Craniofacial Autonomic Dysfunction in Migraine: Implications for Treatment and Prognosis

Background: Craniofacial autonomic signs and symptoms (CASS) are relatively underrecognized in the evaluation of migraine headache. Yet, these features provide insight into diagnostic criterion, therapeutic approaches, and overarching disease burden. Evidence acquisition: This review aims to summarize relevant literature evaluating autonomic dysfunction, with focus on CASS, in migraine through targeted literature searches in PubMed. Full articles of original data published between 1974 and 2019 were identified using MeSH terms with no search limits. Results: Although CASS are typically clinically evaluated by subjective patient report, investigational measures of cranial autonomic function have identified marked distinctions between headache attack and attack-free intervals. The presence of CASS during an attack does not differ based on age, sex, or presence of aura. Unilateral CASS may be predictive of longer, more frequent, and/or severe attacks and often co-occur with sensory dysfunction such as allodynia and photophobia. Although limited research has been performed to evaluate targeted therapeutics for migraine with CASS, triptans and onabotulinumtoxinA may demonstrate greater effects in this group. Conclusions: Migraine remains a debilitating disorder with significant community-wide impacts, necessitating continued evaluation of contributing features. Consideration of CASS provides important insight into potential treatment approaches and the effectiveness of novel therapeutic interventions aimed at improving overall disease burden. However, further investigation is needed to fully understand primary craniofacial features in migraine, and how these might inform individualized treatment decisions.

Disease of the Year 2019: Migraine-An Encore Publication Section Editors: Kathleen B. Digre, MD Deborah I. Friedman, MD, MPH Craniofacial Autonomic Dysfunction in Migraine: Implications for Treatment and Prognosis Melissa M. Cortez, DO, Leah Millsap, BS, K. C. Brennan, MD, Corey L. Campbell, PhD Background: Craniofacial autonomic signs and symptoms (CASS) are relatively underrecognized in the evaluation of migraine headache. Yet, these features provide insight into diagnostic criterion, therapeutic approaches, and overarching disease burden. Evidence Acquisition: This review aims to summarize relevant literature evaluating autonomic dysfunction, with focus on CASS, in migraine through targeted literature searches in PubMed. Full articles of original data published between 1974 and 2019 were identified using MeSH terms with no search limits. Results: Although CASS are typically clinically evaluated by subjective patient report, investigational measures of cranial autonomic function have identified marked distinctions between headache attack and attack-free intervals. The presence of CASS during an attack does not differ based on age, sex, or presence of aura. Unilateral CASS may be predictive of longer, more frequent, and/or severe attacks and often co-occur with sensory dysfunction such as allodynia and photophobia. Although limited research has been performed to evaluate targeted therapeutics for migraine with CASS, triptans and onabotulinumtoxinA may demonstrate greater effects in this group. Conclusions: Migraine remains a debilitating disorder with significant community-wide impacts, necessitating continued evaluation of contributing features. Consideration of CASS provides important insight into potential treatment approaches and the effectiveness of novel therapeutic interventions aimed at improving overall disease burden. However, further investigation is needed to fully understand primary craniofacial features in migraine, and how these might inform individualized treatment decisions. Journal of Neuro-Ophthalmology 2020;40:67-73 doi: 10.1097/WNO.0000000000000876 © 2019 by North American Neuro-Ophthalmology Society Department of Microbiology, Immunology and Pathology (CLC), Colorado State University, Fort Collins, Colorado; and Department of Neurology, University of Utah (MMC, LM, KCB, CLC), Salt Lake City, Utah. NIH NIMHD LRP, American Academy of Neurology Institute Clinical Research