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Wade Cooper, D.O. University of Michigan Assistant Professor Departments of Neurology & Anesthesiology

The Integrative Road Less Traveled: Autonomic Dysfunction and Headache

Disclosures •  Consultant / Share holder – Dolor Technologies

Trigeminal System in Headache Meningeal Nerves

–  First division of V1 –  First division of V2 –  First division of V3

Trigeminal Nucleus descends into neck

C2, C3, C4 form Greater Occipital Nerve complex

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Trigeminal Nucleas Caudalis

Chronic sympathetic nervous system activation contributes to migraine?

•  Depletes: –  Norepinephrine

•  Increases: –  Dopamine –  Adenosine triphosphate, –  Adenosine –  Prostagladins

Autonomic influence on the Dura mater

•  Dense network of autonomic and sensory fibers within the Dura Mater

•  Parasympathetic stimulation (Carbachol) did not change levels of CGRP or PGE2

•  Sympathetic stimulation (Norepinephrine) show increased PGE2 and reduced serotonin

Ebersberger A et al. Effect of sympathetic and parasympathetic mediators on the release of calcitonin gene-related peptide and prostaglandin E2 for rat dura mater in vitro. Cephalalgia. 2006: 26:282-289.

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Migraine and Anxiety

•  Strong association with migraine

•  Possibly more prognostic for progression and intractability

•  Autonomic hypersensitivity? •  Associated with the

hyperactive migraine state

(Aurora et al., 2009) (Smitherman et al., 2008)

Migraine Comorbidity Disorders highly associated with migraine that occur at a rate significantly

greater than chance

•  Irritable bowel syndrome •  Gastritis •  Peptic ulcer disease •  H. pylori •  GERD •  Colitis

Gut Cluster

Migraine and Orthostatic Intolerance •  Lifetime prevalence

–  Syncope •  46% migraine •  31% controls

–  Orthostatic Intolerance •  32% Migraine •  12% Controls

(Thijs et al., 2006)

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Migraine and Autonomic Instability •  Raynauds Phenomenon

– Well established comorbidity –  Typically not treated –  Marker of neural

hypersensitivity? •  Environmental intolerance

–  Meal skipping –  Heat –  Sleep pattern

Red Ear Syndrome

Lambru et al. The red ear syndrome. The Journal of Headache and Pain 2013, 14:83

Wade Cooper, DO

Positional Orthostatic Tachycardia Syndrome (POTS)

•  Neuropathic (partial dysautonomic) POTS •  Orthostatic Intolerance •  120 bpm or ↑>30bpm within 10 min of upright

posture •  90% of all POTS

•  Hyperadrenergic POTS •  ↑SBP>10mm Hg during upright posture and

tachycardia •  Serum norepinephrine >600pg/ml

–  Associated with Mast Cell dysfunction?

(Kanjwal et al., 2011)

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Wade Cooper, DO

Hyperadrenergic POTS •  Clinical Symptoms:

–  Migraine > 50% –  Flushing > 60%

–  Hypermobility 20% –  Anxiety 60% –  Sweat 60% –  Fatigue 40%

•  Possible related Mast cell mediators: •  Histamine •  Renin •  ACE •  CGRP

•  May contribute to vasogenic edema and syncope

•  Associated “viral prodrome”

(Shibao et al., 2005)

Patient Video

Hemicrania Continua •  Daily strictly one sided HA

•  May have associated idiopathic stabbing HA

•  May wax and wane

•  Exacerbations associated with autonomic features –  Ptosis –  Miosis –  Lacrimation

•  Refractory to almost everything

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Indomethacin •  Typical trial:

–  Indomethacin 50mg –  One TID x 6 days –  Prescribe 30 – no refills.

•  May use SR preparations –  75mg BID x 30 days

•  Alternate bosweilla –  750mg TID

Mucosal Edema Improved acutely following treatment

•  Headache with right sided rhinorhea and lacrimation

•  MRI brain- R nasal edema •  Occipital nerve block

–  Acute improvement •  MRI Brain 2 days later

2 hrs later

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Cervical Sympathetic Chain •  Provides Sympathetic

Input to face and head •  May have anatomical

variations –  Arise below T1

•  T2, T3, T4 –  Vertebral division –  Dual middle / superior

plexus formations Cervical Thoracic Ganglion

Superior Cerv. Ganglion

Lower Cervical Ganglion Block (Stellate)

•  C6 Injection of bupivacaine

•  Inhibits cervical sympathetic pathway

•  Previously shown benefit for facial pain syndromes

•  Greater superior petrosal nerve associated with CNVII

•  Deep petrosal nerve associated with mucous membranes of nose and palate via phenopalatine ganglia

(Rusu & Pop, 2009)

Superior Cervical Ganglion •  Postganglionic

sympathetic fibers distributed to: –  Sphenopalatine ganglia –  Periarterial plexus of

maxillary artery •  From vidian nerve and

internal carotid plexus

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–  Sympathetic activity •  Sympathetic fibers course through the SPG on way to

cranial structures –  Parasympathetic synapse

•  Fibers from the brainstem (superior salvitory nucleaus) synapse in the SPG, then travel to cranial structures

–  Trigeminal nociception –  All the above

What role does the Sphenopalatine Ganglion have in migraine?

