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Peripheral Nervous System Targets:

Therapeutic Targets of the Future

Chelsea M. Hesterman, MDAssistant Professor of Neurology

Goldberg Migraine ProgramDavid Geffen School of Medicine at UCLA

Disclosures

None

Overview

Pathophysiology and Rationale for Peripheral Nervous System (PNS) Targets

Nerve blocks/Nerve ablations

Occipital nerve blocks

Neuromodulation

Transcutaneous nerve stimulator

Vagus nerve stimulator

Cervical nerve targets

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Pathophysiology and Rationale

Input through peripheral afferents may modulate trigeminal nociceptive signaling through convergence on the trigeminal nucleus caudalis(TNC) in the trigeminocervical complex

Benefits of PNS targets:

Nonpharmacologic

May reduce abortive use

Fewer systemic side effects

Fewer medical contraindications

New mechanism for nonresponders

Akerman et al., Nat Rev Neurosci 2011

How do we target the PNS?

Modalities

Nerve blocks Nerve ablations Neuromodulation

Targets for Nerve Blocks and Lesioning

Nerve Blocks

Trigeminal Nerve

Branches of V1: Supraorbital, Supratrochlear

Branches of V2: Infraorbital

Branches of V3: Auriculotemporal

Sphenopalatine Ganglion

Transnasal versus Injection

Occipital Nerve

Greater Occipital Nerve (LON)

Lesser Occipital Nerve (GON)

Nerve Lesioning

Trigeminal Nerve (V2, V3)

Radiofrequency ablation (RFA)

Sphenopalatine Ganglion

RFA

Occipital Nerves

RFA

Earthslab.com

Kemp et al., Surg Neurol Int 2011

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Occipital Nerve Blocks

69% -76.9% adult neurologists perform nerve blocks 1,2

63% pediatric neurologists perform nerve blocks 3

Not included in treatment guidelines for migraine by AHS, AAN, IHS, EFNS, or CHS

Observational studies often with conflicting or weakly positive data

Seven randomized, controlled studies

Six show GON benefit

1. Blumenfeld et al., Headache 2010; 2. Lasaosa et al., Neurologia 2018; 3. Szperka et al., Headache 2016

Updates to the Literature

Gul et al., Acta Neurol Scand 2016: double-blind, randomized, placebo-controlled study

Repeated GON block with bupivacaine decreased headache days and pain scores at 1, 2 and 3 months

Cuadrado et al., Cephalalgia 2017: double-blind, randomized, placebo-controlled study

Decrease in mod-severe headache days in week after block

Increase in pressure pain thresholds in trigeminal area

Figure 1 from Gul et al., Acta Neurol Scand 2017

Updates to the Literature, cont. Allen et al., J Am Board Fam Med 2018: retrospective cohort study

82% of patients had ≥ 30% reduction in pain

58% of patients had ≥ 50% reduction in pain

Correlation between ≥ 2 GON blocks and reduction in pain score

Zhang et al., Clin Neurol Neurosurg 2018: meta-analysis

GON block decreases pain intensity and analgesic med use

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RCTs on GON Blocks in Migraine

GON BLOCK EFFECTIVE FOR ACUTE AND CHRONIC MIGRAINE MANAGEMENT

Modified from Zhang et al., Clin Neurol Neurosurg 2018

Final Thoughts on Occipital Nerve Blocks

Effective, safe, well-tolerated, rapid, inexpensive

Insurance considerations

Questions remaining:

Ideal treatment frequency

Ideal injectate combination

Acute, preventive or both?

Neuromodulation

Botulinum toxin

Implantable nerve stimulators (Occipital, SPG, Vagus)

Transcutaneous nerve stimulator

Cefaly: external trigeminal nerve stimulation (eTNS)

Vagus Nerve Stimulator

gammaCore: Noninvasive vagus nerve stimulation (nVNS)

Caloric Vestibular Stimulator

Remote Nonpainful Electrical Upper Arm Skin Stimulation

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eTNS: Cefaly

May involve modulation of central pain processing centers

Increase in metabolism of orbitofrontal cortex and rostral angeriorcingulate cortex in migraineurs after 3 months of Cefaly use 1

Approved for acute migraine treatment in 2017

Cefaly.us

1. Magis et al., Cephalalgia 2017

ACME trial

Primary endpoint:

Mean change in pain score after 1h

Secondary endpoints:

Mean change in pain intensity 2h and 24h

Percentage not using rescue meds at 2h and 24h

Met primary endpoint

Pain intensity reduced by 59% vs. 30%

Secondary endpoints

Pain intensity reduced at 2h and 24h

No difference in use of pain meds at 24h

Chou et al. 2017, Image used with permission from Jens Peterson

Cefaly

Safe, well-tolerated

Considerations: cost

Use in special populations

Cefaly.us

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nVNS: gammaCore

Mechanism of action may involve :

Inhibition of nociceptive pathways that converge on TNC 1

Decreasing CSDs 2

Inhibition of dural evoked trigeminocervical nociceptive firing 3

Approved for acute migraine treatment in 2018

Gammacore.com

1. Oshinsky et al., Pain 2014; 2. Chen et al., Pain 2016; 3. Akerman et al., Neurobiol Dis 2017

PRESTO trial

Primary endpoint:

Pain freedom at 2h

Secondary endpoints:

Pain relief at 2h

≥ 50% responder rate

Did not meet primary endpoint

30.4% vs 19.7% (P=0.067)