Training Scholarship Grant (M.M.C.); Fairclough Endowment for Headache Research (L.M.); NIH NINDS R01 NS 085413, NS 102978 (K.C.B.). The authors report no conflicts of interest. Address correspondence to Melissa M. Cortez, Department of Neurology, University of Utah, 729 Arapeen Dr, Salt Lake City, UT 84108; E-mail: [e-mail] Cortez et al: J Neuro-Ophthalmol 2020; 40: 67-73 C ranial autonomic signs and symptoms (CASS) are a relatively underappreciated feature of migraine headache. Yet, such features may inform underlying pathophysiology, guide diagnosis, and provide therapeutic insight. Recent data suggest that changes in craniofacial autonomic physiology are functionally linked to sensory dysfunction in migraine, such as photophobia and allodynia, and may predict therapeutic responsiveness (1-11). Importantly, underappreciation of migraine-associated CASS can lead to misdiagnosis, inappropriate therapies, or delayed migraine diagnosis (12-15). The goal of this review is to summarize the literature relevant to cranial autonomic function in migraine headache, with special emphasis on CASS, and describe emerging study areas that show promise for understanding disease burden and influencing therapeutic options. METHODOLOGY Full-text articles of interest, which presented original data, were identified from PubMed searches of peer-reviewed medical journals published between 1974 and 2019. PubMed MeSH terms included migraine, anisocoria, pupillometry, ptosis, mydriasis, pupil changes, headache disorders, trigeminal, craniofacial autonomic symptoms, craniofacial autonomic function, sensory, photophobia, triptans in migraine, triptans, medication use for autonomic dysfunction in migraine, calcitonin generelated peptide (CGRP) migraine, onabotulinumtoxin migraine, botulinum toxin migraine facial symptoms, and combinations of individual terms. No search limits were used. Review articles found for the subject area of interest were also assessed to identify additional peer-reviewed original research articles of interest, as well as background review relevance where indicated. Case reports and case control studies were generally not included, except where lack of other data is available, and thus are noted herein for completeness. Overview of Autonomic Dysfunction in Migraine Broad autonomic dysfunction has been documented in migraine, both during and between headache attacks. However, definitive patterns of sympathetic and 67 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019: Migraine-An Encore Publication parasympathetic dysregulation have not been consistently demonstrated across studies (3,16-18). We believe that this apparent lack of consistency could be reflective of statedependent differences across the prodromal, attack, postattack, and interval phases inherent to episodic migraine- these migraine phases are not consistently defined, especially in the earlier literature. Furthermore, severity of autonomic dysfunction likely differs across the spectrum of disease (episodic to chronic), wherein changes in autonomic function present between migrainous attacks may be the most apparent in those with the most severe migraine burden. Previous reviews broadly address autonomic dysfunction in migraine and have generally focused on cardiovascular measures such as heart rate variability and vasoreactivity. Many, but not all, conclude that the most consistent pattern is that of subtle sympathetic nervous system (SNS) hypofunction between headache attacks (reviewed in (18-20)). Others implicate increased resting sympathetic tone (21), which leads to blunted sympathetic responses to physiologic stressors (22,23). Finally, reductions in vagally mediated resting heart rate variability have also been widely reported (reviewed in (24)). In sum, the theme is supportive of a shift in overall sympathetic/parasympathetic balance, toward a systemic state of increased sympathetic resting tone, which thereby depletes peripheral noradrenergic stores yielding apparent hypofunction to reflex-mediated activation. Finally, beyond cardiovascular autonomic changes, temperature dysregulation, urinary symptoms, and gastrointestinal dysfunction are also common attack-related changes in autonomic function (20). Gastric