More Than Meets the Eye: The Eye and Migraine -- What You Need to Know

Migraine has long been associated with disturbances of vision, especially migraine with aura. However, the eye plays an important role in sensory processing as well. We have found that the visual quality of life is reduced in migraine. In this review, we discuss how the migraine and eye pain pathways are similar and affect many of the common complaints which are seen in ophthalmology and neuro-ophthalmology offices, such as dry eye and postoperative eye pain. We also review other related phenomena, including visual snow and photophobia, which also are related to altered sensory processing in migraine.

Hoyt Lecture Williams F. Hoyt, MD The North American Neuro-Ophthalmology Society, in conjunction with the American Academy of Ophthalmology, established the annual Hoyt Lecture in 2001 in honor of William Fletcher Hoyt, MD, whose contributions to neuro-ophthalmology have spanned seven decades. A fellow of Frank Walsh, MD, the grandfather of clinical neuro-ophthalmology, Dr. Hoyt co-authored the 3rd edition of Clinical NeuroOphthalmology, the "bible" of our specialty. A faculty member of the departments of Ophthalmology, Neurology and Neurosurgery at the University of California San Francisco since 1958, Dr. Hoyt is world-renowned as a clinician, scholar and educator. He has published more than 300 scientific contributions and has trained more than 100 fellows, many of whom are senior professors in their own right, training the next generations of neuro-ophthalmologists on six continents. More Than Meets the Eye: The Eye and Migraine-What You Need to Know Kathleen B. Digre, MD Abstract: Migraine has long been associated with disturbances of vision, especially migraine with aura. However, the eye plays an important role in sensory processing as well. We have found that the visual quality of life is reduced in migraine. In this review, we discuss how the migraine and eye pain pathways are similar and affect many of the common complaints which are seen in ophthalmology and neuro-ophthalmology offices, such as dry eye and postoperative eye pain. We also review other related phenomena, including visual snow and photophobia, which also are related to altered sensory processing in migraine. Journal of Neuro-Ophthalmology 2018;38:237-243 doi: 10.1097/WNO.0000000000000660 © 2018 by North American Neuro-Ophthalmology Society I am deeply honored to give the 15th Hoyt lecture. The man we honor in this lecture, Dr. William F. Hoyt, was my academic grandfather; he trained both of my mentors- James J. Corbett and H. Stanley Thompson-with whom I trained at the University of Iowa. Dr. Hoyt left a huge legacy-not only the number of fellows he trained and the textbook he wrote, which for many years served as Departments of Ophthalmology and Neurology, Moran Eye Center, University of Utah, Salt Lake City,Utah This work was supported in part by an Unrestricted Grant from Research to Prevent Blindness, Inc, New York, NY, to the Department of Ophthalmology & Visual Sciences, University of Utah. The author reports no conflicts of interest. Address correspondence to Kathleen B. Digre, MD, Departments of Ophthalmology and Neurology, Moran Eye Center, University of Utah, Salt Lake City, UT; E-mail: [e-mail] Digre: J Neuro-Ophthalmol 2018; 38: 237-243 the definitive information source in neuro-ophthalmology, but also an entire optic disc collection that we include in the North American Neuro-ophthalmology Society (NANOS) Neuro-ophthalmology Virtual Education Library (https:// novel.utah.edu/Hoyt/). In his textbook, Hoyt recognized the prevalence of migraine, the many associated visual symptoms, and even mentioned the appearance of the cornea at the height of a migraine attack (1). Dr. Corbett also inspired my interest in migraine and headache when he and I would staff the Headache Clinic at the University of Iowa during my fellowship in neuro-ophthalmology. In addition, Dr. Thomson had me study the pupil in cluster headache patients. When I joined the faculty at the University of Utah, I started a headache clinic and restarted the neuroophthalmology clinic. So, you might say that for me, neuroophthalmology and migraine and headaches have been interwoven throughout my career. Although many of my colleagues in neuro-ophthalmology eschew migraine and headache, I hope that by connecting the 2 topics, I will at least spur better understanding between the 2 fields, and perhaps inspire neuro-ophthalmologists to embrace migraine and its various phenomena, as well as inspire headache specialists to appreciate how the eye and visual system help us understand migraine. Approximately 18% of women and 6% of men suffer from migraine (2). This means that migraine is more common than asthma