Stewart J. Tepper, MD l 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
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Stewart J. Tepper, MD l 1 Neuromodulation and Headache Disorders Stewart J. Tepper, MD Professor of Medicine (Neurology) Cleveland Clinic Lerner College.
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Stewart J. Tepper, MD l 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
Disclosures for 2015• Grants/Research Support (no personal compensation):
Clinical Plan is to Work Up from the Bottom, Least Invasive, Most Convenient, to Maximally Invasive
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
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
Non-invasive FDA Approved Neuromodulation2. 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.
Summary of TMS Prevention Randomized Controlled Trials (RCTs) Authors N Methods Results Comments
Brighina et al. 2004.
11 Hi-f 10 hz rTMS NS
Teepker et al. 2010.
27 Low-f rTMS NS
Misra et al. 2013.
100 Hi-f 10 hz rTMS60 CM, 28 MOH, MO & MA, >4 attacks/mo, no preventive meds
Positive1-month:↓ HA f↓ VAS severity↓ Disability
One patient withdrawn due to drowsiness
Conforto et al. 2014.
18 Hi-f 10 hz rTMS forCM
NS ↓ HA f >50% in sham group
Stewart J. Tepper, MD l 7
• 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)
CCourtesy of Jean Schoenen and Stephen Silberstein, MD
Afferent limb
+
• 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
Development of a Non-Invasive Vagus Nerve Stimulator (nVNS)
Prevention of Chronic Migraine (EVENT) Study RCT
Author Methods Results Comments
Silberstein et al. 2014 (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
Silberstein et al. Headache 2014;54:1426-7 (Abstracts LBP19, 21).
• Two 90 second stimulations TID• No effect observed with sham,
no significant difference from nVNS (-2.0 vs -0.1; P=.1821)
Two 90 second stimulations TID
-2.0 -0.1
17
nVNS Duration on Headache Days per Month: The Longer Used, the Better
Ch
ang
e F
rom
Bas
elin
e in
Nu
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er o
f H
ead
ach
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ays
per
28
Day
s O
ver
Tim
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0 Months 2 Months 4 Months
6 Months
nVNS Treatment Duration
Silberstein et al. Headache 2014;54:1426-7 (Abstracts LBP19, 21).Data presented as mean change from baseline. Post hoc analysis of the pooled per-protocol populations.
*P<.05 vs baseline (0 months)†P<.01 vs baseline (0 months)
*
*†
Cluster RCTs nVNS
Authors N Methods Results Comments
Gaul et al. EHMTIC 2014.
Silberstein et al.AHS 2015
93
150
CCHPrevention: SOC + nVNS vs SOC (no placebo), then OLE w/nVNS + SOC
ECH & CCHAcute, sham controlled
Positive ↓CH attacks/wk from baseline;-50% responder rate-↓ rescue meds & O2, compared with SoC
• 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
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
.1. Silberstein et al. Headache 2014;54:1426-7 (Abstracts LBP19, 21).2. Gaul. EHMTIC meeting, Copenhagen, Sept 2014. 3. Silberstein et al. AHS scientific meeting, June 2015.
Neuromodulation for migraine
• FDA approved:o Transcranial magnetic stimulator for acute treatment of migraine w/aura (SpringTMS)- Phase 4 in
selected centers
o Transcutaneous supraorbital neurostimulation (tSNS) for prevention of migraine (CEFALY)- available
o Not FDA approved:– Non-invasive vagal nerve stimulator (nVNS, gammaCore)
• 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
30Schoenen et al. Cephalalgia 2013;33:816-30; Hillerup et al. ICOMS, Barcelona, October 2013. Hillerup et al. (Poster) Presented at the 4th EHMTIC, Sept. 2014.
Safety profile
Circling back to the mechanism of action: is the SPG Stimulator Inhibiting or Activating SPG Parasympathetic Output?
Stewart J. Tepper, MD l 31
Is the SPG Stimulator Inhibiting or Activating SPG Parasympathetic Output?• Hypotheses: Information block on outflow; Stimulation depletes
• 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
Stewart J. Tepper, MD l 32 Schytz et al. Cephalalgia 2013; 33:831–841.
Hyper-activation and Neurotransmitter depletion
Information block on outflow
Stewart J. Tepper, MD l 33
SPG Stimulation from Implant Inhibits Outflow
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):101-102; Lainez et al. Cephalalgia 2013;33 (Supplement 8): 103-104.Jensen et al. presented at World Congress of Neurology, Vienna, Austria, Sept 22, 2013.
Neuromodulation for migraine
• FDA approved:o Transcranial magnetic stimulator for acute treatment of migraine w/aura (SpringTMS)-
Phase 4 in selected centers
o Transcutaneous supraorbital neurostimulation (tSNS) for prevention of migraine (CEFALY)- available
o Not FDA approved:– Non-invasive vagal nerve stimulator (nVNS, gammaCore)
–Occipital Nerve Stimulation (ONS) – Deep Brain Stimulation (DBS)
Stewart J. Tepper, MD l 35
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 significant @ 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
1. Lipton et al. Cephalalgia 2009; 29 (Supplement 1): 30. 2. Saper et al. Cephalalgia 2011; 41: 271–285.3. Silberstein et al. Cephalalgia 2012; 32: 1165–1179.
Invasive Neuromodulation,
In Development
Occipital Nerve Stimulation
Stewart J. Tepper, MD l 37
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
Stewart J. Tepper, MD l 38 Wilbrink et al. Cephalalgia 2013;33:1238–1247.
• 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
ONS: main adverse effects
• In 2014, the EU rescinded the CE Mark for the St Jude Genesis ONS device, presumably because of these issues
Invasive Neuromodulation for Cluster headache in development
Hypothalamic deep brain stimulation (DBS)
Stewart J. Tepper, MD l 40
DBS implanted in ipsilateral posterior hypothalamus
DBS in CH: Summary of Case Series
• Magis and Schoenen summarized 14 case series published from 2005-20131,2
• 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; 11:708-19.Magis. EHMTIC, 2014.Leone et al. Pain. 2013;154:89-94.
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
Levels of EvidenceNon-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
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!