stasis during the migraine attack is believed to be secondary to generalized imbalance of sympathetic and parasympathetic autonomic regulation (25), which in turn contributes to nausea, vomiting, and bloating associated with migraine attacks, and is believed to potentially impact absorption of abortive medications (26). Trigeminally Mediated Autonomic Function and Craniofacial Autonomic Signs and Symptoms Current models implicate abnormal activation of the trigeminal autonomic reflex as a mediator of CASS in migraine. This reflex pathway, which links cranial autonomic function through the trigeminal nerve with those of the cerebral blood vessels, is implicated in headache attack- related pain, as well as mechanisms leading to migraineassociated cutaneous allodynia, photophobia, and other sensory features (11,27). More specifically, nociceptive trigeminal afferents activate parasympathetic efferents (reviewed in (28)), carried through cranial nerves VII and VIII targeting the lacrimal glands and nasal mucosa. For additional reading, these circuits are well-reviewed by May and Goadsby 1999 and Noseda et al 2013. A combination of trigeminal activation and generalized SNS hypofunction, as introduced above, may contribute to migraine recurrence (reviewed in (29)). Finally, trigeminovascular projections to hypothalamic 68 and brainstem nuclei also likely contribute to other aspects of migraine autonomic symptomatology and homeostatic disruption, including loss of appetite, fluid retention, sleepiness, irritability, stress, and pursuit of solitude (reviewed in (30)). Overview of Craniofacial Autonomic Signs and Symptoms in Migraine The International Classification of Headache Disorders, third edition (ICHD III), outlines 7 key CASS for use in headache diagnosis: (1) conjunctival injection and/or lacrimation, (2) nasal congestion and/or rhinorrhea, (3) eyelid edema, (4) forehead and facial sweating, (5) forehead and facial flushing, (6) sensation of fullness in the ear, and (7) miosis and/or ptosis (Fig. 1) (31). Gelfand et al whose study examined CASS in pediatric migraine, added an additional symptom in this domain, to include sense of grittiness or scratchiness in the eye (32). Beyond these, varying changes in pupil size, including mydriasis, miosis, and anisocoria have been reported in association with migraine attacks (3,32-38). The reported frequency and/or incidence is summarized in Figure 1. Cranial autonomic symptom incidence has been variably reported in adult migraineurs, ranging from 27%-73% (3,38-41) (Table 1), and is associated with impaired quality of life (42). It is likely that some studies underestimate CASS, due to an overly restrictive definition, focusing on strictly unilateral CASS (27%-46% (6,11,43)). In fact, bilateral CASS are present in 67%-95% of migraine subjects reporting $1 migraine-associated CASS (40). Age, sex, and presence of aura do not consistently predict the likelihood of having cranial autonomic symptoms during a headache attack (6,32,39). However, when combined with unilateral presentation, migraineurs with CASS generally have more severe head pain, and longer and/or more frequent attacks (11,43), reflective of an increased disease burden associated with CASS. Interestingly, migraineurs reporting seasonal variation of their migraine attack frequency may also have more prominent migraineassociated CASS (38). Pupillary Dysfunction in Migraine Migraine-associated change in pupillary size is widely discussed clinically, although less commonly included in the context of CASS-related reports in migraine (Table 1). As a result, it is difficult to estimate the true incidence of various patterns, ranging from attack-associated miosis (with or without ptosis) or mydriasis, to anisocoria without reference to laterality. In general, comorbid rates of Adie's pupil and physiological anisocoria are believed to be higher in the migraine population, although differences in terminology, methods, and reporting rates across the literature limit conclusions that can be based on these observations. Perhaps the best-studied pattern of attack-related pupillary Cortez et al: J Neuro-Ophthalmol 2020; 40: 67-73 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019: