Headache:

Using Neuromodulation

as Therapy

Rashmi Halker, MD, FAHSAssistant Professor of NeurologyDepartment of NeurologyMayo Clinic Phoenix Arizona

Disclosures

• Nothing to disclose

©2013 MFMER | slide-2

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

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

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

• 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

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

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

Occipital Nerve Stimulation

Bilateral Extracranial Stimulation of the Greater Occipital Nerve for Chronic Migraine

Patients reported in literature >500

Three ‘failed’ RCTs

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:

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.

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)

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

Literature-Based Adverse Event Rate

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

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

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

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:

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

• 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

Supraorbital Transcutaneous Stimulation

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm388765.htm

http://www.cefaly.us/en/cefaly-shop

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

Prescription controlled by SIM card

Compliments Tony Barker

Lipton et al., Lancet Neurol 2010;9:373-80

Performance Goal = -0.63

ESPOUSE: Mean Reduction in Headache Days

Presented EHMTIC 2016; Glasgow

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

VNS: Mean Change in CH attacks per week

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

Summary

MIGRAINE CLUSTER

***

***

*** FDA approved

*

* Phase III

*

**

** FDA Submission