Hypnic Amaurosis Fugax

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Hypnic Amaurosis Fugax Alec Thoveson, BS, Iyza F. Baig, MD, Peter W. Mortensen, MD, Andrew G. Lee, MD A cute, unilateral, painless vision loss followed by rapid, complete recovery typically suggests transient ischemia and impending retinal artery occlusion. This symptom of transient monocular vision loss (TMVL), or amaurosis fugax, necessitates urgent evaluation because it can herald the risk of developing a disabling or fatal vascular complication (1). Young patients with or without migraine, with negative thrombotic and embolic stroke evaluations, and without vasculopathic risk factors are presumed to have had retinal vasospasm as their etiology for TMVL. Some of these patients are believed to have a migraine equivalent. We report a unique case of recurrent, stereotyped, episodes of TMVL to no light perception (NLP) with complete recovery after several minutes that awakened the patient from sleep within the same time interval of 4–5 o’clock in the morning. Hypnic headaches are well known to be stereotyped and occur in a defined circadian pattern awakening the patient from sleep. Recurring episodes of TMVL with a circadian pattern, however, is an undescribed phenomenon within neuro-ophthalmology (2). We present a rare case of recurrent TMVL with an apparent circadian component to its pathophysiology. To our knowledge, this hypnic amaurosis fugax is the first such case to be described in the English language ophthalmic literature. A 54-year-old Caucasian woman presented to the emergency department after an episode of TMVL of the left eye (left eye) that awakened her from sleep between 4:00 and 5:00 in the morning. The patient reported acute, painless, NLP vision in the left eye for 10 minutes immediately upon awakening, after which her symptoms completely resolved. Hospital evaluation included noncontrast computed tomographic (CT) scan of the head, electrocardiogram, complete blood count with differential, complete metabolic panels, carotid Doppler study, and continuous cardiac rhythm monitoring, which were all within normal limits. Past medical history included well-controlled hypertension, asthma, and nonspecific anxiety. At discharge, patient was Texas A&M College of Medicine (AT), Bryan, Texas; Baylor College of Medicine (IFB), Houston, Texas; and Department of Ophthalmology (PWM, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Department Chair and Professor, Neuro-Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street, Suite 450, Houston, TX 77030; E-mail address: [e-mail] Thoveson et al: J Neuro-Ophthalmol 2022; 42: e357-e358 started on clopidogrel and a statin, with a presumptive diagnosis of left retinal transient ischemic attack (TIA). Outpatient ophthalmologic exam 3 days later showed no abnormalities. MRI of the brain and MR angiography of the head and neck was normal. Another stereotyped episode of TMVL occurred between 4:00 and 5:00 AM 1 month later. A second emergency department visit with repeated stroke workup was negative and she was again diagnosed with “left retinal TIA.” A cardiac loop monitor was negative for paroxysmal atrial fibrillation. Outpatient neurology found a normal exam. An electroencephalogram showed no epileptiform activity. She was subsequently started on magnesium because of suspicion for migraine aura equivalent. Despite antiplatelet, statin, and magnesium therapy, the patient went on to experience additional stereotyped, recurrent episodes of TMVL. All 6 episodes were similar. Four occurred in the left eye and 2 in the right eye. All awakened the patient from sleep, resolved within 5– 10 minutes with no residual deficit, and varied from NLP vision to counting fingers severity throughout her monocular field of vision. The patient denied any triggers or precipitants the night before these episodes, including recent stress, lack of sleep, and specific foods/drinks that are frequently cited as migraine triggers (e.g., red wine, chocolate, smoked cheese, and caffeine). Five of the episodes occurred precisely between 4:00 AM and 5:00 AM, and one occurred at 2:00 AM No additional signs or symptoms indicative of stroke or autonomic dysfunction were present during any episode. The patient was questioned extensively regarding the reason she awoke just before these episodes and denied additional physical symptoms including abdominal pain, chest pain, headache, nausea/vomiting, shortness of breath, muscle aches/pain, and numbness/tingling. Because of the stereotyped, atypical nature of her TMVL, and lack of findings on neuroimaging to suggest an alternative diagnosis, she