Migraine-An Encore Publication FIG. 1. Cranial autonomic symptoms of migraine. Illustration by Jeremy Theriot. change in migraine is of mydriasis, ipsilateral to the headache side (33,34), which is believed to be linked to similar mechanisms that underly generation of lacrimation, congestion, and conjunctival injection during the pain attack (through trigeminovascular reflex activation discussed above). There are also a number of case reports of Adie's tonic pupil (44-46), although larger prospective studies of this association are lacking. Anisocoria can also be present between headache attacks and, in one study of 20 migraineurs, seemed to be unrelated to the habitual headache side (36,37). Pharmacological studies of pupillary function in migraineurs with attackassociated anisocoria have revealed cholinergic supersensitivity in the symptomatic pupil, evoking possible ganglionic parasympathetic dysfunction on the affected side. These changes in function may persist in excess of 1 year in some patients (34). Apraclonidine challenge, coupled with pupillometry, demonstrated that migraineurs demonstrate SNS hypofunction between and during attacks, with the effects being most pronounced during attacks (35). Fewer reports describe the presence of miosis during attacks, with or without ptosis, although this has been reported in up to 42% of migraine patients as a symptom accompanying headache (43). Generally, these manifestations are believed to be of secondary origin, rather than tied directly to trigeminovascular reflex activation (e.g., linked to symptoms of lacrimation, congestion, and conjunctival injection). Pharmacological assessment of postganglionic Cortez et al: J Neuro-Ophthalmol 2020; 40: 67-73 sympathetic function in the symptom-free period has also shown possible reduction in cervical sympathetic outflow in a subset of migraine subjects (35,47,48), which may be linked to the sympathetic hypofunction more widely observed in cardiovascular autonomic testing (18-20). Beyond differences in resting pupil size, changes in light response reflex arcs have also been widely demonstrated in migraine (Table 2); the overall theme across most of these studies is that of mixed hypofunction of both sympathetic and parasympathetic pupillary measures. Pupil cycle time (PCT) is a test of the pupillary light reflex arc, which was developed as a test of sympathetic and parasympathetic dysfunction (52-54). Although considered physiologically nonspecific (e.g., in contrast to quantitative light reflex testing, PCT does not distinguish between PNS and SNS impairment), this technique seems quite sensitive to physiological differences in even the mildest cases of migraine headache (e.g., ICHD-based probable migraine) compared with nonheadache controls (1). To the best of our knowledge, this was the first work to differentiate probable migraine from nonmigraineurs using a physiologic method, although further study is needed to better understand the neurophysiological underpinnings to this finding. Harle et al demonstrated an increased intereye difference in latency of pupil light responses in migraineurs, with a significant correlation between anisocoria and lateralization of headache. There was no significant relationship between interval since last headache, the side of 69 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019: Migraine-An Encore Publication TABLE 1. Cranial autonomic signs and symptoms of migraine Sign/Symptom Clinical Testing Attack-Related Frequency/Incidence Lacrimation Schirmer testing Nasal/sinus congestion or rhinorrhea Examination imaging: computed tomography and MRI Conjunctival injection Examination Ptosis or miosis Examination pharmacological testing Facial swelling (periorbital), flushing, and sweating Examination *2%-28% (Barbanti 2016, 2002) 44% (Gupta 2007) 44% (Lai 2009) *40% (Obermann 2007) †49% (Riesco 2015) 11%-20% (Shin 2015) 71% (Uluduz 2016) *6%-12% (Barbanti 2016, 2002) 10% (Gupta 2007) 36% (Lai 2009) *18% (Obermann 2007) †20% (Riesco 2015) 3%-5% (Shin 2015) 5% (Uluduz 2016) 37% (Gupta 2007) 24% (Lai 2009) *25% (Obermann 2007) †44% (Riesco 2015) 14%-25% (Shin 2015) 34% (Uluduz 2016) *20% (Obermann 2007) †42% (Riesco 2015) 11%-23% (Shin 2015) 7% (Uluduz 2016) 