Neuro-Ophthalmic Symptoms of Primary Headache Disorders: Why the Patient With Headache May Present to Neuro-Ophthalmology

Background: Primary headache disorders can cause many ophthalmic symptoms that lead many patients to present for neuro-ophthalmic evaluation. Neuro-ophthalmologists frequently encounter these patients in clinical practice. Evidence acquisition: A literature review was completed in PubMed using the following terms paired with 'migraine' and 'headache:' dry eye, eye pain, monocular diplopia, binocular diplopia, photophobia, visual field defect, tunnel vision, floaters, amaurosis fugax, transient visual obscuration, autonomic symptoms, anisocoria, visual snow, Alice in Wonderland syndrome, and palinopsia. Results: Patients with migraine experience a wide range of visual disturbances including aura and more complex perceptual abnormalities such as Alice in Wonderland syndrome and visual snow. Visual disturbances may consist of positive and/or negative phenomena and may be binocular or monocular. Migraine and other primary headache disorders can be associated with photophobia, eye pain, dry eye, autonomic features, and anisocoria. Conclusions: Patients with primary headache disorders may experience a wide range of visual and ophthalmic symptoms. An understanding of the typical features of these disorders allows providers to help patients find appropriate treatment without unnecessary testing and to recognize when atypical presentations require additional evaluation.

Disease of the Year: Migraine Section Editors: Kathleen B. Digre, MD Deborah I. Friedman, MD, MPH Neuro-Ophthalmic Symptoms of Primary Headache Disorders: Why the Patient With Headache May Present to Neuro-Ophthalmology Stacy V. Smith, MD Background: Primary headache disorders can cause many ophthalmic symptoms that lead many patients to present for neuro-ophthalmic evaluation. Neuroophthalmologists frequently encounter these patients in clinical practice. Evidence Acquisition: A literature review was completed in PubMed using the following terms paired with "migraine" and "headache:" dry eye, eye pain, monocular diplopia, binocular diplopia, photophobia, visual field defect, tunnel vision, floaters, amaurosis fugax, transient visual obscuration, autonomic symptoms, anisocoria, visual snow, Alice in Wonderland syndrome, and palinopsia. Results: Patients with migraine experience a wide range of visual disturbances including aura and more complex perceptual abnormalities such as Alice in Wonderland syndrome and visual snow. Visual disturbances may consist of positive and/or negative phenomena and may be binocular or monocular. Migraine and other primary headache disorders can be associated with photophobia, eye pain, dry eye, autonomic features, and anisocoria. Conclusions: Patients with primary headache disorders may experience a wide range of visual and ophthalmic symptoms. An understanding of the typical features of these disorders allows providers to help patients find appropriate treatment without unnecessary testing and to recognize when atypical presentations require additional evaluation. Journal of Neuro-Ophthalmology 2019;39:200-207 doi: 10.1097/WNO.0000000000000790 © 2019 by North American Neuro-Ophthalmology Society Department of Neurology, Houston Methodist Neurological Institute, Houston, Texas; and Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas. S.V. Smith is a member of the speaker bureaus for Teva Pharmaceutics and Lilly USA, and a neurology consultant for concussion with the AMR NASCAR Safety team. Address correspondence to Stacy V. Smith, MD, Houston Methodist Institute of Academic Medicine and Weill Cornell Medicine, Houston Methodist Neurological Institute, Houston Methodist The Woodlands Hospital, 17183 I-45 South, Suite 690, The Woodlands, TX 77385; E-mail: [e-mail] 200 P rimary headache disorders are associated with multiple neuro-ophthalmic symptoms. These complaints lead many patients to present first to the ophthalmology or neuro-ophthalmology clinic for evaluation. Migraine is a complex disorder that causes multiple visual disturbances. Unfortunately, the intermittent and subjective nature of the complaints leads to frustration for patients and for providers alike because of the lack of objective findings on clinical examination. In addition, this leads to significantly reduced vision-specific quality of life (1). The other class of primary headache disorders that frequently present with ophthalmic symptoms is the trigeminal autonomic cephalalgias (TACs). Although the symptoms are benign, they can be distressing for the patient and mistaken for more severe ocular pathology. All patients should be screened for red flag symptoms that may suggest a secondary headache syndrome (Table 1) (2); but, appropriate recognition of the many ophthalmic complaints that characterize primary headache disorders is key to tailoring the evaluation and to obtaining effective treatment in a timely manner. This review will focus on the common neuro-ophthalmic symptoms of patients with headache that lead them to seek ophthalmological evaluation. INTERNATIONAL CLASSIFICATION OF HEADACHE