1. Neuromodulation and Headache Disorders
Stewart J. Tepper, MD
Professor of Medicine (Neurology)
Cleveland Clinic Lerner College of Medicine
Co-Director of Research
Neurological Center for Restoration
Neurological Institute
Cleveland Clinic
Stewart J. Tepper, MD l 1

2. Disclosures for 2015
Grants/Research Support (no personal compensation): 
Alder, Allergan/MAP, Amgen, ATI, ElectroCore, eNeura, GSK, Labrys/Teva, Pernix, Optinose/Avanir/Otsuka
Consultant:
Acorda, Allergan, Amgen, ATI, Avanir, Depomed, Impax, Pfizer, Teva, Zosana,
Speakers Bureau:
Allergan, Depomed, Impax, Pernix, Teva
Advisors Board:
Allergan/MAP, Amgen, ATI, Avanir, Dr. Reddy’s, Lilly, Merck, Labrys/Teva, Pfizer
Stock options:
ATI
Royalties:
University of Mississippi Press, Springer
Stewart J. Tepper, MD l 2

3. Neuromodulation and Headache Outline
Overview
FDA approved:
Transcranial magnetic stimulator for acute treatment of migraine w/aura (SpringTMS)- Phase 4 in selected centers
Transcutaneous supraorbital neurostimulation (tSNS) for prevention of migraine (CEFALY)- available
Not FDA approved:
Non-invasive vagal nerve stimulator (nVNS, gammaCore)
Sphenopalatine ganglion stimulation (SPG, PULSANTE)
Occipital Nerve Stimulation (ONS)
Deep Brain Stimulation (DBS)
Stewart J. Tepper, MD l 3

4. Clinical Plan is to Work Up from the Bottom, Least Invasive, Most Convenient, to Maximally Invasive
Deep brain Stimulation (DBS)
Minimally invasive
Occipital Nerve Stimulation (ONS)
SPG Stimulation
Noninvasive
tSNS
Transcranial Magnetic Stim (TMS)
nVNS
Stewart J. Tepper, MD l 4

5. Neuromodulation for migraine: FDA approved
Transcranial magnetic stimulator for acute treatment of migraine with aura (SpringTMS)
Transcutaneous supraorbital neurostimulation (tSNS) for prevention of migraine (CEFALY)
Stewart J. Tepper, MD l 5

6. TMS is able to disrupt rat cortical spreading depression
Non-invasive FDA Approved Neuromodulation 2. Transcranial Magnetic Stimulation (TMS)
TMS is able to disrupt rat cortical spreading depression
TMS modifies excitability of cortical areas
Effect may also be thalamocortical inhibition
sTMS = single pulse
rTMS = repetitive (trains)
1Hz=inhibitory, 10Hz=excitatory
Holland et al. Cephalalgia. 2009;29(Suppl 1):22.
Andreou et al. Headache. 2010;50(Suppl 1):58.

7. Summary of TMS Prevention Randomized Controlled Trials (RCTs)
Authors N
Methods
Results
Comments
Brighina et al 11
Hi-f 10 hz rTMS NS
Teepker et al 27
Low-f rTMS
Misra et al
100
60 CM,
28 MOH, MO & MA,
>4 attacks/mo, no preventive meds
Positive
1-month:
↓ HA f
↓ VAS severity
↓ Disability
One patient withdrawn due to drowsiness
Conforto et al 18
Hi-f 10 hz rTMS for CM
↓ HA f >50% in sham group
Stewart J. Tepper, MD l 7

8. sTMS RCT for Acute treatment of M W/Aura (≥30% of attacks)
N=164 (82 sham); 2 pulses 30 sec apart within 1 hour of aura onset
2 h pain-free (PF): 39% TMS vs 22% sham (p=0.0179)
Sustained 2-24 h PF: 29% TMS vs 16% sham (p=0.0405)
Sustained 2-48 h PF: 27% TMS vs 13% sham (p=0.0327)
AEs rare: sinusitis, aphasia, vertigo, dizziness
Therapeutic gain = 17%
SpringTMS
Lipton et al. Lancet Neurol. 2010;9:

9. Transcranial Magnetic Stimulation (TMS) Acute Level of Evidence is B, Prevention U
CE mark in the EU 2013 for single pulse TMS
FDA approved sTMS on Dec 13, 2013 for “acute treatment of pain associated with migraine with aura” with 2 pulses / 24 hours
The FDA approved sTMS through a “de novo premarket review pathway …for some low- to moderate-risk medical devices”
For Acute treatment:
One Class 1 RCT (Lipton et al), for acute treatment of migraine with aura
Level B, Probably Effective, based on one Class 1 study, but it is FDA approved already
For prevention of migraine, Level U, 4 RCTs with conflicting data:
One positive RCT (Misra et al), 3 negative RCTs
Future RCTs need to be on dose ranging, MO, prevention, and AEs
Phase 4 studies underway at selected centers in US and UK

10. Neuromodulation for migraine: FDA approved
Transcranial magnetic stimulator for acute treatment of migraine with aura (SpringTMS)
Transcutaneous supraorbital neurostimulation (tSNS) for prevention of migraine (CEFALY)
Stewart J. Tepper, MD l 10

11. tSNS RCT PREMICE Trial
67 patients randomized to verum (n = 34) and sham (n = 33)
Episodic migraine wwo aura, with ≥2 attacks/month, no prevention for 3 mos, 30 day baseline using paper diaries
3 months of 20 minutes/day device vs sham (90 sessions)
Adverse events “none” yet all subjects experienced “strong paresthesias”
Primary outcomes in third month: 1. Change in monthly migraine days in run-in vs third month: not significant
2. ≥ 50% reduction in migraine days/month: (+) for 38.2%
50% Responder Rates
P = 0.023
Change in HA days (NS)
P = 0.054
Schoenen et al. Neurology 2013;80;
Stewart J. Tepper, MD l 11

12. More on the tSNS One setting with 2 ramping intensities
Cost: $349 plus $35 for shipping, not generally covered by insurance
Prescription must accompany each order
3 pack of electrodes is $25, with an additional $5 for shipping
Each electrode pad lasts between 15 and 30 sessions
The company accepts only Visa, Mastercard, and PayPal
It can be returned within 60 days
tSNS received FDA approval March 2014 for minimal risk device: 1 RCT
Level of Evidence: Level B, probably effective, based on 1 RCT
Tepper D. Headache 2014;54:
Stewart J. Tepper, MD l 12

13. Neuromodulation FDA approved: Not FDA approved:
Transcranial magnetic stimulator for acute treatment of migraine w/aura (SpringTMS)- Phase 4 in selected centers
Transcutaneous supraorbital neurostimulation (tSNS) for prevention of migraine (CEFALY)- available
Not FDA approved:
Non-invasive vagal nerve stimulator (nVNS, gammaCore)
Sphenopalatine ganglion stimulation (SPG, PULSANTE)
Occipital Nerve Stimulation (ONS)
Deep Brain Stimulation (DBS)
Stewart J. Tepper, MD l 13

14. Emotional & autonomic dimensions of pain
Sensory-discriminative aspects of pain
Emotional & autonomic dimensions of pain
Thalamus
Other limbic regions
Somato-sensory
cortex
Amygdala
Hypothalamus
Frontal
Attention
arousal
Medial
parabrachial
nuclei
LPB
Parabrachial
Complex
Pain inhibition
Vagus nerve +
N. tractus solitarius
Afferent limb
Trigemino-cervical complex spinal cord
CCourtesy of Jean Schoenen and
Stephen Silberstein, MD

