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Headache:
Using Neuromodulation
as Therapy
Rashmi Halker, MD, FAHSAssistant Professor of NeurologyDepartment of NeurologyMayo Clinic Phoenix Arizona
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Disclosures
• Nothing to disclose
©2013 MFMER | slide-2
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Objectives
• Discuss invasive neuromodulation options for headache
• Deep brain stimulation
• Occipital nerve stimulation
• Sphenopalataine ganglion stimulation
• Discuss noninvasive neuromodulation options for headache
• Vagal nerve stimulation
• Supraorbital nerve stimulation
• Single-pulse transcranial magnetic stimulation
©2013 MFMER | slide-3
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Migraine is the 3rd most prevalent medical disorder on the planet
Migraine accounts for > 50% of the disability burden attributable to
all neurological disease worldwide.
Overall, it is the 4th ranking cause among women and the 6th
ranking cause of all disease-associated disability worldwide.
Lancet 2012; 380: 2197–223
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43 AD Scribonius Largus, Court Physician of Emperor Claudius:“ To immediately remove and permanently cure aheadache, …. a live black torpedo is put on theplace which is in pain, until the pain ceases andthe part grows numb.”
Neuromodulation: The Early Days
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• Deep brain stimulation [Hypothalamic]• Occipital nerve stimulation [ONS]• Sphenopalatine ganglion stimulation [SPGS]
• Vagal nerve stimulation [VNS]• Supraorbital nerve stimulation [Cefaly]• Single pulse transcranial magnetic stimulation [sTMS]• Vestibular neuromodulation
Invasive
Non-Invasive
Refractoryheadaches
Anyheadache
Neuromodulation Methods For Headache
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Hypothalamic Deep Brain Stimulation for Drug-Resistant Chronic Cluster Headache
Leone M, et al. Cephalalgia 2008;28:787-797
Lyons M, et al. J Neurosurg 2009;279-281Leone M, et al. Ann Neurol;2005:924-927
Outcome Number %
Pain Free 29 45
Response
(>50%)
12 19
Total 41/64 64%
Leone et al Cephalalgia 2015
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Leone M et al. Pain. 2013;154:89–94.
Adverse Events
Electrode displacement (n=2)
Electrode malpositioning (n=1)Persistent slight muscle weakness on one side (n=1)
Infection (electrode n=3; generator n=1)
Transient nonsymptomatic third ventricle hemorrhage (n=1)
Seizure (n=1)
Efficacy (median 8.7 year follow up in 17 patients)
• 6 are almost pain-free; Stimulators off for a median of 3 years
• 6 no longer experience daily attacks (ECH with long-lasting remissions)
• 5 did not improve
Hypothalamic Deep Brain Stimulation for Drug-Resistant Chronic Cluster Headache
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Occipital Nerve Stimulation
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Bilateral Extracranial Stimulation of the Greater Occipital Nerve for Chronic Migraine
Patients reported in literature >500
Three ‘failed’ RCTs
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ONS for Chronic MigraineMigraine Headache Days
VisitControl Group
(n=52)Active Group
(n=105)P-Value
Baseline
Mean (± std) 20,1 (± 7,2) 22,4 (± 6,9) 0,049
Week 12
Mean Change1 -3,0 (14,9%) -6,1 (27,2%) 0,008
Difference (95% CI) -3,1 (-5,4, -0,8)
Silberstein SD, et al. Cephalalgia 2012;32(16) 1165–1179:
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Occipital Nerve Stimulation for CM:Long-term Data
• Adults with chronic migraine (N=157); 12 weeks randomized, 40 weeks open label follow-up
• Efficacy
• Significant reduction in headache days (P<0.001) and disability (p<0.001)
• 50% reduction in headache days and/or pain intensity: 47.8%
• 2/3 of patients satisfied
• Adverse effects: 70%
• 8.6% required hospitalization
• 40.7% required surgical intervention
Dodick DW et al. Cephalalgia. 2015;35:344–358.
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Occipital Nerve Stimulationfor Trigeminal Autonomic Cephalalgias
1. Burns B et al. Lancet Neurol. 2008; 2. Dodick D et al. Headache. 2007; 3.Strand NH et al. Pain Physician. 2011;14:435–440.; 4. de Quintana-Schmidt C et al. Rev Neurol
2010;51:19–26.; 5. Burns et al. Neurology. 2009;72:341–345; 6. Magis D et al. Lancet Neurology. 2007;6:314–321.; 7. Fontaine D et al. Cephalalgia. 2011;31:1101–1105.; 8.