DISORDERS The International Classification of Headache Disorders, third edition (ICHD-3) is an essential tool in correctly diagnosing headache disorders. In addition to standardized diagnostic criteria, the ICHD-3 also provides information on typical patient demographics and the varieties of clinical presentation for headache disorders. Although tension-type headache is the most common primary headache disorder overall, migraine is the most common primary headache disorder seen clinically because of the multiple associated symptoms and relative disability of this headache syndrome. Migraine affects approximately 18% of women and 6% of men (3). The diagnosis of migraine requires at least 5 Smith: J Neuro-Ophthalmol 2019; 39: 200-207 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine TABLE 1. "Red flag" symptoms in patients with headache warranting specialized investigation (2) "Red Flag" Symptom Systemic complaints High-risk comorbid disorders Neurological symptoms Abrupt onset Age .50 years Acute change in headache or progression of symptoms Postural Example Fever and weight loss Malignancy, immunosuppression, and pregnancy Weakness, gait instability, and speech change Pain peaks in ,1 min Pain significantly worse in a particular position (lying vs standing) Precipitated by Valsalva-type activities Pulsatile tinnitus Persistent symptoms New, unresolving vision change episodes of headache lasting 4-72 hours with at least 2 of 4 of the following criteria: moderate to severe intensity, unilateral location, pulsating or throbbing quality, and worsening with physical activity. Associated symptoms include nausea, photophobia, and phonophobia. Patients with at least 8 migraine days and 15 or more headache days per month for at least 3 months meet criteria for chronic migraine. Those with fewer than 15 headache days per month have episodic migraine (Table 2) (4). The TACs are much less common, but most of these patients experience one or more ophthalmic complaints. The class includes cluster headache, paroxysmal hemicrania, shortlasting unilateral neuralgiform headache attacks, and hemicrania continua. These disorders are characterized by severe, unilateral headache. The pain typically occurs in the periorbital area but can involve other areas of the head. Patients have autonomic symptoms and/or restlessness during the pain attacks. The disorders are differentiated by the frequency and duration of the pain episodes (Table 3) (4). Paroxysmal hemicrania and hemicrania continua also exhibit absolute response to appropriately dosed indomethacin as a defining characteristic. Other primary headache disorders that may cause ophthalmic complaints include tension-type headache with photophobia and primary stabbing headache occurring in the periorbital region. Tension-type headache is the most common headache disorder, but because it is less disabling, patients do not present for evaluation as frequently. It is defined by meeting 2 of the 4 criteria: bilateral location, nonpulsatile pain, mild to moderate intensity, and lack of exacerbation with routine physical activity. Nausea and vomiting cannot be Smith: J Neuro-Ophthalmol 2019; 39: 200-207 Differential Diagnosis Infection and autoimmune disease Mass lesion, infection, and venous sinus thrombosis Mass lesion and vascular lesion Intracranial bleed and vasospasm Mass lesion and vascular lesion Mass lesion, vascular lesion, and uncontrolled systemic disease (e.g., hypertension) Mass lesion, intracranial hypertension, and intracranial hypotension Mass lesion, intracranial hypertension, and intracranial hypotension Mass lesion, intracranial hypertension, and intracranial hypotension Optic nerve ischemia, cerebral ischemia, and epileptic activity present, and the patient cannot have both photophobia and phonophobia (one of these symptoms is allowed). Primary stabbing headache consists of sharp pains lasting up to seconds and occurring with irregular frequency. Although it typically occurs in extratrigeminal regions, the pain can occur in or around the eye (4). However, unlike the TACs, primary stabbing headache does not have autonomic features. It is a common comorbid headache disorder with migraine. VISUAL DISTURBANCES The classic visual disturbance of migraine is an aura. This occurs in approximately 30% of patients with migraine and also in some patients with TACs. The typical teichopsia or fortification scotoma starts as a small, crescent-shaped zigzag image in the paracentral field that slowly grows in size as it moves toward the periphery. It often has a shimmering quality, and some patients may perceive colors as well. Other positive phenomena may include phosphenes, sparkles, and spots in the vision. As the scotoma evolves, an area of decreased or blurred vision may accompany it. The positive and negative phenomena of the aura correspond with cortical spreading depression of Leão, a wave of excitation followed by inhibition and oligemia that spreads through the cortex (5). It is thus a binocular phenomenon, but many patients perceive it as monocular. A typical aura builds gradually over at least 5 minutes and lasts 5-60 minutes. Other less common features of a migraine aura include sensory and/or speech changes. Headache should accompany it or follow within 60 minutes, but some patients experience a typical 201 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine TABLE 2. ICHD diagnosis of migraine (4) Migraine without aura A. At least 5 attacks fulfilling criteria B-D B. Headache attacks lasting 4-72 h C. At least 2 of the following characteristics are 1. present: 2. 