26% (Gupta 2007) 16%-52% (Lai 2009) *16% (Obermann 2007) †39% (Riesco 2015) 10%-22% (Shin 2015) 12% (Uluduz 2016) *Studied unilateral only. † Studied chronic migraine only. lateralization relative to the anisocoric side, severity of headache, nor number of headaches. These findings support the widely observed clinical association of anisocoria in migraineurs and demonstrate that functional differences in pupillary control persist between attacks (36). By contrast, other studies have suggested a phase-dependent difference in pupillary function, showing maximal dysfunction within days of the headache attack itself (35,50). Finally, autonomically medicated changes in pupillary response to light may be associated with altered sensory function in severe migraine (2). Secretory Dysfunction in Migraine Sinus symptoms can also occur in migraine and may sometimes lead to misdiagnosis as sinus headache, potentially leading to unnecessary diagnostic studies, surgical interventions, and medical treatments (15). This was illustrated by an observational study sampling 2,991 patients with a history of clinician or self-diagnosed sinus headaches, wherein 88% of these patients fulfilled clinical diagnostic criteria for migraine headache 70 (14). In the patients with migraine, sinus-associated discomfort and congestion commonly accompanied other typical migraine features, such as pulsating head pain and sensitivity to light. Clinically, pain related to sinus conditions can be differentiated from migraine based on the character of the pain, which is typically pressure-like and reproduced by palpation over the sinuses, as outlined by the ICHD III diagnostic criteria (headache attributed to disorder of the nose or paranasal sinuses; no longer termed "sinus headache") (31). Increased lacrimation may occur in up to 71% of migraineurs reporting CASS during a headache attack (Table 1). Interestingly, migraineurs, and in particular chronic migraineurs, may actually endorse symptoms of dry eye, which was supported by increased tear osmolarity analysis in one study (55). Dry eye symptoms in migraine patients may also correlate with reduced corneal nerve fiber density (56). Although these features have been discussed as potential biomarkers of disease, continued evaluation is warranted to better understand the relationship between such structural changes and the onset and progression of migraine. Cortez et al: J Neuro-Ophthalmol 2020; 40: 67-73 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019: Migraine-An Encore Publication TABLE 2. Summary of light reflex-mediated pupillary testing in migraine Method/Test TV pupillometry of PLR, paired with sural stimulation Infrared PLR Headache Type (Inter-, Intra- Ictal, or Both) Unilateral predominant migraine Interictal, tested within 1 week of an attack Infrared PLR Interictal Infrared PLR with apraclonidine challenge Interictal ictal Infrared pupillometry, paired with quantitative light sensitivity testing Interictal Infrared PLR Interictal Pupil cycle time Interictal Conclusions Possible parasympathetic deficiency SNS and parasympathetic hypofunction within 2 days of an attack, manifested by smaller resting pupil diameter (no difference in habitual side of pain) and slowed constriction velocity/amplitude SNS and parasympathetic hypofunction, not related to interval since last headache, manifested by greater anisocoria and prolonged latency of light response (significant interocular difference) Mild SNS hypofunction, revealed by apraclonidine challenge (using alpha-1 adrenoreceptor supersensitivity), most pronounced ictally SNS and parasympathetic hypofunction, most marked in severe migraine Increased pupil constriction (parasympathetic) during cold pressor test (prolonged SNS stimulation) Increased PCT in probable, episodic, and chronic migraine, correlated with CASS Reference Micieli (49) Mylius (50) Harle (36) Cambron (35) Cortez (2) Eren (51) Cortez (1) CASS, craniofacial autonomic signs and symptoms; PCT, pupil cycle time; PLR, pupillometry of light reflex; SNS, sympathetic nervous system; TV, television. Cortez et al: J Neuro-Ophthalmol 2020; 40: 67-73 71 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019: Migraine-An Encore Publication Therapeutics