Targeting the intrinsically photosensitive retinal ganglion cell to reduce headache pain and light sensitivity in migraine: A randomized double-blind trial.

Approximately 80% of patients with migraine report light sensitivity during attacks and almost half report that following headache, light sensitivity is the most bothersome symptom. Light wavelengths stimulating intrinsically photosensitive retinal ganglion cells (IPRGCs) exacerbate headache-associated light sensitivity; green light is most comfortable. We developed optical tints that block wavelengths exacerbating migraine pain and transmit wavelengths that are most comfortable. We studied patients with migraine to determine if spectacles with these tints ameliorate headache pain and light sensitivity. Randomized participants wore control lenses or lenses blocking light wavelengths that stimulate IPRGCs. Participants applied the lenses at migraine onset and recorded baseline, two- and four-hour headache pain on an 11-point scale. Primary endpoint was pain reduction at two hours following the first severe or very severe headache. Statistical tests used included mixed-effects model analysis, Mann-Whitney test, Cochran-Mantel-Haenszel test, Shapiro-Wilk test, Welch t-test. In 78 subjects, two- and four-hour pain reduction was not significantly different between groups. In post-hoc analyses of headaches with baseline pain scores ≥ 2, a mixed-effects model suggested that IPRGC lenses were associated with clinically and statistically significant reductions in two- and four-hour headache pain. In post-hoc analyses, fewer subjects wearing IPRGC lenses reported two-hour light sensitivity. Preliminary evidence suggests that optical tints engineered to reduce stimulation of IPRGCs may reduce migraine-associated pain and light sensitivity. Trial Registration: This study was registered at ClinicalTrials.gov (NCT04341298).

Validation of the Utah Photophobia Symptom Impact Scale (version 2) as a headache-specific photophobia assessment tool.

OBJECTIVE: To present an updated version of the Utah Photophobia Symptom Impact Scale version 2 (UPSIS2), providing robust clinical and psychometric validation, to improve headache-specific evaluation of light sensitivity and headache-related photophobia. BACKGROUND: The original UPSIS filled a gap in available tools for assessment of headache-associated light sensitivity by providing patient-reported evaluation of the impact of light sensitivity on activities of daily living (ADLs). We have since revised the original questionnaire to provide a more robust item construct and refined validation approach. METHODS: We conducted a psychometric validation of the UPSIS2 through a primary analysis of an online survey of volunteers with recurrent headaches recruited from the University of Utah clinics and surrounding community. Volunteers completed the original UPSIS and UPSIS2 questionnaire versions in addition to measures of headache impact, disability, and frequency. The UPSIS2 now includes a pre-defined recall period and a 1-4 Likert scale with standardized response anchors to improve clarity. Internal construct validity, external construct validity, and test-retest reliability, were evaluated. RESULTS: Responses were obtained from 163 volunteers, with UPSIS2 scores ranging from 15 to 57 (out of a possible 15-60) with a mean (standard deviation) of 32.4 (8.80). Construct validity was satisfactory, as evidenced by sufficient unidimensionality, monotonicity, and local independence. Reliability was excellent, with Rasch test reliability = 0.90 and Cronbach's alpha = 0.92, and an intraclass correlation of 0.79 (95% confidence interval 0.65-0.88) for participants who took the test twice. UPSIS2 correlates well with other headache measures (Spearman's correlations >0.50), as well as the original UPSIS (Spearman's correlation = 0.87), indicating good convergent validity. UPSIS2 scores differ significantly across International Classification of Headache Disorders (third edition) groups, indicating good known group validity. CONCLUSION: The UPSIS2 provides a well-validated headache-specific outcome measure for the assessment of photophobia impact on ADLs.

Sharp Edge Eye Syndrome: A Case Report and Survey of Self-Identified Individuals.

