Peripheral Nervous System Targets · Sphenopalatine Ganglion Transnasalversus Injection Occipital...
Transcript of Peripheral Nervous System Targets · Sphenopalatine Ganglion Transnasalversus Injection Occipital...
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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)
References Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nature Reviews Neuroscience 2011;12:570-584.
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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Kemp WJ, 3rd, Tubbs RS, Cohen-Gadol AA. The innervation of the scalp: A comprehensive review including anatomy, pathology, and neurosurgical correlates. Surgical Neurology International 2011;2:178.
Magis D, D'Ostilio K, Thibaut A, et al. Cerebral metabolism before and after external trigeminal nerve stimulation in episodic migraine. Cephalalgia 2017;37:881-891.
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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.