A wide variety of pharmacological treatments have been used clinically to treat migraine, including antiepileptics, tricyclics, serotonin reuptake inhibitors, alpha- and betaadrenergic receptor blockers, CGRP antagonists and antibodies, 5-HT1b/d receptor agonists ("triptans"), and "gepants," although most studies have not specifically evaluated their effects on CASS in migraine (57-60). Classically, serotonergic pathways are targeted for headache rescue, using triptans (8,9). In addition to addressing the migraine attack-associated pain, triptans may also improve unilateral autonomic symptoms such as lacrimation, eye redness, eyelid edema, nasal congestion, and rhinorrhea (6). This observation suggests that CASS generation may be downstream of the attack generation itself. Barbanti et al evaluated sumatriptan efficacy in migraine patients with unilateral cranial autonomic signs and symptoms (uCASS) (7). They found that migraineurs with uCASS responded better to this medication than other migraineurs after both 1- and 2-hour intervals, compared to those without uCASS. Migrainous allodynia most commonly occurs during the headache attack, maximally over the habitual headache side, but can also occur outside of headache attacks and/or spread to the contralateral side and extracranial sites in many patients (9). Facial allodynia is believed to be due to peripheral trigeminal sensitization, with similar underlying mechanisms as those that propagate CASS (57). Some have postulated that triptan effectiveness may be more likely in migraine patients with craniofacial allodynia and/or CASS, reflective of peripheral-but not yet central-sensitization (8,9), although this relationship has yet to be adequately studied. OnabotulinumtoxinA is used as a headache prophylactic in cases where previous treatments have failed (10,61). Up to 70%-80% of patients with chronic migraine will show an improvement with this therapy. However, in clinical practice, Bravo et al reported an estimated 20%-30% of patients have no response to treatment. Potential predictors for onabotulinumtoxinA treatment efficacy may include CASS, facial allodynia, and aura (5) implying that it may reduce autonomic outflow, thus diminishing headache triggering and/or the symptomatic burden of a headache attack. CONCLUSIONS Migraine is a chronic debilitating headache disorder that widely associated with craniofacial signs and symptoms during the headache attack and measurable physiological dysfunction during and between attacks. The presence of CASS in migraine is associated with more severe migraine, impaired quality of life, and features of central sensitization. Emerging data suggest a role for CASS in the prediction of treatment response to some abortive and prophylactic treatments. In summary, although long-overlooked in migraine, the presence of CASS merits our ongoing clinical and investigative attention, with the potential to advance 72 our understanding of underlying pathophysiology and migraine treatment. ACKNOWLEDGMENTS The authors thanks Jeremy Theriot for drafting of artwork. REFERENCES 1. Cortez MM, Rae N, Millsap L, McKean N, Brennan KC. Pupil cycle time distinguishes migraineurs from subjects without headache. Front Neurol. 2019;10:478. 2. Cortez MM, Rea NA, Hunter LA, Digre KB, Brennan KC. Altered pupillary light response scales with disease severity in migrainous photophobia. Cephalalgia. 2017;37:801-811. 3. Riesco N, Pérez-Alvarez AI, Verano L, García-Cabo C, MartínezRamos J, Sánchez-Lozano P, Cernuda-Morollón E, Pascual J. Prevalence of cranial autonomic parasympathetic symptoms in chronic migraine: usefulness of a new scale. Cephalalgia. 2016;36:346-350. 4. Uluduz D, Ayta S, Özge A, Yalin OÖ, Temel GÖ, Taşdelen B. Cranial autonomic features in migraine and migrainous features in cluster headache. Noro Psikiyatr Ars. 2016;55:220-224. 5. Winner PK, Sadowsky CH, Martinez WC, Zuniga JA, Poulette A. Concurrent onabotulinumtoxinA treatment of cervical dystonia and concomitant migraine. Headache. 2012;52:1219-1225. 6. Barbanti P, Fabbrini G, Pesare M, Vanacore N, Cerbo R. Unilateral cranial autonomic symptoms in migraine. Cephalalgia. 2002;22:256-259. 