3. 4. D. At least one of the following is present: Migraine with aura E. Not better accounted for by another ICHD-3 diagnosis A. At least 2 attacks fulfilling criteria B-C B. One or more of the following fully reversible aura symptoms: C. At least 3 of the following characteristics are present: Unilateral location Pulsating quality Moderate to severe pain intensity Aggravated by routine physical activity (or causes avoidance of the activity) 1. Nausea and/or vomiting 2. Photophobia and phonophobia 1. Visual 2. Sensory 3. Speech and/or language 4. Motor 5. Brainstem 6. Retinal 1. At least 1 aura symptom spreads gradually over $5 min 2. Two or more aura symptoms occur in succession 3. Each individual aura symptom lasts 5-60 min (1) 4. At least 1 aura symptom is unilateral (2) 5. At least 1 aura symptom is positive (4) 6. The aura is accompanied, or followed within 60 min, by headache D. Not better accounted for by another ICHD-3 diagnosis ICHD-3, International Classification of Headache Disorders, Third Edition. aura without a headache. It is also possible for an aura to become prolonged, with "persistent aura without infarction" defined as an aura that remains continuous for a minimum of 1 week, with cases lasting as long as 28 years (4,6). Those with persistent visual phenomena merit evaluation for cerebral ischemia. Generally, stereotyped visual symptoms that recur multiple times with complete return to baseline suggest against transient ischemic attack or stroke. Occipital lobe epileptic activity can also cause visual aura. However, this has abrupt onset, and the duration is typically shorter than 5 minutes. The image tends to remain lateralized in a single hemifield, whereas a migraine aura can alternate sides and/or cross the vertical midline. The epilepsy aura commonly remains fixed, as opposed to the slow spread of the migraine aura (7). Patients with a visual aura can also experience perceptual abnormalities. They may describe this as viewing through a kaleidoscope, cracked glass, or rain on a window (8). Polyopia and palinopsia can also occur (9,10). Various forms of metamorphopsia have been described, with migraine being the most common cause of Alice in Wonderland syndrome (AWS) (11). This is an episodic perception of distortion of one's own body or objects in the environment, including micropsia, macropsia, teleopsia (objects appear unusually far away), and pelopsia (objects 202 appear unusually close). Although this can occur before a migraine, as expected for an aura, many patients experience AWS symptoms separate from headache. It is unclear whether this represents a form of aura without headache because it does not meet criteria for a typical aura as defined by the ICHD-3 (4,12). Regardless, AWS is closely associated with migraine, occurs in 15% of patients, and can respond to migraine preventive therapy (11,13). Visual snow is another visual perceptual disorder closely associated with migraine. Patients experience a constant positive visual disturbance that consists of fine flickering dots similar to "television static;" this is present throughout the entire visual field. Patients also experience other visual disturbances, such as palinopsia, entopic phenomena, photophobia, and nyctalopia (2 of the 4 are required as per the proposed diagnostic criteria) (14). A small functional imaging study showed hypermetabolism in the supplemental visual cortex of these patients (15). The symptoms may be due to dysfunctional central sensory processing (16). Despite the multiple visual complaints, clinical ophthalmological and neurological examinations are normal, thus often leading to a neuro-ophthalmological consultation. Visual snow is considered a distinct entity from a migraine aura because it lacks the characteristic features (14,15). However, Smith: J Neuro-Ophthalmol 2019; 39: 200-207 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine TABLE 3. ICHD-defining characteristics of trigeminal autonomic cephalalgias (4) TAC Location Duration Frequency Cluster Headache Paroxysmal Hemicrania Severe unilateral orbital, supraorbital, and/ or temporal pain 15-180 minutes Severe unilateral orbital, supraorbital, and/or temporal pain One every other day to 8 per day Short-Lasting Neuralgiform Headache Attacks 2-30 minutes Moderate or severe orbital, supraorbital, temporal, and/or other trigeminal distribution of pain 1-600 seconds .5 per day .1 per day Hemicrania Continua Unilateral headache, with exacerbations of moderate or greater intensity Baseline headache .3 months; exacerbations variable Baseline headache constant; exacerbations variable ICHD, International Classification of Headache Disorders, Third Edition; TAC, trigeminal