BACKGROUND: Sharp edge eye syndrome (SEES), sometimes known as visual looming syndrome, is a condition in which the patient experiences ocular pain or discomfort when viewing or mentally picturing sharp objects and edges. Patients may present for medical care because they perceive the condition to represent an ophthalmic problem or a sign of a more serious underlying condition. An individual case report of SEES is included to aid in illustrating syndrome characteristics. Our aim is to describe the syndrome, vision-related quality of life (VRQOL), and psychosocial characteristics in patients with self-identified SEES. METHODS: A cross-sectional web-based survey was made available on social media webpages dedicated to SEES. The study included 22 questions developed by the research team, demographic questions, and 4 standardized questionnaires [ID Migraine, the National Eye Institute's Visual Function Questionnaire (NEI-VFQ-25), General Anxiety Disorder-2 (GAD-2), and Patient Health Questionnaire (depression) Scale-2]. RESULTS: Seventy-seven respondents had an average age of 29 and were 57% male. 92% reported symptoms before age 18. The main site of pain or discomfort was the eyes, with onset resulting from viewing or thinking of sharp objects and edges. Symptoms lasted from seconds to hours and could be prolonged even after closing eyes or avoiding viewing the trigger. The composite and subscale scores on the NEI-VFQ-25 were low, with a mean composite score of 78 and selected subscores of general health (61), general vision (73), ocular pain (68), driving (79), mental health (61), and role difficulties (72). Anxiety was reported in 58% of participants, and depression in 57%. Migraine or headache was reported in 46% of participants. Participants reported Alice in Wonderland syndrome, visual snow, obsessive-compulsive disorder, attention deficit hyperactivity disorder, stripe-induced visual discomfort, and synesthesia. CONCLUSION: From this survey, we have the beginnings of an understanding of the characteristics of SEES, as well as VRQOL impacts. These survey responses lead us to postulate that SEES may be a distinct visual phenomenon and to propose SEES criteria. Systematic studies of this condition's clinical features and treatment responses will be additional steps toward improving patient care.

Interdisciplinary Protocol for the Management of Vision-Threatening Papilledema.

BACKGROUND: This study evaluates the effectiveness of a multidisciplinary protocol for management of patients with papilledema and vision loss secondary to increased intracranial pressure. METHODS: Retrospective record review of all adult patients who presented with vision-threatening papilledema (VTPE) and were treated under this protocol. Patients are admitted for lumbar drain placement and diuretics and followed daily to determine if they may be managed medically or require surgery (optic nerve sheath fenestration [ONSF] and/or cerebrospinal fluid [CSF] shunting). RESULTS: Nineteen patients were included. Twelve had body mass index in the obese range and 6 were morbidly obese. Fourteen had idiopathic intracranial hypertension. Five had secondary pseudotumor cerebri syndrome related to medication use, dural venous sinus thrombosis, hypothyroidism, end-stage renal disease, pulmonary disease, and diastolic heart failure. Three patients did not require surgery and were discharged on oral diuretics; 3 patients underwent unilateral ONSF, 9 underwent bilateral ONSF, and 4 underwent bilateral ONSF followed by ventriculoperitoneal shunt placement. The average follow-up was 10.1 months. The visual acuity improved bilaterally in 12 patients and unilaterally in 4 patients. The remaining 3 patients had worsened vision in both eyes. Fifteen patients had bilateral improvement in their visual fields. Five eyes in 3 patients showed further constriction of the visual field at follow-up. CONCLUSIONS: We demonstrate how a multidisciplinary complex care protocol for treating VTPE can expedite and streamline treatment and restore vision. We found that most patients had improved symptoms and signs, including visual acuity, visual fields, and papilledema. We encourage institutions that manage VTPE to adopt similar institutional protocols.

The Unmet Challenge of Diagnosing and Treating Photophobia.

BACKGROUND: Although patients with abnormal light sensitivity may present to an ophthalmologist or optometrist for the evaluation of photophobia, there are no previous reviews of the most common causes of this symptom. METHODS: We conducted a retrospective chart review of patients who presented to our eye center between 2001 and 2009 primarily for the evaluation of photophobia. We recorded demographics, ocular examination findings, and diagnoses of these patients. RESULTS: Our population included 58 women and 53 men. The mean age at presentation to the clinic was 37 years (range 6 months-94 years). The most frequent cause of photophobia was migraine headache (53.7%), followed by dry eye syndrome (36.1), ocular trauma (8.2%), progressive supranuclear palsy (6.8%), and traumatic brain injury (4.1%). A significant proportion of patients (25.9%) left the clinic without a cause for their photophobia documented by the examining physician (11.7% of adults and 69.4% of children). CONCLUSIONS: Photophobia affects patients of all ages, and many patients are left without a specific diagnosis, indicating a significant knowledge gap among ophthalmologists and optometrists evaluating these patients.