7. Barbanti P, Fabbrini G, Vanacore N, Pesare M, Buzzi MG. Sumatriptan in migraine with unilateral cranial autonomic symptoms: an open study. Headache. 2003;43:400-403. 8. Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol. 2012;8:89-99. 9. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain. 2000;123:1703- 1709. 10. Parrales Bravo F, Del Barrio García AA, Gallego MM, Gago Veiga AB, Ruiz M, Guerrero Peral A, Ayala JL. Prediction of patient's response to onabotulinumtoxinA treatment for migraine. Heliyon. 2019;5:e01043. 11. Barbanti P, Aurilia C, Dall'Armi V, Egeo G, Fofi L, Bonassi S. The phenotype of migraine with unilateral cranial autonomic symptoms documents increased peripheral and central trigeminal sensitization. A case series of 757 patients. Cephalalgia. 2016;36:1334-1340. 12. Eross E, Dodick D, Eross M. The Sinus, Allergy and Migraine Study (SAMS). Headache. 2007;47:213-224. 13. Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WF. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache. 2001;41:638-645. 14. Schreiber CP, Hutchinson S, Webster CJ, Ames M, Richardson MS, Powers C. Prevalence of migraine in patients with a history of self-reported or physician-diagnosed "sinus" headache. Arch Intern Med. 2004;164:1769-1772. 15. Cady RK, Schreiber CP. Sinus headache: a clinical conundrum. Otolaryngol Clin North Am. 2004;37:267-288. 16. Gupta VK. Sympathetic nervous system dysfunction in migraine: pearls and pitfalls in the theorizing process. Headache. 2004;44:841-842. 17. Rubin LS, Graham D, Pasker R, Calhoun W. Autonomic nervous system dysfunction in common migraine. Headache. 1985;25:40-48. 18. Thomsen LL, Olesen J. The autonomic nervous system and the regulation of arterial tone in migraine. Clin Auton Res. 1995;5:243-250. 19. Peroutka SJ. Migraine: a chronic sympathetic nervous system disorder. Headache. 2004;44:53-64. Cortez et al: J Neuro-Ophthalmol 2020; 40: 67-73 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019: Migraine-An Encore Publication 20. Miglis MG. Migraine and autonomic dysfunction: which is the horse and which is the jockey? Curr Pain Headache Rep. 2018;22:19. 21. Rauschel V, Straube A, Süß F, Ruscheweyh R. Responsiveness of the autonomic nervous system during paced breathing and mental stress in migraine patients. J Headache Pain. 2015;16:82. 22. Gotoh F, Komatsumoto S, Araki N, Gomi S. Noradrenergic nervous activity in migraine. Arch Neurol. 1984;41:951-955. 23. Napoli R, Guardasole V, Zarra E, Sena AD, Saccà F, Ruvolo A, Grassi S, Giugliano S, Michele GD, Cittadini A, Carrieri PB, Saccà L. Migraine attack restores the response of vascular smooth muscle cells to nitric oxide but not to norepinephrine. World J Cardiol. 2013;5:375-381. 24. Koenig J, Williams DP, Kemp AH, Thayer JF. Vagally mediated heart rate variability in headache patients-a systematic review and meta-analysis. Cephalalgia. 2016;36:265-278. 25. Tokola RA, Neuvonen PJ. Effects of migraine attack and metoclopramide on the absorption of tolfenamic acid. Br J Clin Pharmacol. 1984;17:67-75. 26. Volans GN. Absorption of effervescent aspirin during migraine. Br Med J. 1974;4:265-268. 27. Noseda R, Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, CSD, sensitization and modulation of pain. Pain. 2013;154(suppl 1):1-21. 28. May A, Goadsby PJ. The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab. 1999;19:115-127. 29. Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol. 2013;75:365-391. 30. Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci. 2011;12:570-584. 31. Headache classification committee of the international headache, S. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629-808. 32. Gelfand AA, Reider AC, Goadsby PJ. Cranial autonomic symptoms in pediatric migraine are the rule, not the exception. Neurology. 2013;81:431-436. 33. Woods D, O'Connor PS, Fleming R. Episodic unilateral mydriasis and migraine. Am J Ophthalmol. 1984;98:229-234. 34. Barriga FJ, López de Silanes C, Gili P, Pareja JA. Ciliary ganglioplegic migraine: migraine-related prolonged mydriasis. Cephalalgia. 2011;31:291-295. 35. Cambron M, Maertens H, Paemeleire K, Crevits L. Autonomic function in migraine patients: ictal and interictal pupillometry. Headache. 2014;54:655-662. 36. Harle DE, Wolffsohn JS, Evans BJ. The pupillary light reflex in migraine. Ophthalmic Physiol Opt. 2005;25:240-245. 