autonomic cephalalgia. providers should be aware of the high degree of comorbidity of visual snow with migraine (59%) or headache (87%), and the fact that migraine can aggravate this syndrome (15,17). Visual snow is often refractory to treatment, but one case report showed efficacy for lamotrigine (18). This antiepileptic is also commonly used in migraine with aura, further supporting a link between visual snow and migraine. A variety of negative visual phenomena also occur with migraine. Vision loss is atypical in other primary headache disorders, and the degree of suspicion for secondary causes is much higher than with positive phenomena. Aura-related vision loss is typically a scotoma that progresses across the visual field, with or without accompanying positive phenomena. As with positive phenomena, stereotyped events that follow the expected slowly progressing timing of an aura rarely suggest secondary pathology. However, patients with migraine often complain of a variety of other forms of vision loss that may require additional evaluation and monitoring. For instance, some patients may experience a homonymous hemianopic pattern of vision loss. This has been documented on automated perimetry during acute migraine (19). Although persistent hemianopia has been reported in migraine (20), a hemianopic visual field defect may also be the sole symptom of acute ischemia. A careful history is necessary to ascertain that the visual disturbance is consistent with migraine etiology as opposed to a vascular disorder. This is particularly important in patients with a history of migraine if this is the first occurrence of the visual complaint or if an associated headache has any other new features. Although headache occurs in only a minority of stroke patients, it is more likely with posterior circulation ischemia (21). Yet, patients without vascular risk factors who describe multiple similar events in close association with a headache and no other focal deficits often can be safely treated as migraine with an aura. Even in patients where transient ischemic attack cannot be completely ruled out, aspirin therapy can be used for migraine prevention and vascular prophylaxis (22). Smith: J Neuro-Ophthalmol 2019; 39: 200-207 Patients with migraine, even those without an aura, are more likely to have abnormal visual field testing, particularly during attacks (23,24). There is also evidence of impaired performance 1 day after the migraine in what is now recognized as the postictal period. Repeat visual field testing 7 days after resolution of a migraine attack did not differ significantly from controls (25). These studies have not identified a particular visual field pattern or defect as "characteristic" of migraine; patients may demonstrate constricted field, peripheral island, generalized depression, nasal step, altitudinal defects, or other nonspecific changes (23,24). Despite the visual field abnormalities, patients with migraine do not have significant changes in the cup:disc ratio or peripapillary retinal nerve fiber layer thickness on optical coherence tomography compared with controls (23,26). Constricted fields were the most common visual field abnormality, occurring in 14% of patients in 1 study (24). This finding correlates with the common complaint of "tunnel vision" in patients with headache. Although many patients describe this as their aura before or during the headache, the pattern of vision loss is atypical for aura and less clearly associated with the concept of cortical spreading depression. It may reflect altered occipital cortex blood flow because similar symptoms can occur in syncope and vertebral basilar insufficiency. However, tunnel vision is also a common pattern of functional vision loss. In a study on the characteristics of patients with functional vision loss, 20% of patients had comorbid migraine or facial pain, suggesting a component of functional overlay may be present in some patients with migraine and constricted visual fields (27). Acute monocular vision loss is another complaint that is commonly encountered in both the neuroophthalmology and headache clinics. Again, the first step is assessment for signs and symptoms that may indicate a secondary etiology, with particular concern for vascular ischemia. Similar to the cortical auras of migraine, the 203 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine visual aura of retinal migraine should spread over at least 5 minutes, last 5-60 minutes, and be followed by a headache within 60 minutes (at least 2 of the 3 criteria must be met). The visual field defect must be monocular and fully reversible (4). Patients commonly experience vision loss but may report positive features such as monocular phosphenes, halos, and teichopsia (28). It is a diagnosis of exclusion after evaluating for other causes of acute vision loss. The onset and duration are in contrast to that of amaurosis fugax due to carotid disease, which onsets abruptly and resolves rapidly (28). In addition, the perception of a shade coming down over the visual field is highly suggestive of an embolic event (29). There are also cases of ischemic