and diabetes mellitus combined, and it will be seen every day in patients who are being evaluated at ophthalmology, neurology, and neuro-ophthalmology clinics. Migraine has associated visual features such as aura and 237 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture light sensitivity. It should not be surprising that there are even more features that intersect with vision, the visual system, and the eye. Although aura may only occur in about 1/3 of patients with migraine, photophobia or light sensitivity is an almost ubiquitous symptom during, and sometimes in between, an attack. Furthermore, 54% of patients when queried in a structured interview reported blurred vision with their migraine (3). Friedman and Evans (4) proposed that the blurred vision may be due to an imbalance in the sympathetic and parasympathetic systems-and may be related to tear film changes. Two facts connect migraine pain and ocular symptoms: first, trigeminal activation causes eye pain and second, autonomic dysfunction in either the sympathetic or parasympathetic pathway gives autonomic symptoms such as pupillary changes, lacrimation, redness to the eye and even blurred vision (5). It is really no wonder why migraine-related eye complaints are common in ophthalmology, neurology and neuroophthalmology offices. Migraine is noted to be the second most disabling neurological condition next to stroke (6). For a disorder that affects vision, we wondered if migraine affected visual quality of life. In fact, when we were evaluating baseline quality of life measures in participants enrolled in the Idiopathic Intracranial Hypertension Treatment Trial (7), an astute reviewer asked: "How does migraine affect the visual quality of life?" Amazingly, that study had not been conducted. We used our headache clinic population to answer this question. We had patients with migraine complete the National Eye Institute (NEI) Visual Quality of Life instrument (VFQ-25) (8), the NEI Neuro-ophthalmic supplement (9), a migraine quality of life self-assessment (MSQ) (10,11), and the Headache Impact Test (HIT-6) (12,13). We found that chronic migraine affected the VFQ-25, Composite score to be 85 compared with controls at 96 (P , 0.001). NEI supplement score was 72 in chronic migraine and 95 in controls (P , 0.001); the MSQ scores compared with those obtained from controls were lower as expected. The higher the HIT-6 score was, the lower the VFQ-25 turned out to be, which was similar to the findings in the 11HTT (7). The subtests most involved included ocular pain. We found that the visual quality of life in chronic migraine affects the visual quality of life as much as Graves disease (14), IIH (7), and multiple sclerosis-associated optic neuritis (15). Why would the eye be so important in migraine? To understand this, we need to understand: what is migraine? Migraine is believed to be an inherited disorder of sensory integration (16). The primary pain for this disorder comes from the trigeminal system, which includes the 3 branches of the peripheral cranial nerve; however, this system is more complicated than that-it also includes several trigeminal nuclei within the brainstem. The caudal nucleus of the trigeminal nerve (V) is an important relay station to the thalamus and then into the sensory system of the brain. 238 The first division of the trigeminal nerve has rich arborizing branches to the eye and orbit. In fact, the cornea has the highest density of trigeminal nerve endings anywhere in the body (17). The first division of V, which supplies sensation to the eye and orbit, also supplies a large part of the dura (18). It has been postulated that dural afferents sensitive to peptides such as calcitonin gene-related peptide and other peptides are important in this migraine process (19). However, pain is only one part of migraine. There are prominent autonomic features in the migraine process, such as nausea and vomiting-and often prominent autonomic features during migraine and cluster headache that affect the eye: eyelid edema, pupillary changes, and tearing. Both the parasympathetic system by way of several nuclei such as the Edinger-Westphal nucleus, superior salivatory nucleus link to ganglia to the ciliary, facial, and lacrimal nerves. The sympathetic system has its headquarters in the hypothalamus and descends to the C8T1 center, where after synapsing, it traverses up the carotid artery and enters the orbit through the first division of V to supply the pupil and lacrimal gland. These autonomic nerves also connect to blood vessels and regulate blood flow in the eye-with parasympathetic function often causing dilation and sympathetic function causing vasoconstriction. So, the proposed mechanisms of migraine, with its connection to the dura and autonomic