15. Development of a Non-Invasive Vagus Nerve Stimulator (nVNS)
gammaCore by electroCore Medical, LLC is a handheld, patient-controlled nVNS device
Produces a uniform electric field across the surface of the electrodes
Selectively stimulates low-threshold myelinated afferent A fibers, but not higher-threshold C fibers
Delivers 90-second stimulations that can be used repeatedly 15

16. Prevention of Chronic Migraine (EVENT) Study RCT
Author
Methods
Results
Comments
Silberstein et al (abstract).
CM sham controlled RCT followed by OLE;
Two 90 sec pulses TID
NS at 2 mos
-With nVNS:
15% had ↓≥50% during RCT
-Clinically meaningful & progressive ↓HA days during OLE
-0.1
Two 90 second stimulations TID
No effect observed with sham, no significant difference from nVNS (-2.0 vs -0.1; P=.1821)
-2.0
Two 90 second stimulations TID
Silberstein et al. Headache 2014;54: (Abstracts LBP19, 21).

17. nVNS Duration on Headache Days per Month: The Longer Used, the Better
Change From Baseline in Number of Headache Days per 28 Days Over Time
0 Months
2 Months
4 Months
6 Months
nVNS Treatment Duration
Silberstein et al. Headache 2014;54: (Abstracts LBP19, 21).
Data presented as mean change from baseline.
Post hoc analysis of the pooled per-protocol populations. *
Longer duration of nVNS treatment appears to enhance the clinical benefit by continuing to decrease the frequency of headache days
Subjects who received 2 months of nVNS treatment (n=44) reported 1 less headache day per month
Subjects who received nVNS treatment for 4 months (n=32) experienced approximately 3 fewer headache days per month
After 6 months of active nVNS treatment (n=26), subjects experienced 6 fewer headache days per month; the subjects in the 6-month nVNS treatment subpopulation demonstrated significant reductions in number of headache days from baseline after 2 months of treatment * †
*P<.05 vs baseline (0 months)
†P<.01 vs baseline (0 months)

18. Cluster RCTs nVNS Authors N Methods Results Comments
Gaul et al. EHMTIC 2014.
Silberstein et al.
AHS 2015 93
150
CCH
Prevention:
SOC + nVNS vs SOC (no placebo), then OLE w/nVNS + SOC
ECH & CCH
Acute, sham controlled
Positive
↓CH attacks/wk from baseline;
-50% responder rate
-↓ rescue meds & O2, compared with SoC NS
15 min response rate
-↓Longer treatment duration associated w/ even better -↓CH attacks f
Few nVNS AEs
Positive for 2° endpoint, sustained response
Gaul. EHMTIC meeting, Copenhagen, Sept 2014.

19. Adverse Events nVNS
AEs are transient, and for the most part, very mild
Most common AEs:
Mild to moderate neck pain (local discomfort)
Mild skin reaction to gel
Worsening of pain
Oropharyngeal pain
Paresthesias
Facial twitching/spasms
Stewart J. Tepper, MD l 19

20. Peripheral Handheld Non-invasive Vagal Nerve Stimulator
(nVNS) for Migraine: Level U;
for Cluster, Level C or U
One RCT for Prevention of Chronic Migraine1, negative for primary endpoint, showed increasing benefit over continued use, Level U, inadequate or conflicting data
One RCT for Prevention of Cluster Headache2, positive for primary endpoint, Level C (no placebo)
One RCT for Acute Treatment of Cluster Headache3, negative for primary endpoint, positive for secondary endpoint, Level U
Already approved with CE mark in the EU; also approved in Canada, may be filing for US approval in 2015
Silberstein et al. Headache 2014;54: (Abstracts LBP19, 21).
Gaul. EHMTIC meeting, Copenhagen, Sept 2014.
Silberstein et al. AHS scientific meeting, June 2015. .