optic neuropathy in association with migraine (30-34). Although migraine pathophysiology is now understood to be much more complex than vasospasm alone, in the case of retinal migraine, there is evidence to support that this phenomenon arises because of retinal arterial vasospasm (35). Spreading depression similar to that of the cerebral cortex has been demonstrated in the retinas of chickens but not confirmed in humans (35- 37). Among preventive therapy options, calcium channel blockers have shown efficacy for this form of migraine and further support the mechanism of vasospasm (38). Although the literature is limited by incorrect diagnoses and the diagnosis of retinal migraine itself remains controversial, there is evidence that many patients who meet diagnostic criteria later develop permanent vision loss and optic atrophy (28,39,40). Therefore, preventive therapy is recommended, and vasoconstrictive agents should be avoided in these patients (28). Rarely, binocular vision loss is reported by patients with migraine. A study by Rozen found that only 1.6% of patients experience this visual phenomenon, and that it typically occurs in patients without a history of aura or other brainstem features. In addition, the blindness episodes occur during the headache and have abrupt onset. Duration is from seconds to 120 minutes (41). As with many of the other visual disturbances, binocular vision loss can be difficult to evaluate clinically because symptoms generally resolve before presentation. Detailed history may elucidate that "blindness" is actually tunnel vision or other visual disturbances, rather than true binocular blindness. There may be a functional overlay with vision loss, yet this is always a diagnosis of exclusion. All patients in the study on binocular blindness had abnormal coagulopathy testing (41). There are 2 documented families with recurrent binocular blindness as part of their headache syndromes who were found to have novel SCN1A mutations (42). PHOTOPHOBIA AND EYE PAIN Photophobia is another common complaint in headache and is part of the diagnostic criteria for migraine. The term 204 "photophobia" is commonly used to refer to increased light sensitivity, exacerbation of the headache by light, or ocular discomfort due to bright lights (43). The painful binocular sensitivity to light is believed to be mediated by the trigeminal autonomic system (44). Migraine is the most common reason for photophobia (45) and is one of the most common causes of eye pain in both ophthalmology and neurology clinics (46). This can occur in the premonitory phase before headache pain and can also persist even between migraine attacks because of baseline central nervous system hypersensitivity in the interictal period (47). Photophobia in patients with TAC occurs ipsilateral to the pain and autonomic features during the headache. Photophobia can be present between attacks of cluster headache, but typically only during the episodic cluster period (48). Photophobia can be a feature of tension-type headache but typically is less severe than in migraine. Multiple complex theories have been proposed regarding the pathophysiology of photophobia. Both photoreceptor cells (rods and cones) and intrinsically photosensitive cells (melanopsin-producing cells) transmit signals to the trigeminovascular system that plays a key role in the pathophysiology of migraine and TACs, and also transmits to thalamic, hypothalamic, and midbrain structures that mediate the autonomic nervous system (43). Dry eye is the most common ocular cause of photophobia and is a frequent cause of eye pain; it is also a comorbid factor in many patients with migraine (45). Dry eye can often explain the most common visual disturbance in migraine, "blurry vision" (3,49). Similarly, diplopia in migraine is generally found to be monocular-another common presentation of dry eye. Chronic dry eye can lead to corneal neuropathy, and corneal confocal microscopy has confirmed neuropathic changes in the corneas of chronic migraine patients compared with those in controls. This lends further support to the role of the trigeminovascular system in the genesis of photophobia and migraine (50). Recognition of the role of dry eye in photophobia is important to improving the quality of life of patients with migraine through symptomatic management; this is true since persistent photophobia between headache attacks is associated with higher incidences of depression and anxiety (51,52). Fluorescent (FL)-41 filters may provide symptomatic relief in migraine and other disorders of photophobia (53). Eye pain is a common complaint of patients with dry eye and photophobia, but because the trigeminal system is the primary pain pathway in migraine, many patients experience their migraine headache pain in and around the orbit (54). Trochlear pain is a frequent comorbid feature in patients with migraine, causing aching, pressure, or dull pain in the medial brow, orbit, temple, retrobulbar region, and/ or forehead. Supraduction of the eye exacerbates the pain (55). Eye pain may also be cervicogenic, with many patients with migraine experiencing greater