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Sphenopalatine Ganglion

Pterygopalatine Fossa Anatomy

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Sphenopalatine Ganglion

Sphenopalatine Ganglia

Sphenopalatine Ganglia Role in Head Pain

•  Trigeminal nociception –  Part of Maxillary nerve (V2) –  Branches to the

Ophthalmic nerve (V1) –  Middle Meningeal nerve

•  Innervates periorbital and parietal dura

SPG has nociceptive activity 5ht1D receptors CGRP receptors

(Csati et al., 2012) (Ooman et al., 2011) (Ivanusic et al., 2011)

Sphenopalatine Ganglion Ophthalmic Nerve Branch

Ooman KP, Ebbeling M, DeRu JA et al. A Previously Undescribed Branch of the Pterygopalatine Ganglion. Am J Rhinol Allergy; 2011:25:50-53

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Sphenopalatine Ganglion Ophthalmic Nerve Branch

Ooman KP, Ebbeling M, DeRu JA et al. A Previously Undescribed Branch of the Pterygopalatine Ganglion. Am J Rhinol Allergy; 2011:25:50-53

Middle Meningeal Nerve •  First branch of the

Trigeminal Maxillary nerve

•  Ascends through foramen spinosum with middle meningeal artery

•  Dural Innervation –  Middle cranial fossa –  Anterior cranial fossa with

Ophthalmic division

• Trigeminal Nerve – V1 • Branch of nasociliary nerve

•  Enters anterior ethmoidal foramen •  Sends sensory fibers to ethmoidal

air cells •  Extends into cranial vault by

cribriform plate •  Sends sensory fibers to the

meninges

Anterior ethmoidal Nerve

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Anterior Ethmoidal Nerve Innervates the Optic Nerve Dura

Burstein R. Research in progress (unpublished). 31

A

Nasal conchae

Cortex

Retina

Skin

II

A

Nasal conchae

Cortex

Retina

Skin

II

CRetina

II

CRetina

II

•  5ht1D receptor within primary afferent neurons

•  May Modulate post synaptic parasympathetic neurons

•  Implications for migraine and cluster HA

Ivanusic JJ, Kwok MMK, Ahn AH, Jennings EA. 5ht1D Receptor Immunoreactivity in the Sphenopalatine Ganglion: Implications for the efficacy of triptans in treatment of autonomic signs Asociated with Cluster HA. Headache. 2011; 51: 392-402

Autonomic influence on the Dura mater

•  Dense network of autonomic and sensory fibers within the Dura Mater

•  Sympathetic stimulation

(Norepinephrine) shows increased PGE2 and reduced serotonin

Ebersberger A et al. Effect of sympathetic and parasympathetic mediators on the release of calcitonin gene-related peptide and prostaglandin E2 for rat dura mater in vitro. Cephalalgia. 2006: 26:282-289.

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SPG Circuit - Role in Migraine

•  Autonomic Nervous System –  Parasympathetic Component

•  Meningeal Vasodilation •  Neurogenic Inflammation

•  Clinical signs –  Facial fullness –  Lacrimation –  Nasal edema

–  Sympathetic Component •  Cerebral vasoconstriction

Sphenopalatine Ganglion

Akerman S, Holland PR, Goadsby PJ. Diencephalic and Brainstem Mechanisms in Migraine. Nat Rev Neurosci. 2011; 12:570-84..

Superior salivatory nucleus (SSN) •  >50 limbic and hypothalamic

brain areas (red dots)

Proposed activation in migraine trigger •  Olfactory stimuli •  Hunger •  Sleep deprivation •  Stress response

Burstein R, Jakubowski M. J Comp Neurol. 2005;493(1):9-14.  

Parasympathetic Pathway of Meningeal Nociceptors

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Ivanusic JJ et al. Headache.2011. 51(3):392-402.

Postganglionic Parasympathetic Neurons in the SPG

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•  Receive input from 5HT1D / CGRP positive Axons in SPG •  May Disrupt communication between 5HT1D/CGRP-positive axons •  May prevent activation of the postganglionic neurons.