21. Neuromodulation for migraine
FDA approved:
Transcranial magnetic stimulator for acute treatment of migraine w/aura (SpringTMS)- Phase 4 in selected centers
Transcutaneous supraorbital neurostimulation (tSNS) for prevention of migraine (CEFALY)- available
Not FDA approved:
Non-invasive vagal nerve stimulator (nVNS, gammaCore)
Sphenopalatine ganglion stimulation (SPG, PULSANTE)
Occipital Nerve Stimulation (ONS)
Deep Brain Stimulation (DBS)
Stewart J. Tepper, MD l 21

22. The Sphenopalatine Ganglion (SPG)
Stewart J. Tepper, MD l 22

23. Parasympathetics synapse in SPG
SPG Innervations: Sympathetic postganglionic pathways pass through the SPG without synapsing;
Parasympathetics synapse in SPG
Lance and Goadsby. Mechanism and Management of Headache. Elsevier:2005.
Stewart J. Tepper, MD l 23

24. The SPG is the final switching station for cluster and migraine
Post/Inferior Hypothalamus
SSN
Sphenopalatine
ganglion [SPG]
Edvinsson, Goadsby.
Cephalalgia 1994;14:320-7.
Burstein,Jakubowski. J Comp Neurol 2005;493:9-14.

25. SPG Stimulation Therapy with Implanted System
Miniaturized implant stimulates the SPG
Change of paradigm - Wirelessly powers and controls the neurostimulator with no external batteries or wires
Implanted through the mouth
On-demand, patient-controlled therapy
Rechargeable through USB port
Internet connected
On / Off Button, Programmable Up / Down Buttons (amplitude adjustment)
Schoenen et al. Cephalalgia 2013;33: 816–830.

26. Efficacy of the Implanted SPG Stimulator (PULSANTE)
Stewart J. Tepper, MD l 26

27. Pathway CH-1 Study: SPG Stimulation for the Treatment of Chronic Cluster Headache
Randomized, controlled, blinded, prospective multi-center study
Minimum 4 attacks/week, dissatisfied with current treatment
Random insertion of placebo & subthreshold stimulation study design
Initial 28 patient results published in Cephalalgia 2013, another 11 recruited subsequently
Final N = 38 patients; 769 cluster attacks treated presented at IHC Boston June 2013
End of Experimental Period
Analyses
Attack Pain relief at 15 minutes
Attack frequency % change vs. baseline
Start of Long-Term Follow-Up (LTFU) Period Analyses
Patient Satisfaction Survey
HIT-6 headache disability change vs. baseline
SF-36v2 quality of life change vs. baseline
Preventive meds usage vs. baseline
Schoenen et al. Cephalalgia 2013; 33
(Supplement 8):
Schoenen et al. Cephalalgia 2013;33: 816–830.

28. The SPG stimulator worked acutely, preventively, or both N=38 patients at end of experimental period, 769 attacks analyzed)
Acute treatment: 55% of attacks with pain relief 15 minutes vs 6% sham
Preventive effect: 42% of patients had 89% decreased attack frequency
Schoenen et al. Cephalalgia 2013;33: 816–830.
Schoenen et al. Cephalalgia 2013; 33 (Supplement 8):
Stewart J. Tepper, MD l 28

29. SPGS Responder Rates (RR) for Cluster, RCT CH-1 through 24 months
Experimental period
18 Months Post Implant
24 Months Post Implant
36% Acute
45% Acute
25% Acute
7% Both
12% Both
15% Both
36% Frequency
39%
Frequency
30% Frequency
61% Overall RR
N = 33 patients
64% Overall RR
N = 33 patients
68% Overall RR
N = 28 patients
Responders:
Pain relief in ≥ 50% of evaluable, treated attacks
≥ 50% reduction in attack frequency vs. baseline
Or both
May A. EHMTIC 2014.
Jensen R. IHC 2015.