occipital nerve allodynia as part of their migraine syndrome and/or comorbid occipital neuralgia. Pain refers to the orbital region because the Smith: J Neuro-Ophthalmol 2019; 39: 200-207 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine TABLE 4. Summary of neuro-ophthalmic symptoms of migraine and trigeminal autonomic cephalalgias Aura and other visual disturbances "Blurry vision" Photophobia Eye pain Autonomic symptoms Anisocoria Migraine Trigeminal Autonomic Cephalalgias Common Common, bilateral Common, bilateral Common, bilateral Occasional Benign episodic mydriasis, miosis Rare Common, unilateral Common, unilateral Common, unilateral Almost always present Miosis trigeminal nucleus caudalis is located in close proximity to the cervical sensory neurons and receives input from both cervical and trigeminal fibers (56,57). Other disorders that may mimic the eye pain and other ophthalmic symptoms of migraine include acute angle-closure episodes and orbital inflammation (58,59). DIPLOPIA Patients with migraine may note double vision. As stated above, history typically reveals this to be bilateral or unilateral monocular diplopia that is suggestive of symptomatic dry eye. Binocular diplopia is exceedingly rare in primary headache disorders and should merit evaluation for secondary etiologies. Idiopathic intracranial hypertension is a common cause of migrainous headache and can cause transient or persistent diplopia because of the sixth nerve palsy. The entity previously known as "ophthalmoplegic migraine" is now understood to be a form of inflammatory cranial neuropathy; this is now termed "recurrent painful ophthalmoplegic neuropathy." It is diagnosed based on at least 2 attacks of unilateral headache associated with ipsilateral paresis of one or more ocular motor nerves (4). Many cases show abnormal enhancement of the oculomotor nerve during the attack, usually at the nerve root exit zone in the interpeduncular cistern (60). AUTONOMIC SYMPTOMS A variety of autonomic symptoms acutely affecting the eye can occur as part of a primary headache syndrome because of parasympathetic-sympathetic tone imbalance. Autonomic fibers are carried by trigeminal nerve branches to the orbital vasculature, pupil, superior tarsal muscle, and lacrimal gland (54). The symptoms are the defining characteristic of the TACs, but also occur in some patients with migraine. Ocular symptoms include ptosis, periorbital and/ or eyelid edema, conjunctival injection, tearing, and miosis. Other nonocular symptoms include nasal congestion, rhinorrhea, aural fullness, and forehead or facial sweating. Lacrimation and conjunctival injection are the most common symptoms (61), and are the defining features of shortlasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, or "SUNCT." Some patients with TAC may appear to have Horner syndrome because of Smith: J Neuro-Ophthalmol 2019; 39: 200-207 the combination of ptosis and miosis. Of note, these patients more typically experience ipsilateral facial sweating vs the anhydrosis of a classic Horner syndrome (4). Although the symptoms usually occur only during the acute headache attack, interictal partial Horner syndrome may occur in cluster headache (61). The autonomic features of TACs should remain ipsilateral to the pain. When present in migraine, the autonomic symptoms are more likely to be bilateral. In addition, they are milder and less consistently present in migraine (62). Physiological signs require consideration of imaging for secondary etiologies; this is due to the association of TAC-type headache with pituitary tumors and other structural lesions (63-67). In those with unremarkable examinations and imaging studies, appropriate diagnosis of primary headache disorder and directed management are essential to improving the patient's quality of life. ANISOCORIA Anisocoria may occur in the setting of primary headache because of either abnormal miosis or mydriasis; both indicate an autonomic imbalance between parasympathetic constriction and sympathetic dilation of the pupil. Miosis may occur in association with other autonomic symptoms, as described above, or in isolation. Benign episodic unilateral mydriasis is a cause of anisocoria that most commonly occurs in young women with migraine (68). It may occur before or during a headache and in isolation from headache (69). The mydriasis may switch eyes during or between attacks. Bilateral autonomic imbalance may also cause bilateral mydriasis during a migraine attack, although symmetric pupil dilation may not be obvious to all patients. Mydriasis may be another factor involved with the frequent, nonspecific complaint of blurry vision with migraine. CONCLUSIONS Migraine and other primary headache disorders cause a variety of neuro-ophthalmic complaints that may be distressing for the patient. Key symptoms and their presentation in migraine and TAC are summarized in Table 4. In almost all cases, examination is normal between and even during episodes of symptoms. It is imperative that the neuro-ophthalmologist be familiar with headache disorders 205 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine because of their frequent presentation with neuroophthalmic complaints. This knowledge also allows the provider to recognize when a patient's symptoms are atypical and merit further investigation for secondary causes. With accurate diagnosis, focus can transition to appropriate treatment and potentially lead to improvement in quality of life for those with headache disorders. REFERENCES 1. Hanson LL, Ahmed Z, Katz BJ, Warner JEA, Crum AV, Zhang Y, Zhang Y, Baggaley S, Pippitt K, Cortez MM, Digre KB. Patients with migraine have substantial reductions in measures of visual quality of life. Headache. 