elements, exactly parallels the innervation of the eye and orbital contents-it is NO surprise that the eye could be intimately involved in migraine (Fig. 1). By way of presentation of 4 cases, I hope that you will gain a greater understanding of these connections. The first patient is a 32-year-old woman who presents with eye pain. She asks her ophthalmologist for help. She has a history of migraine which used to be episodic but is now chronic (more than 15 days each month of migraine or migrainous features). Her eye examination is normal, but her Schirmer test result is 4 mm in each eye. Are these related? Can tear film dysfunction (either dry eye or dry eye symptoms) be related to migraine? There are several clues in the literature. First, patients with classic dry eye associated with Sjögren disease have a higher prevalence of migraine- 46% of patients have migraine (20). However, other studies have shown that you do not have to have Sjögren disease to have dry eye symptoms in migraine. Sarac et al (21) demonstrated that dry eyes and dry eye symptoms were more common in individuals with migraine than in normal controls, and that none of these individuals who were systematically studied had Sjögren disease. Although some studies (22) have shown that patients with migraine have lower Schirmer test results and tear film break-up time, many studies (22-26) have shown that the ocular symptoms of dry eyes are definitely increased in migraine. Shetty et al (25) found that even the optical properties of the tear film are abnormal in individuals with chronic migraine. Digre: J Neuro-Ophthalmol 2018; 38: 237-243 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture FIG. 1. The pathophysiology of migraine as a sensory processing disorder receives peripheral pain input from the dura and from the ocular sensory system-both by way of the first division of the trigeminal nerve. This, in turn, connects to the central trigeminal system including the nucleus caudalis. The autonomic system by way of the superior salivatory nucleus connects to both the dura and the eye through nerves emanating from the pterygopalatine (sphenopalatine) ganglia. These connections to the autonomic system affect blood vessels in the eye and dura and these autonomic connections cause many migraine symptoms such as nausea, tearing, pupillary changes, and others. Centrally, pain fibers ascend to connect to the thalamus, the amygdala, and the somatosensory cortices to give us conscious perception of pain, photophobia, and even an emotional aspect to migraine pain. The eye almost exactly mirrors the trigeminal input of the dura to the central structures and should, therefore, connect the eye into the pathophysiology of migraine. Reproduced with permission from (30). Celikbilik and Adam (26) found that individuals with dry eye symptoms had longer duration of migraine attacks. There are several clues as to why dry eye symptoms are increased in chronic migraine patients. First, the tear film is a balance between the trigeminal innervation to the eye (lacrimal gland along with the parasympathetic and sympathetic tone). Pflugfelder (27) has written extensively about the "integrated lacrimal functional unit." The importance of the unit is that the trigeminal system and the parasympathetic/sympathetic systems are linked together. However, individuals may have more pain and normal or dysfunctional tear function. Migraine patients may have more trigeminal symptoms than nonmigraine patients related to the corneal nerve irritation. We have shown that patients with chronic migraine had excessive dry eye symptoms on questionnaires but normal basal tear secretion, corneal sensitivity, and results of Schirmer testing (28). Moreover, patients with chronic migraine exhibited decreased corneal nerve fiber density on confocal microscopy (28). A change in corneal nerve density also has been documented by Shetty et al (29). So, the corneal nerves may be abnormal in chronic migraine as a result of the migraine disease process, or the corneal nerve changes may be exacerbating the migraine disease process. Just as researchers have proposed Digre: J Neuro-Ophthalmol 2018; 38: 237-243 that dural afferents play a role in migraine (19), so, too, the eye innervated by the same trigeminal system plays a role in the migraine process (Fig. 1). We do not know if treatment of dry eye symptoms will improve migraine or not-but at least this is another level of understanding that we can add in taking care of our migraine patients, especially those with chronic migraine. Shetty et al (25) opined that treating dry eye symptoms may help with tear film aberrations and also may improve chronic migraine. In the patient described above, we treated her dry eye symptoms and her migraine, with