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Sympathetic post-ganglionic: CGRP-positive neurons in the

superior cervical ganglion1

1.  Baffi J. et al. Brain Res. 1992. 570(1):272-278. 2.  Lennerz JK et al. J Comp Neurol. 2008;507(3):1277-1299

Trigeminal ganglion: CGRP-positive neurons in the

trigeminal ganglion2

Origins of CGRP Input to the SPG

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SPG Circuit - Treatment

–  Local anesthetic blockade may terminate Migraine or Cluster

–  Reduced pain signals from dura

•  middle meningeal nerve

–  Autonomic nervous system effects •  ↓ Neurogenic inflammation •  ↓ Meningeal vasodilation

Pterygopalatine Fossa

Sphenopalatine ganglion

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Sphenopalatine Foramen

v  3 mm of connective tissue / mucous

membrane

v  Connects nasal passages to pterygopalatine fossa

v  Transmits vessels and nerves from the pteryogopalatine fossa

Sphenopalatine foramen is located above middle turbinate

Cadaver study examined location of sphenopalatine foramen

(N=54 hemi skulls)

v  At superior turbinate = 81.5%

v  Between middle & sup. turbinate

= 14.8%

v  At middle turbinate = 01.9%

Scanavine ABA, Navarro JAC, Megale SRM, Anselmo-Lima WM. Anatomical study of the sphenopalatine foramen. Brazilian Journal of Otolaryngology. 2009;75(1):37-41.

Sup. Turb. Middle Turb.

Inferior. Turbinate

Sphenopalatine Foramen

Sphenopalatine Ganglion

Sphenopalatine Foramen

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If someone has autonomic symptoms, its probably not migraine

Cranial Autonomic Parasympathetic Symptoms in Chronic Migraine

82% reported at least one CAPS –  Lacrimation 49% –  Conjunctival inj. 44% –  Eyelid edema 39% –  Ear fullness 30% –  Nasal congestion 20% –  Eyelid ptosis 42% (Cranial Sympathetic Autonomic Symptom)

Riesco N, Perez-Alvarez AI, Verano L, Garcia-Cabo C, Martinez-Ramos J, Sanchez-Lozano P, Cernuda-Morollon E, Pascual J. Prevalence of cranial autonomic parasympathetic symptoms in chronic migraine: Usefulness of a new scale. Cephalalgia. 2015.

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Yarnitsky D, Goor-Aryeh I, Bajwa ZH, Ransil BI, Cutrer FM, Sottile A, Burstein R. 2003 Wolff Award: Possible parasympathetic contributions to peripheral and central sensitization during migraine. Headache 2003;43:704-714

Sphenopalatine Ganglion Block Intranasal Rigid Applicator (Q-tip)

•  Topical anesthetic near SPG

•  Minimally invasive

•  Duration - 1 day to 6 weeks

•  Nasal anatomy does not permit easy placement –  Turbinates block access –  Lateral location of

sphenopalatine foramen

Sphenopalatine Ganglion Block Infra-Zygomatic Approach

•  Long needle advanced to pterygoid plate

•  Injection of medication to the pterygopalatine fossa

•  Relative poor tolerability –  Risk of hemorrhage –  Needle trauma –  Pain

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Injectate at the Sphenopalatine Foramen

Sphenopalatine Foramen

Contrast injectate

CT axial image of SPF Injectate of contrast at SPF

SPG Block - Clinical Autonomic Effects

Physiologic manifestations of “blocking” components of cranial autonomic circuit:

v  Cutaneous temperature changes v Typically ipsilateral cheek ↑ 3-5° F

v  Tearing v Lateral canthus of ipsilateral eye

Occurs within seconds

v  Facial erythema

SPG Block - Clinical Autonomic Effects •  Cutaneous temperature monitoring at zygoma •  SPG block via intranasal catheter – 63 cases

Left cheek –  Pre treatment = 32.6°C –  Post treatment = 35.4°C

Difference = 2.8°C Right cheek

–  Pre treatment = 32.3°C –  Post treatment = 34.0°C

Difference = 1.7°C

Cooper, WM. Internal data – not published

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Adverse Events from intranasal SPG block •  Temporary numbness of the throat •  Headache initiation / escalation •  Temporary dizziness

–  Inadvertent injectate into the eustacian tube •  Do not rotate head when delivering injectate •  Resolves in minutes/hours •  Very rare

–  Autonomic effects from SPG block •  Typically occurs hours after. •  May >24 hours •  Described as unsteady or spacey

Summary •  The autonomic nervous system plays an

integral role in head pain syndromes

•  Autonomic symptoms are common in migraine

•  The Sphenopalatine Ganglion plays a vital role in headache

–  Trigeminal nociception –  Parasympathetic pathway –  Sympathetic pathway

•  Intranasal anesthestic blockade may be an effective option for those with headache or facial pain