30. Safety profile Does lead motion interfere with jaw motion? No
The system is well tolerated
Safety evaluated in 99 cluster patients (Pathway CH-1 & Registry studies)
Most common surgical side effects occur within 30 days of the surgery and are mild and temporary:
67% experience sensory disturbances
47% experience pain and/or swelling
Peri-operative AEs resolved within avg. 90 days
Does lead motion interfere with jaw motion? No
After insertion, no scars and the device cannot be seen
Adverse events and side effects similar to those reported in other oral procedures
Schoenen et al. Cephalalgia 2013;33:816-30; Hillerup et al. ICOMS, Barcelona, October 2013.
Hillerup et al. (Poster) Presented at the 4th EHMTIC, Sept

31. Circling back to the mechanism of action: is the SPG Stimulator Inhibiting or Activating SPG Parasympathetic Output?
Stewart J. Tepper, MD l 31

32. Is the SPG Stimulator Inhibiting or Activating SPG Parasympathetic Output?
Hypotheses: Information block on outflow; Stimulation depletes neurotransmitters, resulting in ↓outflow
Study: Low frequency SPG neurostimulation induces immediate cluster-like headache attacks w/autonomic symptoms: activates
High frequency SPG neurostimulation terminates cluster attacks : inhibits outflow
This study is a dramatic confirmation of the pathophysiology of the device and how SPG stimulation affects cluster
Hyper-activation and Neurotransmitter depletion
Information block on outflow
Schytz et al. Cephalalgia 2013; 33:831–841.
Stewart J. Tepper, MD l 32

33. SPG Stimulation from Implant Inhibits Outflow
Stewart J. Tepper, MD l 33

34. Level of Evidence Implanted SPG stimulation for Cluster: For primary acute endpoint: Level B, probably effective For additional preventive endpoint: Level C, possibly effective
Cluster RCT showed both acute and preventive efficacy, one RCT, CH-11
Implanted ATI SPG stimulator (brand name Pulsante) has a CE Mark in Europe & is reimbursed for implant in several countries including Germany and Denmark as first-line treatment for CCH based on the RCT and open-label f/u2-4
>200 Chronic and Episodic Cluster patients implanted in Europe, with about 2/3 of them responding, some remitting
US pivotal RCT, CH-2, is underway and implanting patients at multiple sites
Once approved in the US, we would use non-invasive neuromodulation first (assuming that works); then, some level of medication failure would be necessary before proceeding to SPG implantation
Schoenen et al. Cephalalgia 2013;33: 816–830; Schoenen et al. Cephalalgia 2013; 33 (Supplement 8): ; Lainez et al. Cephalalgia 2013;33 (Supplement 8):
Jensen et al. presented at World Congress of Neurology, Vienna, Austria, Sept 22, 2013.

35. Neuromodulation for migraine
FDA approved:
Transcranial magnetic stimulator for acute treatment of migraine w/aura (SpringTMS)- Phase 4 in selected centers
Transcutaneous supraorbital neurostimulation (tSNS) for prevention of migraine (CEFALY)- available
Not FDA approved:
Non-invasive vagal nerve stimulator (nVNS, gammaCore)
Sphenopalatine ganglion stimulation (SPG, PULSANTE)
Occipital Nerve Stimulation (ONS)
Deep Brain Stimulation (DBS)
Stewart J. Tepper, MD l 35

36. ONS for Chronic Migraine: 3 trials, Level U, Conflicting or Inadequate Data
3 studies, 3 different systems, none reached 1°endpoint, all had methodologic problems, all Class III at best
Lipton et al1, abstract only
1° endpoint: ↓ migraine days/month not 12 wks vs sham
Saper et al2: no primary endpoint pre-specified; adjustable stimulation, no sham group (vs medical management)
39% had ≥ 50% decreased frequency or ≥ 50% decreased severity
Silberstein et al3: no blinding
negative for primary endpoint, responder rate for ≥ 50% decrease in mean daily VAS at 12 weeks
Decrease of ≥ 30%, HA days, disability, & pain relief achieved
Lipton et al. Cephalalgia 2009; 29 (Supplement 1): 30.
Saper et al. Cephalalgia 2011; 41: 271–285.
3. Silberstein et al. Cephalalgia 2012; 32: 1165–1179.