2018;58:1007-1013. 2. Dodick DW. Pearls: headache. Semin Neurol. 2010;30:74-81. Updated: Scottsdale Headache Symposium, 2018: Diagnosis of Migraine. 3. Robbins MS, Lipton RB. The epidemiology of primary headache disorders. Semin Neurol. 2010;30:107-119. 4. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38:1- 211. 5. Leao AAP. Spreading depression of activity in cerebral cortex. J Neurophysiol. 1944;7:359-390. 6. Thissen S, Vos IG, Schreuder TH, Schreurs WM, Postma LA, Koehler PJ. Persistent migraine aura: new cases, a literature review, and ideas about pathophysiology. Headache. 2014;54:1290-1309. 7. Hartl E, Gonzalez-Victores JA, Remi J, Schankin CJ, Noachtar S. Visual auras in epilepsy and migraine-an analysis of clinical characteristics. Headache. 2017;57:908-916. 8. Friedman DI, Evans RW. Are blurred vision and short-duration visual phenomena migraine aura symptoms? Headache. 2017;57:643-647. 9. Belcastro V, Cupini LM, Corbelli I, Pieroni A, D'Amore C, Caproni S, Gorgone G, Ferlazzo E, Di Palma F, Sarchielli P, Calabresi P. Palinopsia in patients with migraine: a casecontrol study. Cephalalgia. 2011;31:999-1004. 10. Lee MS, Volpe NJ. Double vision. Curr Treat Options Neurol. 2001;3:383-388. 11. Blom JD. Alice in Wonderland syndrome: a systematic review. Neurol Clin Pract. 2016;6:259-270. 12. Rastogi RG, VanderPluym J, Lewis KS. Migrainous aura, visual snow, and "Alice in Wonderland" syndrome in childhood. Semin Pediatr Neurol. 2016;23:14-17. 13. Beh SC, Masrour S, Smith SV, Friedman DI. Clinical characteristics of Alice in Wonderland syndrome in a cohort with vestibular migraine. Neurol Clin Pract. 2018;8:389-396. 14. Schankin CJ, Maniyar FH, Digre KB, Goadsby PJ. "Visual snow"-a disorder distinct from persistent migraine aura. Brain. 2014;137:1419-1428. 15. White OB, Clough M, McKendrick AM, Fielding J. Visual snow: visual misperception. J Neuroophthalmol. 2018;38:514- 521. 16. Schankin CJ, Maniyar FH, Sprenger T, Chou DE, Eller M, Goadsby PJ. The relation between migraine, typical migraine aura, and "visual snow." Headache. 2014;54:957-966. 17. Puledda F, Schankin C, Digre K, Goadsby PJ. Visual snow syndrome: what we know so far. Curr Opin Neurol. 2018;31:52-58. 18. Unal-Cevik I, Yildiz FG. Visual snow in migraine with aura: further characterization by brain imaging, electrophysiology, and treatment-case report. Headache. 2015;55:1436- 1441. 19. Luu ST, Pesudovs K, Lee AW, Chen CS. Homonymous hemianopia captured on automated perimetry during a migraine episode. Intern Med J. 2010;40:310-311. 20. Wakakura M, Ichibe Y. Permanent homonymous hemianopias following migraine. J Clin Neuroophthalmol. 1992;12:198- 202. 206 21. Pollak L, Shlomo N, Korn Lubetzki I; National Acute Stroke Israeli Survey Group. Headache in stroke according to National Acute Stroke Israeli Survey. Acta Neurol Scand. 2017;135:469-475. 22. Baena CP, D'Amico RC, Slongo H, Brunoni AR, Goulart AC, Benenor I. The effectiveness of aspirin for migraine prophylaxis: a systematic review. Sao Paulo Med J. 2017;135:42-49. 23. Salman AG, Hamid MA, Mansour DE. Correlation of visual field defects and optical coherence tomography finding in migraine patients. Saudi J Ophthalmol. 2015;29:76-80. 24. Yener AÜ, Korucu O. Visual field losses in patients with migraine without aura and tension-type headache. Neuroophthalmology. 2017;41:59-67. 25. McKendrick AM, Badcock DR. Decreased visual field sensitivity measured 1 day, then 1 week, after migraine. Invest Ophthalmol Vis Sci. 2004;45:1061-1070. 26. Dersu II, Thostenson J, Durcan FJ, Hamilton SM, Digre KB. Optic disc and visual field findings in patients with migraine. J Clin Neurosci. 2013;20:72-74. 27. Lim SA, Siatkowski RM, Farris BK. Functional visual loss in adults and children patient characteristics, management, and outcomes. Ophthalmology. 2005;112:1821-1828. Also: Platform presentation, 31st Annual North American NeuroOphthalmology Society Meeting, February 12-17, 2005; Copper Mountain, Colorado. 28. Grosberg BM, Solomon S, Friedman DI, Lipton RB. Retinal migraine reappraised. Cephalalgia. 2006;26:1275-1286. 29. Pula JH, Kwan K, Yuen CA, Kattah JC. Update on the evaluation of transient visual loss. Clin Ophthalmol. 2016;10:297-303. 30. Weinstein JM, Feman SS. Ischemic optic neuropathy in migraine. Arch Ophthalmol. 1982;100:1097-1100. 31. O'Hara M, O'Connor PS. Migrainous optic neuropathy. J Clin Neuroophthalmol. 1984;4:85-90. 32. Lee AG, Brazis PW, Miller NR. Posterior ischemic optic neuropathy associated with migraine. Headache. 1996;36:506-510. 