improvement in her complaints. Knowledge about migraine also helps the clinician when evaluating a patient with eye pain. The second case is a 30year-old woman who had laser in situ keratomileusis (LASIK) surgery 6 months before we saw her. The procedure had gone well, but she returned with severe eye pain. She reported a "burning pain" (7 out of a 10-point pain scale) and worse when she used the computer. She had moderate photophobia and was using eye drops regularly. Her examination was normal except for a mild papillary reaction of the conjunctiva and very small punctate corneal erosions. She has a history of fibromyalgia and also migraines. She has some post-LASIK eye pain but we can learn 239 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture more from her (30). Eye pain in the ophthalmology clinic usually divides between "red eye pain" due to conjunctivitis, dry eye, blepharitis, keratopathy, uveitis, iritis, foreign body, postsurgical, and scleritis/episcleritis. With "white eye pain," we are thinking migraine, cluster headaches, optic neuritis, and idiopathic intracranial hypertension. We reviewed all the causes of eye pain in an ophthalmology clinic and a neurology clinic at 2 tertiary centers-University of Zurich and University of Utah (31). The most common causes of eye pain in the ophthalmology clinic were those "red eye pain" complaints: conjunctivitis, keratitis, dry eye, blepharitis, keratopathy; however, in the neurology clinic, migraine, optic neuritis, and cranial neuropathy were most common. You may find that asking about migraine will help you understand your patient's eye complaint. Although post-LASIK eye pain can be seen 6 months after LASIK in 20%-50% of patients (32), knowledge about the aforementioned anatomical structures involving migraine may hold true for persistent postoperative pain complaints of our patients. We begin to see that migraine and eye pain can be a pain-processing problem. A recent study by Shtein et al (33) brings home this point. They compared patients with dry eyes to patients with fibromyalgia (a central pain processing problem) and normal controls (without any eye disease). They divided the dry eye patients into 2 groups: those with eyes that looked dry vs those whose eyes appeared normal. They found that the dry eye testing results with the Schirmer test were indeed lower in eyes that appeared dry, but dry eye symptom score was higher in those whose eyes did not look dry and who were similar to patients with fibromyalgia. They proposed that this was due to phenomenon of central sensitization (which we also see in migraine); this would account for patients who complained of dry eye symptoms but did not have dry eye signs (33). They also found that those patients with discordant dry eye scores (normal Schirmer test but abnormal dry eye scores) showed decreased corneal nerve density similar to what was seen in chronic migraine (28) as well as decreased visual quality of life. The decreased nerve density suggests that there is a neuropathic component to the pain which sets up peripheral sensitization (firing of peripheral nerves after an insult has occurred) and central sensitization where trigeminal neurons of the brainstem can fire independently. In migraine, central sensitization is believed to be a key factor in the migraine process leading to allodynia (34). The eye pain associated with dry eye symptoms could be another form of allodynia as a result of peripheral and/or central sensitization (35), and that just as allodynia may play a role in the chronicity of migraine (36), the dry eye symptoms may also play a similar role. This means that migraine as a sensory processing disorder also can involve the eye! In the case presented above, treating the cornea maximally with tears but also treating the patient's migraine with a preventative medication brought improvement of her complaints. 240 A third case shows us that patients with migraine have other visual symptoms-some related to the eye. A 17-yearold high school student presented with the chief complaint: "what is wrong with my vision?" He had a family history of migraine, and typical migraine with aura started when he was 9 years old. Typical migraines with aura occurred every 3-6 months. When questioned, he said he was experiencing several visual symptoms. First, he had "silvery lines" that were always present when he concentrated on them. He had floating and squiggly lines when he looked at the sky or snow. He stated he has had "grainy vision" all the time-as long as he can remember. These visual symptoms were NOT associated with any headache, and while he could see through these phenomena, they were very distracting. His entire examination is normal. He was exhibiting the symptom of visual snow-a term that