was referred to the Houston Methodist Hospital neuro-ophthalmology service. On examination, her visual acuity measured 20/20 in both eyes. Ishihara color plates were 14/14 in both eyes. There was no anisocoria or relative afferent pupillary defect. External exam showed no scalp tenderness or temporal artery nodularity. Her intraocular pressure was normal OU. Slit-lamp biomicroscopy and dilated fundus examinations were unremarkable. No retinal emboli or prior ischemic damage was seen. Humphrey 24-2 visual field testing showed no abnormalities. Optical coherence tomography e357 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence of the macula and retinal nerve fiber layer yielded normal findings. A diagnosis of presumed retinal vasospasm (migraine equivalent) was made. We believe however in light of the stereotypic, repetitive, circadian nature of her TMVL episodes that awaken her from sleep that these symptoms may be analogous to hypnic headache (HH) (3,4). However, given the patient’s history of nonspecific anxiety and her unusual statement that painless, unilateral vision loss awoke her from sleep, the possibility that these episodes were nonorganic in nature cannot be completely excluded. Bouffard et al described a cohort of 29 patients with similar recurrence of TMVL noted immediately upon awakening with subsequent resolution of symptoms. Our patient fits within the demography of their cohort; a middle-aged woman, few episodes of occurrence, and no other symptoms indicative of a TIA. Of these patients, 7 also experienced symptoms in either eye rather than only recurrent attacks of the same eye. All 29 patients had a benign course with thorough negative stroke workups. Differentiating this case from the cohort in Bouffard et al is the circadian component to the attacks which awakened her from sleep, rather than symptoms being noticed immediately upon awakening. Variations in circadian rhythms affect broad metabolic and physiologic processes, and of emerging interest is the relevance of circadian rhythms in headache pathology. Genetic variants of circadian genes have been linked to HH, cluster headache, and migraine (4). HH and cluster headache are known to attack patients at very specific times of day (4). The circadian component of HH is theoretically attributed to hypothalamic control of circadian rhythms and the trigemino-hypothalamic tract influence on trigeminal pain processing (3). Furthermore, an interesting relationship between withdrawal of long-term lithium therapy and development of transient HH symptoms has been observed (3). Lithium is known to influence the circadian rhythms via alteration of transcription factor BMAL1 e358 expression, resulting in a restoration of normal circadian rhythms, and may be the possible mechanism explaining lithium efficacy in HH patients. Bouffard et al (2) proposed autoregulatory failure as a potential mechanism for the symptoms in the retrobulbar or retinal vasculature resulting in a supply–demand mismatch. Theoretically, this mismatch could be because of variations in circadian signaling and hormone levels that occur during a specific window of the patient’s own internal clock. Clinicians should be aware of the significance and necessary evaluation for both hypnic headache and TMVL. To our knowledge, this is the first reported case in the English language ophthalmic literature of recurrent hypnic amaurosis fugax with a circadian component to its pathophysiology. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. Thoveson, I. F. Baig, P. W. Mortensen, and A. G. Lee; b. Acquisition of data: A. Thoveson, I. F. Baig, P. W. Mortensen, and A. G. Lee; c. Analysis and interpretation of data: A. Thoveson, I. F. Baig, P. W. Mortensen, and A. G. Lee. Category 2: a. Drafting the manuscript: A. Thoveson, I. F. Baig, P. W. Mortensen, and A. G. Lee; b. Revising it for intellectual content: P. W. Mortensen and A. G. Lee. Category 3: a. Final approval of the completed manuscript: A. G. Lee. REFERENCES 1. Bidot S, Biotti D. Transient monocular blindness: vascular causes and differential diagnoses. J Fr Ophtalmol. 2018;41:129–136. 2. Bouffard MA, Cornblath WT, Rizzo JF III, Lee MS, DeLott LB, Eggenberger ER, Torun N. Transient monocular vision loss on awakening: a benign amaurotic phenomenon. J Neuroophthalmol. 2017;37:122–125. 3. Holle D, Naegel S, Obermann M. Hypnic headache. Cephalalgia. 2013;33:1349–1357. 4. Burish MJ, Chen Z, Yoo SH. Emerging relevance of circadian rhythms in headaches and neuropathic pain. Acta Physiol. 2019;225:13161. Thoveson et al: J Neuro-Ophthalmol 2022; 42: e357-e358 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.