33. Foroozan R, Marx DP, Evans RW. Posterior ischemic optic neuropathy associated with migraine. Headache. 2008;48:1135-1139. 34. Codeluppi L, Bonifacio G, Chiari A, Ariatti A, Nichelli PF. Optic nerve involvement in retinal migraine. Headache. 2015;55:562-564. 35. Evans RW, Grosberg BM. Retinal migraine: migraine associated with monocular visual symptoms. Headache. 2008;48:142-145. 36. Van Harreveld A. Two mechanisms for spreading depression in the chicken retina. J Neurobiol. 1978;9:419-431. 37. Hanke W, de Lima VM. Central nervous tissue: an excitable medium. A study using the retinal spreading depression as a tool. Philos Trans A Math Phys Eng Sci. 2008;366:359- 368. 38. Pitkänen H, Saarela V. Vasospastic transient monocular visual loss: effect of treatment with different doses of nifedipine. J Neuroophthalmol. 2014;34:386-388. 39. Hill DL, Daroff RB, Duros A, Newman NJ, Biousse V. Most cases labeled as "retinal migraine" are not migraine. J Neuroophthalmol. 2007;27:3-8. 40. Winterkorn JM. "Retinal migraine" is an oxymoron. J Neuroophthalmol. 2007;27:1-2. 41. Rozen TD. Migraine with binocular blindness: a clinic-based study. Headache. 2011;51:1529-1536. 42. Valhedi V, Depienne C, Le Fort D, Riant F, Chaine P, Trouillard O, Gaudric A, Morris MA, Leguern E, Tournier-Lasserve E, Boussser MG. Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations. Neurology. 2009;72:1178-1183. 43. Noseda R, Copenhagen D, Burstein R. Current understanding of photophobia, visual networks and headaches. Cephalalgia. [published online ahead of print January 1, 2018] doi: 10.1177/0333102418784750. 44. Evans RW, Digre KB. Light sensitivity in migraineurs. Headache. 2003;43:917-920. Smith: J Neuro-Ophthalmol 2019; 39: 200-207 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine 45. Buchanan T, Digre K, Warner JE, Katz BJ. A review of the symptom of photophobia in an eye clinic. Neurology. 2009;72:A 184. 46. Bowen RC, Koeppel JN, Christensen CD, Snow KB, Ma J, Katz BJ, Krauss HR, Landau K, Warner JEA, Crum AV, Straumann D, Digre KB. The most common causes of eye pain at 2 tertiary ophthalmology and neurology clinics. J Neuroophthalmol. 2018;38:320-327. 47. Maniyar FH, Sprenger T, Schankin C, Goadsby PJ. Photic hypersensitivity in the premonitory phase of migraine- a positron emission tomography study. Eur J Neurol. 2014;21:1178-1183. 48. Vingen JV, Pareja JA, Stovner LJ. Quantitative evaluation of photophobia and phonophobia in cluster headache. Cephalalgia. 1998;18:250-256. 49. Vincent MB. Vision and migraine. Headache. 2015;55:595- 599. 50. 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. 51. Llop SM, Frandsen JE, Digre KB, Katz BJ, Crum AV, Zhang C, Warner JE. Increased prevalence of depression and anxiety in patients with migraine and interictal photophobia. J Headache Pain. 2016;17:34. 52. Seidel S, Beisteiner R, Manecke M, Aslan TS, Wober C. Psychiatric comorbidities and photophobia in patients with migraine. J Headache Pain. 2017;18:18. 53. Katz BJ, Digre KB. Diagnosis, pathophysiology, and treatment of photophobia. Surv Ophthalmol. 2016;61:466-477. 54. Digre KB. More than meets the eye: the eye and migraine- what you need to know. J Neuroophthalmol. 2018;38:237-243. 55. Friedman DI. The eye and headache. Continuum (Minneap Minn). 2015;21:1109-1117. 56. Armbrust KR, Kosmorsky GS, Lee MS, Friedman DI. A pain in the eye. Surv Ophthalmol. 2014;59:474-477. Smith: J Neuro-Ophthalmol 2019; 39: 200-207 57. Ashkenazi A, Levin M. Greater occipital nerve block for migraine and other headaches; is it useful? Curr Pain Headache Rep. 2007;11:231-235. 58. Evans RW, Foroozan R. Eye pain without visual symptoms. Headache. 2007;47:1206-1209. 59. Gilbert ME, Friedman D. Migraine and anisocoria. Surv Ophthalmol. 2007;52:209-212. 60. Gelfand AA, Gelfand JM, Prabakhar P, Goadsby PJ. Ophthalmoplegic "migraine" or recurrent ophthalmoplegic cranial neuropathy: new cases and a systematic review. J Child Neurol. 2012;27:759-766. 61. Schwartz DP, Robbins MS. Primary headache disorders and neuro-ophthalmologic manifestations. Eye Brain. 2012;4:49-61. 62. 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. 63. Wilbrink LA, Ferrari MD, Kruit MC, Haan J. Neuroimaging in trigeminal autonomic cephalgias: when, how, what? Curr Opin Neurol. 2009;22:247-253. 64. Donovan LE, Welch MR. Headaches in patients with pituitary tumors: a clinical conundrum. Curr Pain Headache Rep. 2018;22:57. 65. Levy MJ, Matharu MS, Meeran K, Powell M, Goadsby PJ. The clinical characteristics of headache in patients with pituitary tumors. Brain. 2005;128(pt 8):1921-1930. 66. Chitsantikul P, Becker WJ. SUNCT, SUNA and pituitary tumors: clinical characteristics and treatment. Cephalalgia. 2013;33:160-170. 67. Carter DM. Cluster headache mimics. Curr Pain Headache Rep. 2004;8:133-139. 68. Jacobson DM. Benign episodic unilateral mydriasis. Clinical characteristics. Ophthalmology. 1995;102:1623-1627. 69. Martin-Santana I, Gonzalez-Hernandez A, Tandon-Cardenes L, Lopez-Mendez P. Benign episodic mydriasis. Experience in a specialist neuro-ophthalmology clinic of a tertiary hospital. Neurologia. 2015;30:290-294. 207 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.