37. Takeshima T, Takao Y, Takahashi K. Pupillary sympathetic hypofunction and asymmetry in muscle contraction headache and migraine. Cephalalgia. 1987;7:257-262. 38. Shin YW, Park HJ, Shim JY, Oh MJ, Kim M. Seasonal variation, cranial autonomic symptoms, and functional disability in migraine: a questionnaire-based study in tertiary care. Headache. 2015;55:1112-1123. 39. Gupta R, Bhatia MS. A report of cranial autonomic symptoms in migraineurs. Cephalalgia. 2007;27:22-28. 40. Lai TH, Fuh JL, Wang SJ. Cranial autonomic symptoms in migraine: characteristics and comparison with cluster headache. J Neurol Neurosurg Psychiatry. 2009;80:1116- 1119. 41. Uluduz D, Ayta S, Özge A, Yalin OÖ, au fnm, Temel GÖ, Taşdelen B. Cranial autonomic features in migraine and Cortez et al: J Neuro-Ophthalmol 2020; 40: 67-73 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. migrainous features in cluster headache. Noro Psikiyatr Ars. 2018;55:220-224. Ceylan M, Yalcin A. Coexistence of symptoms associated with trigeminal pathways in chronic and episodic migraine and the effects on quality of life. Pain Med. 2019;20:172-179. Obermann M, Mueller D, Hansen N, Poitz F, Slomke M, Dommes P, Diener HC, Katsarava Z, Obermann M. Prevalence of trigeminal autonomic symptoms in migraine: a populationbased study. Cephalalgia. 2007;27:504-509. Massey EW. Pupillary dysautonomia and migraine: is Adie's pupil caused by migraine? Headache. 1981;21:143-146. Purvin VA. Adie's tonic pupil secondary to migraine. J Neuroophthalmol. 1995;15:43-44. Tafakhori A, Aghamollaii V, Modabbernia A, Pourmahmoodian H. Adie's pupil during migraine attack: case report and review of literature. Acta Neurol Belg. 2011;111:66-68. Drummond PD. Cervical sympathetic deficit in unilateral migraine headache. Headache. 1991;31:669-672. De Marinis M. Pupillary abnormalities due to sympathetic dysfunction in different forms of idiopathic headache. Clin Auton Res. 1994;4:331-338. Micieli G, Tassorelli C, Magri M, Sandrini G, Cavallini A, Nappi G. Vegetative imbalance in migraine. A dynamic TV pupillometric evaluation. Funct Neurol. 1989;4:105-111. Mylius V, Braune HJ, Schepelmann K. Dysfunction of the pupillary light reflex following migraine headache. Clin Auton Res. 2003;13:16-21. Eren OE, Ruscheweyh R, Schankin C, Schöberl F, Straube A. The cold pressor test in interictal migraine patients - different parasympathetic pupillary response indicates dysbalance of the cranial autonomic nervous system. BMC Neurol. 2018;18:41. Blumen SC, Feiler-Ofry V, Korczyn AD. The pupil cycle time in Horner's syndrome. J Clin Neuroophthalmol. 1986;6:232- 235. Martyn CN, Ewing DJ. Pupil cycle time: a simple way of measuring an autonomic reflex. J Neurol Neurosurg Psychiatry. 1986;49:771-774. Miller SD, Thompson HS. Edge-light pupil cycle time. Br J Ophthalmol. 1978;62:495-500. Wong M, Dodd MM, Masiowski P, Sharma V. Tear osmolarity and subjective dry eye symptoms in migraine sufferers. Can J Ophthalmol. 2017;52:513-518. Kinard KI, Smith AG, Singleton JR, Lessard MK, Katz BJ, Warner JE, Crum AV, Mifflin MD, Brennan KC, Digre KB. Chronic migraine is associated with reduced corneal nerve fiber density and symptoms of dry eye. Headache. 2015;55:543-549. Edvinsson L, Mulder H, Goadsby PJ, Uddman R. Calcitonin gene-related peptide and nitric oxide in the trigeminal ganglion: cerebral vasodilatation from trigeminal nerve stimulation involves mainly calcitonin gene-related peptide. J Auton Nerv Syst. 1998;70:15-22. Bartolini M, Silvestrini M, Taffi R, Lanciotti C, Luconi R, Capecci M, Provinciali L. Efficacy of topiramate and valproate in chronic migraine. Clin Neuropharmacol. 2005;28:277-279. Dodick DW, Freitag F, Banks J, Saper J, Xiang J, Rupnow M, Biondi D, Greenberg SJ, Hulihan J. Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs. Clin Ther. 2009;31:542-559. Edvardsson B. Atenolol in the prophylaxis of chronic migraine: a 3-month open-label study. Springerplus. 2013;2:479. Matharu M, Halker R, Pozo-Rosich P, DeGryse R, Manack Adams A, Aurora SK. The impact of onabotulinumtoxinA on severe headache days: PREEMPT 56-week pooled analysis. J Headache Pain. 2017;18:78. 73 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.