) (Fisher 2010) 28

29 Long term data- DBS- SANTE 80% 60% 40% Seizure reduction 67.0% 54.0% 43.0% Hemorrhages non-clinical Pain Infection Tolerability 0.5% 4.5% 12.7% 20% 12.7% Paresthesias 18.2% 7.4% 0% NR =not reported NR 1 year 2 year median sz reduction Responders > 50% seizure free NR 3 year Sz free long term Withdrawal Blinded phase withdrawal 16.4% 0.0% 0% 20% 40% 60% (Fisher 2010) 29

30 Special populations- SANTE Temporal lobe epilepsy: median seizure reduction was significant compared to other neocortical epilepsies Complex partial seizures and most severe seizures improved significantly Current European Registry: Medtronic Registry for Epilepsy (MORE) may help to identify specific patient populations. 30

31 ? Future: hippocampal stimulation In small case series the hippocampal stimulation seems to be effective Controlled Randomized Stimulation Versus Resection (CoRaStiR) still ongoing in Europe Hippocampal stimulation may improve memory (Boon 2007, clinicaltrials.gov, Suthana 2012) 31

32 Seizure reduction Seizure reduction Seizure reduction Seizure reduction 32

33 Responsive stimulation: RNS -System ma (< current density of 3µC/cm 2) Hz Responsive single pulses Battery life 3 years Restricted to investigational use only by US law 33

34 Responsive Stimulation Single pulses delivered after individualized seizure detection, delivered multiple times per day Detection and Stimulation up to 5 times Stimulation targeted at seizure onset zone Overall current delivered is low as only single pulses are delivered Restricted to investigational use only by US law 34

35 Alternative implantations Neocortical stimulation: (only 8 electrodes are connected) Hippocampal and neocortical stimulation Restricted to investigational use only by US law 35

36 RNS - System: double blind data Implantation effect * N=191 GEE: mean percent difference -37.9%, (p=0.012) last month evaluation period -41.5% (p=0.008) (Morrell 2011) 36

37 Long term treatment trial 2 years 3 years 5 years 7 years (Jobst 2011, Bergey 2011) 37

38 Long term data- RNS -System 80% Seizure free Tolerability 60% Hemorrhage 2.1% 40% Pain 9.0% 20% 15.0% Infection 5.1% 0% 7.1% 2 year Sz free long term Paresthesias Explantion 3.0% 0.2% 0% 20% 40% 60% seizure free (Morrell 2011) 38

39 RNS -System in different populations No difference between mesial temporal or other location No difference whether previous epilepsy surgery No difference whether one or two seizure foci 39

40 ? The future: Responsive treatment Responsive treatment could evolve into - improved electrical seizure abortion - improved technology treating directly at seizure focus local drug delivery local cooling 40

41 The future: Seizure Risk Alerting Devices Records, analyzes, and archives real-time, ambulatory ieeg data from 16 contacts N= 15 for safety Modulation of life style and acute treatment (Courtesy Mark Cook) 41

42 Where do devices fit in Bitemporal epilepsy Epilepsy with > 1 seizure focus Seizure onset eloquent regions Failed surgery Generalized epilepsies? Additive effects Lower complication rate Basis for further development such as target drug delivery, cooling, stimulation, seizure detection 42

43 Seizure reduction Seizure reduction Seizure reduction Seizure reduction Seizure reduction 43

44 Device versus callosotomy (CC) Responder rates VNS n=21 CC n=50 Tolerability CC 77.8% 79.9% CC VNS 8.0% 21.0% 79.0% 0% 20% 40% 60% complications VNS 66.7% 50.0% 40.0% 0% 20% 40% 60% 80% Tonic-atonic GTC all seizures CC Death Status Infection Hemiparesis Gait difficulties Disconnection syndrome DVT VNS Site infection Defective battery Class I: CC 17% --VNS 0% (Nei 2006) 44

45 Seizure reduction Seizure reduction Seizure reduction Seizure reduction Seizure reduction Seizure reduction Seizures 45

46 The patient: Esther She had a VNS implanted. Could not tolerate it because of choking sensations. Multiple medication changes were unsuccessful. Finally had callosotomy. Significant reduced generalized tonic seizures with falling, but still has continued seizures 46

47 S Y N D R O M E Seizure reduction Seizure reduction Seizure reduction Seizure reduction Seizure reduction Seizure reduction Seizures 47

48 Thank you 48

49 Quality of life and co-morbidities Overall QOLIE Depression medications? ++/-- -- Memory/ Cognition VNS + ++ neutral DBS + -?? RNS + neutral + callosotomy?? -- 49

50 Summary Devices RNS -System DBS VNS TNS Target Cortical: varies according to seizure focus Anterior nucleus thalamus Ascending vagus nerve Type of stimulation Closed loop: responsive Open loop scheduled Trigeminal nerve Neurostimulator Cranially implanted Pectorally implanted Not implanted visible Stimulation time/ day Approx. 5 min Hours-Continuous Programming changes Adjusted to clinical and electrographic response According to clinical response Information from device Device data, detections, electrocorticogram Device data Physician data review At programming and online access to stored data At programming 50