37. Invasive Neuromodulation, In Development Occipital Nerve Stimulation
Stewart J. Tepper, MD l 37

38. ONS Multicenter RCT for CH is underway
ICON study: Prospective, double-blind, parallel group multi-center international RCT for CCH prevention between two different ONS stimulations: high (100%) and low (30%) amplitude
High vs. low stimulation design, instead of on vs. off design, should minimize unblinding due to paresthesias
They hypothesize a dose response relationship
Until this is completed, no RCTs for evidence: It appears to work about 60% of the time in case series but has unclassifiable evidence
Level U for Cluster, Inadequate data so far
Wilbrink et al. Cephalalgia 2013;33:1238–1247.
Stewart J. Tepper, MD l 38

39. ONS: main adverse effects
Electrode migration
Can be very frequent, and more common when placed by anesthesia rather than neurosurgeon
Mobility of cervical region
Electrode type
AEs: intolerance to paresthesias, cable discomfort, muscular spasm
Infection
Battery depletion:
high intensities increase cost
In 2014, the EU rescinded the CE Mark for the St Jude Genesis ONS device, presumably because of these issues

40. Invasive Neuromodulation for Cluster headache in development
Hypothalamic deep brain stimulation (DBS)
DBS implanted in ipsilateral
posterior hypothalamus
Stewart J. Tepper, MD l 40

41. DBS in CH: Summary of Case Series
Magis and Schoenen summarized 14 case series published from ,2
65 patients have been implanted with a mean of 2.8 years follow-up
Pain Free: 20/65 (31%)
# of patients with ≥50% decrease in HA f or intensity: 23/35 (35%)
Therefore, 66% improved
Leone et al’s follow-up was 17 patients, 8.7 years, sustained significant improvement in 6/17 (35%)
 42 days mean to effectiveness
 Turning off stimulator blind to patient: clusters recur, then stop when turned back on
Magis and Schoenen. Lancet Neurol 2012; 11:
Magis. EHMTIC, 2014.
Leone et al. Pain. 2013;154:89-94.

42. Deep Brain Stimulation for Cluster Headache
Adverse events:
Oculomotor disturbance & vertigo
Infections
Sleep disorders
Intracerebral hemorrhage: 2/64 cases (1 fatal) = 3%
One death in Belgium; TIAs, strokes, hemorrhages described
No RCTs for evidence: It works but has unclassifiable case series evidence
Level U, Inadequate data so far 42

43. Levels of Evidence Non-invasive Minimally invasive
tSNS (Cephaly): Level B for Preventive Treatment Episodic Migraine, FDA-approved
sTMS (SpringTMS): Level B for Acute Treatment Episodic Migraine with aura, FDA-approved
rTMS: Level U for Prevention of Migraine
nVNS (gammaCore) [Approved in EU and Canada]:
Level U for Acute and Level C for Preventive Treatment of Cluster
Level U for Migraine
Minimally invasive
Implantable SPG Stimulator (Pulsante) [Approved in EU]:
Level B for Acute Treatment of Cluster
Level C for Preventive Treatment of Cluster
Invasive
Occipital Nerve Stimulation: Level U for Cluster and Migraine
Deep Brain Stimulation: Level U for Cluster
Stewart J. Tepper, MD l 43

44. The Future will be real soon
Very soon, we might try non-invasive neuromodulation before drugs or O2 for acute and preventive treatment of cluster and migraine, if nVNS works
Minimally invasive neuromodulation such as the SPG stimulator would come after non-invasive neuromodulation, and after some, but not excessive medication failures
Significantly invasive neuromodulation would wait until multiple and significant medication failures
Once nVNS and sTMS are widely available, trials of these (and, sometimes tSNS) for migraine may precede drugs. This could be in 2015 for many centers!
Stewart J. Tepper, MD l 44

45. Thank you for your attention!