comes from analog television sets of the past when they were poorly tuned. Schankin et al (37) proposed several criteria for visual snow, including dynamic and continuous tiny dots in the visual field for at least 3 months. In addition, visual snow may include the presence of 2 additional visual symptoms: palinopsia (either trailing images or seeing the intact image when looking away), and enhanced entoptic phenomena (excessive floaters, "self-light of the eye" photopsias), photophobia, and nyctalopia. The symptoms are not typical of migraine aura and are not explained by another disorder (37). These symptoms are NOT migraine aura, which according to the International Classification of Headache Disorders 3 (38) is defined as a unilateral visual symptom gradually developing over 5-60 minutes and either followed by a headache (migraine with aura) or not (migraine aura without headache). It is not prolonged aura (an aura lasting over 60 minutes but less than 4 hours) (39); it is not persistent aura without infarction (38), which is a typical visual aura that lasts longer than a week with no imaging signs of infarction. It is not migraine aura status (38), which is a typical visual aura in a patient with migraine aura who experiences 2 aura episodes each day for at least 3 days. Visual snow was described by Liu et al (40) as "persistent positive visual phenomena of migraine." Visual snow is more commonly seen in individuals with migraine. About 60% of all patients with visual snow have migraine, but headache is a more ubiquitous complaint in almost 90% (37). The disorder is seen in both women and men and often is present in childhood (as in our case) in about 25% of cases. There is a high prevalence of tinnitus (63%). Other complaints include palinopsia 86%, floaters 81%, blue field entoptic phenomenon 79%, photopsias 63%, photophobia 74%, and nyctalopia 74% (37). Many of these symptoms, including floaters and blue field entoptic phenomenon, must come from the eye (retina, vitreous) (41); but, it also is recognized that visual snow is associated with a central processing problem-"noise" in the visual system (41). Positron emission tomography has shown hypermetabolism in the right and left lingual gyri Digre: J Neuro-Ophthalmol 2018; 38: 237-243 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture (supplementary visual cortex), as well as in the cerebellum (42). Lauschke et al (43) called it a "thalamocortical dysrhythmia" due to dysfunctional neuronal excitability and impaired habituation response. Bou Ghannam and Pelak (44) called it a hyperexcitability of the primary visual cortex. Whatever the mechanism, visual snow is another example of a sensory integration problem seen with migraine (16)-integrating input along the visual pathway from the retina to the cortex. Treatment of visual snow may be as simple as reassurance. Medications do not always work, but include lamotrigine, nortriptyline, carbamazepine, sertraline (45), and blue-yellow filters and FL-41 lens filters (43). We treated our patient with gentle reassurance that the phenomenon that he was experiencing was not aura but rather visual snow. We used migraine-specific treatments for his migraine. Our final case is a 35-year-old woman with severe photophobia since a minor motor vehicle accident 6 months previously. She was no longer leaving her house due to her extreme photophobia. She did have a previous history of migraine, and her migraines had been somewhat more frequent (from 1 each month to 4-5 per month). She was wearing sunglasses in the office. Her visual and neurological examinations were normal. Photophobia is a very common complaint (46). Many of the causes, including iritis, corneal abrasion, uveitis, and retinitis pigmentosa, will be readily diagnosed by an ophthalmic examination. Other causes such as blepharospasm, migraine, or posttraumatic brain injury may not be so obvious (47,48). Photophobia is a symptom worthy of an approach to a diagnosis. First, take a careful history and conduct a careful eye examination-look for dry eyes and corneal neuropathy. A drop of lidocaine eye drops can assist in making a diagnosis of a peripheral cause of photophobia. A complete eye examination will uncover ocular inflammatory or retinal disease. Then, look for blepharospasm-not all blepharospasm will be frequent blinking and squeezing, but can be "reflexive" to a light shine in the eye. Ask about migraine. Three simple questions can help you diagnose migraine. Are headaches disabling? Is there associated photophobia? Is there nausea and/or vomiting? If 2/3 of your questions are answered affirmatively, the predictive value is very high that this is migraine (49). If the patient complains of unilateral photophobia, also consider a trigeminal autonomic