Mueller OM et al. Cen Eur Neurosurg. 2011;72: 84–89 .; 9. Shanahan et al. Cephalalgia. 2009;29(suppl 1):150.
Headache Treated Outcomes
Hemicrania continua1,2 >80% response (n=6/8)
Chronic cluster 3-8 74% responder rate (n=39/53 >50% improvement)
SUNCT (n=5) and SUNA (n=1)9 >50% benefit (n=4 patients nearly pain-free)
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Long-term Outcome in Drug-resistant Chronic Cluster Headache (ONS)
• 35 patients with mean 6.7 years DR-CCH followed for 6.1 years
(1.6-10.7 years)
• 20/35 (68%) > 50% reduction in headaches per day.
• 10 non-responders; 5 initial responders efficacy waned.
• Adverse events: battery change (21); lead migration, malfunction,
tip erosion (10).
Leone M, et al. Cephalalgia 2016
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Literature-Based Adverse Event Rate
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Deactivation of Migraine/Cluster Generator?
Magis et al. BMC Neurology. 2011;11:25; Matharu et al. Brain. 2003;127:220–230
Activation of Descending Opioid System in Responders
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Sphenopalatine Ganglion Stimulation Microstimulator System
• Microstimulator requires no batteries
• Insertion via trans-oral procedure
• Activated by external hand-held wireless remote controller
• Patient controlled, on-demand therapy
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Schoenen J, et al. Cephalalgia 2013;;33,:816-830:
SPG Stimulation for Cluster Headache: A randomized, Sham-Controlled Study
Responders 67.1% (FS) vs 7.4% (sham) vs 7.3% (SP)
43% had >50% reduction in CH attacks
p<0.0001
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78% effective therapy
in ~4000 attacks
treated in responders
SPG stimulation acute and frequency responses through 2 years post-implant
83% reduction in
attack frequency
in 33% of patients
Schoenen J, et al. Cephalalgia 2013;;33,:816-830:
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SPG for the Treatment of Chronic Cluster Headache
• Primary Efficacy: Proportion of cluster
attacks relieved at 15 minutes (7mo).
• Primary Safety: All SAEs through the
completion of the Open Label Period.
• N=120
• July 2014-January 2017
NCT 02168764
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• Deep brain stimulation [Hypothalamic]• Occipital nerve stimulation [ONS]• Sphenopalatine ganglion stimulation [SPGS]
• Vagal nerve stimulation [VNS]• Supraorbital nerve stimulation [Cefaly]• Single pulse transcranial magnetic stimulation [sTMS]• Vestibular neuromodulation
Invasive
Non-Invasive
Refractoryheadaches
Anyheadache
Neuromodulation Methods For Headache
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Supraorbital Transcutaneous Stimulation
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm388765.htm
http://www.cefaly.us/en/cefaly-shop
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Supraorbital Transcutaneous Stimulation
3 months Active Sham P-value
Decrease in mean
migraine days6.94 4.88 6.54 6.22 0.054
50% responder rate 38.1% 12.1% 0.023*
Schoenen J et al, Neurology 2013
• Double-blind, sham-controlled trial, n=67
• Stimulation 250 µs, 60 Hz, 16 mA, 20 min / day
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Prescription controlled by SIM card
Compliments Tony Barker
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Lipton et al., Lancet Neurol 2010;9:373-80
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Performance Goal = -0.63
ESPOUSE: Mean Reduction in Headache Days
Presented EHMTIC 2016; Glasgow
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Non-Invasive Vagus Nerve Stimulator
(nVNS)
• Selectively stimulates low-
threshold myelinated afferent A
fibers, not high-threshold C-fibers
• Delivers 90-second stimulations
that can be used repeatedly
• Maximum 24V and 60mA output
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VNS: Mean Change in CH attacks per week
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Summary
• Deep-brain (hypothalamic), SPG, and vagus nerve
stimulation emerging as effective for treatment of cluster
headache
• Non-invasive technologies preferred
• Occipital nerve stimulation may be effective for wide
range of primary headache disorders
• sTMS, supraorbital nerve stimulation, and vestibular
neuromodulation
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Summary
MIGRAINE CLUSTER
***
***
*** FDA approved
*
* Phase III
*
**
** FDA Submission