Met secondary endpoints

40.8% vs 27.6% had pain relief

47.6% of patients had relief for ≥50% of all treated attacks

Tassorelli et al. 2018 , Image used with permission from Eric Liebler

gammaCore

Safe, relatively well tolerated

Considerations: cost

Use in special populations

Gammacore.co.uk

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Cervical Targets of Headache

No sensory dermatomal or cutaneous branches of C1 have been described

C1 spinal nerve present in 100% of cadaveric specimens 1

C1 dorsal roots in 46.6%

C1 DRG in 28.5%

100% of C1 DRGs have neuronal cell bodies and sensory neurons 2

C1 structures never examined in living individuals

Tubbs et al., Clin Anat 2007

1. Tubbs et al., Clin Anat 2007; 2. Hovorka et al., Anat Rec 2013

C1 Referral Patterns

Stimulation of C1 spinal nerve evokes periorbital and frontal pain in migraineurs versus occipital or cervical pain in nonmigraine controls 1

1. Johnston et al., Ann Neurol 2013

UCLA Cervical Nerve Imaging Study

Specialized craniovertebral junction MRI

Migraineurs with periorbital pain

Cluster headache patients

Controls with no headache disorder

Research questions:

Difference in incidence of C1 in primary headache disorder vs. controls?

Laterality of structure correspond with pain?

Variations in anatomy of C1 and surrounding structures

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Images provided by Ben Ellingson

C1 Study ImagesmDESS Echo

(3D Diffusion Imaging)mDESS FID

(3D T2w Imaging)MPRAGE Pre

(3D T1w Imaging)

MPRAGE Post(3D Post-Contrast T1w Imaging)

T1 Subtraction(Contrast-Enhanced) DRG INDEX

DRG INDEX = T2 Hyperintensity and Restricted Diffusion on DWI and Contrast EnhancementDRG INDEX = (mDESS FID) x (mDESS Echo) x (MPRAGE T1 Subt)

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Akerman S, Simon B, Romero-Reyes M. Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animal models of primary headache. Neurobiology of Disease 2017;102:96-104.

Allen SM, Mookadam F, Cha SS, Freeman JA, Starling AJ, Mookadam M. Greater Occipital Nerve Block for Acute Treatment of Migraine Headache: A Large Retrospective Cohort Study. Journal of the American Board of Family Medicine : JABFM 2018;31:211-218.

Blumenfeld A, Ashkenazi A, Grosberg B, et al. Patterns of use of peripheral nerve blocks and trigger point injections among headache practitioners in the USA: Results of the American Headache Society Interventional Procedure Survey (AHS-IPS). Headache 2010;50:937-942.

Chen SP, Ay I, de Morais AL, et al. Vagus nerve stimulation inhibits cortical spreading depression. Pain 2016;157:797-805.

Chou DE, Gross GJ, Casadei CH, Yugrakh MS. External Trigeminal Nerve Stimulation for the Acute Treatment of Migraine: Open-Label Trial on Safety and Efficacy. Neuromodulation 2017;20:678-683.

Chou DE, Yugrakh MS, Gross G et al. on behalf of the ACME study group. Acute treatment of migraine with e-TNS: a multi-center, double-blind, randomized, sham-controlled trial. Presented at the Scottsdale Headache Symposium; Scottsdale; Nov 2017.

Cuadrado ML, Aledo-Serrano A, Navarro P, et al. Short-term effects of greater occipital nerve blocks in chronic migraine: A double-blind, randomised, placebo-controlled clinical trial. Cephalalgia 2017;37:864-872.

Grazzi L, Egeo G, Liebler E, Padovan AM, Barbanti P. Non-invasive vagus nerve stimulation (nVNS) as symptomatic treatment of migraine in young patients: a preliminary safety study. Neurological Sciences 2017;38:197 -199.

Gul HL, Ozon AO, Karadas O, Koc G, Inan LE. The efficacy of greater occipital nerve blockade in chronic migraine: A placebo-controlled study. Acta Neurologica Scandinavica 2017;136:138-144.

Hovorka MS, Uray NJ. Microscopic clusters of sensory neurons in C1 spinal nerve roots and in the C1 level of the spinal accessory nerve in adu lt humans. Anatomical Record 2013;296:1588-1593.

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Santos Lasaosa S, Gago Veiga A, Guerrero Peral AL, Viguera Romero J, Pozo-Rosich P. Patterns of anaesthetic pericranial nerve block in headache patients. Neurologia 2018;33:160-164.

Szperka CL, Gelfand AA, Hershey AD. Patterns of Use of Peripheral Nerve Blocks and Trigger Point Injections for Pediatric Headache: Results of a Survey of the American Headache Society Pediatric and Adolescent Section. Headache 2016;56:1597-1607.

Tassorelli C, Grazzi L, deTommasso M et al; on behalf of the PRESTO Study Group. The PRospectivE Study of nVNS for the Acute Treatment Of Migraine (PRESTO): A Sham-controlled, Double-blind, Randomised Study. Presented at the American Academy of Neurology; Los Angeles; April 2018.

Tubbs RS, Loukas M, Slappey JB, Shoja MM, Oakes WJ, Salter EG. Clinical anatomy of the C1 dorsal root, ganglion, and ramus: a review and anatomical study. Clinical Anatomy 2007;20:624-627.

Zhang H, Yang X, Lin Y, Chen L, Ye H. The efficacy of greater occipital nerve block for the treatment of migraine: A systemat ic review and meta-analysis. Clinical Neurology and Neurosurgery 2018;165:129-133.