cephalagia (50). Of importance is that green light has been found to be the most tolerable light (51). When we examine patients with photophobia, we usually use the green light during ophthalmoscopy. Photophobia also is a disorder of sensory processing. Whether it is processing input from rod/cones or the intrinsically photosensitive ganglion cells of the eye to the thalamus, these light sensors connect with dural/trigeminal pain afferents in the area of the posterior thalamus (52). Numerous studies have shown that the melanopsin pathway Digre: J Neuro-Ophthalmol 2018; 38: 237-243 plays an active role in photophobia. Hattar et al (53) showed that mice with disruption of rods/cones but an intact melanopsin system were still light sensitive despite no formed vision, but those without melanopsin were light insensitive. Photophobia also involves disruption in the integration of the autonomic nervous system because pupillary light reflexes are altered in individuals with chronic migraine (54). Why do we avoid seeing a patient wearing sunglasses in our waiting rooms? The "sunglass sign" may be an indicator of a psychogenic disorder (55). Is there an emotional component to photophobia? We studied this question in patients with migraine with interictal photophobia, migraine without interictal photophobia, and controls without migraine. We found depression and anxiety scores to be elevated in the patients with interictal photophobia (56). Animal studies have shown that emotional brain centers are involved in the process. Delwig et al found (57) that newborn mice (having only intrinsically photosensitive ganglion cells [melanopsin] at this stage) responded to light shone on them with vocalizations similar to distressed vocalizations when isolated from the litter. They also found that there was C-Fos expression in the posterior thalamus and light-induced activation in the amygdala (57). Recober et al (58) found that calcitonin gene-related peptide (CGRP) also was important in light sensitivity in mice. In fact, CGRP inhibitors reversed behavioral light aversion. Treatment of photophobia requires a correct diagnosis. There are some principles to follow. First, reduce dark adaptation-those in the dark need to slowly come into the light. Treat underlying migraine, anxiety, and depression. Consider the use of tinted lenses. First described by Good et al (59) for prevention of migraine, FL41 tinted lenses have been studied in blepharospasm and migraine (60,61). All ophthalmologists should look carefully for dry eyes or dry eye symptoms and treat with lubrication, as well as with lid hygiene. Onabotulinum toxin has been reported to be helpful in the treatment of photophobia after head injury (62). Other treatments to consider include a sympathetic block, which has been shown to be helpful both in photophobia after a corneal injury (63) and in blepharospasm with severe photophobia (64). In our patient, we diagnosed that she had dry eyes and treated her with tears and lid hygiene, and we maximally treated her migraines with preventive medications. If she did not respond, we were considering treatment with onabotulinum toxin. Migraine is a sensory processing disorder that involves the eye in many ways. Ophthalmologists, neurologists, and neuro-ophthalmologists need to know all about migraine- we will see it every day. We must realize that migraine is a factor in dry eyes, corneal neuropathy, and central sensitization after corneal surgery or injuries. We should be aware of symptoms of visual snow and correctly diagnose and treat our patients with photophobia. Ultimately, our 241 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hoyt Lecture efforts will lead to an improved quality of life for our patients with migraine. ACKNOWLEDGMENTS The author would like to acknowledge her great neuroophthalmic partners Bradley Katz, Judith Warner, and Alison Crum; and her great headache partners Susan Baggaley, KC Brennan, Melissa Cortez, Karly Pippitt, and Christina Bokat, who collectively understand the importance of knowing neuro-ophthalmology and migraine phenomena. Also, the author would like to thank all the fellows he have had who have worked on projects related to migraine and the eye including Krista Kinard, Laura Hanson, Zubair Ahmed, Anastasia Neufeld, and Seniha Ozudogru. Finally, the author would like to thank the great medical students she has worked with in many of the studies mentioned above. And of course, the author would like to thank all of her patients that have taught her clinical headache and neuro-ophthalmology every day. The author would like to thank Susan Schulman for her help in finalizing this manuscript. REFERENCES 1. Walsh FB, Hoyt WF. Clinical Neuro-Ophthalmology. 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