Increased Incidence of Pseudotumor Cerebri Syndrome Among Users of Tetracycline Antibiotics.

BACKGROUND: To determine whether the use of a tetracycline-class antibiotic is associated with an increased risk of developing pseudotumor cerebri syndrome (PTCS). METHODS: We identified patients in the University of Utah Health system who were prescribed a tetracycline-class antibiotic and determined what percentage of those individuals were subsequently diagnosed with PTCS secondary to tetracycline use. We compared this calculation to the number of patients with PTCS unrelated to tetracycline use. RESULTS: Between 2007 and 2014, a total of 960 patients in the University system between the ages of 12 and 50 were prescribed a tetracycline antibiotic. Among those, 45 were diagnosed with tetracycline-induced PTCS. We estimate the incidence of tetracycline-induced PTCS to be 63.9 per 100,000 person-years. By comparison, the incidence of idiopathic intracranial hypertension (IIH) is estimated to be less than one per 100,000 person-years (Calculated Risk Ratio = 178). CONCLUSIONS: Although a causative link between tetracycline use and pseudotumor cerebri has yet to be firmly established, our study suggests that the incidence of pseudotumor cerebri among tetracycline users is significantly higher than the incidence of IIH in the general population.

Multiple Cranial Neuropathies and Pachymeningitis in a Patient With a Pathogenic Nucleotide-Binding Oligomerization Domain 2 Polymorphism.

ABSTRACT: An 11-year-old boy presented with 2 weeks of intermittent headache, right orbital pain, and constant diplopia. Brain MRI showed dural thickening and enhancement of the right lateral cavernous sinus, right orbital apex, and tentorium. Initial cerebral spinal fluid analysis showed only mild pleocytosis, and serum diagnostics were unrevealing. The working diagnosis was Tolosa-Hunt syndrome. His pain and sixth nerve palsy resolved with corticosteroids. Five months after initial presentation, he developed new numbness of the right cheek, complete right ophthalmoplegia, and weakness and numbness of his right hand and leg, all of which were responsive to steroids. Fifteen months later, he returned to the emergency department with 2 weeks of left-sided headaches and acute diplopia. On examination, he had a left cranial nerve 6 palsy. Dural biopsy showed diffuse mononuclear inflammatory cell reaction consisting mostly of lymphocytes with no signs of granuloma formation, nor any epithelioid or giant cells. His clinical course was consistent with an autoinflammatory condition of unknown etiology. Genetic testing with an immunodeficiency panel showed a risk allele in NOD2 (nucleotide-binding oligomerization domain 2) c.3019dup (p.Leu1007Prof*2) that is associated with an increased risk for Crohn disease. His clinical condition had similarities to central nervous system sarcoidosis. Because of the similarities between our patient's clinical, imaging, and genetic findings and neurosarcoidosis, he was switched to a more targeted therapy-infliximab. His condition has since been stable for nearly 2 years. In conclusion, genetic testing should be considered in patients with suspected occult autoimmunity.

A Comparison Between the Clinical Features of Pseudotumor Cerebri Secondary to Tetracyclines and Idiopathic Intracranial Hypertension.

PURPOSE: Comparisons between clinical features of tetracycline-induced pseudotumor cerebri (PTC-T) and those of idiopathic intracranial hypertension (IIH) are absent in the literature. We hypothesized that significant clinical differences between these etiologies exist and could be better understood by retrospective analysis. DESIGN: Retrospective cohort study. METHODS: We reviewed patients diagnosed with pseudotumor cerebri syndrome (PTCS) at our center and identified those who developed PTC-T after treatment with a tetracycline-class antibiotic and those with IIH. Groups were compared by demographics, body mass index, ophthalmic examination, treatment, clinical course, and visual outcomes. RESULTS: We identified 52 cases of PTC-T and 302 cases of IIH. Obesity rates were significantly different (43.8% for PTC-T vs 79.2% for IIH, P < .001). The mean age at diagnosis was younger for PTC-T (19.8 years vs 28.1 years for IIH, P < .001). Diplopia was more common with PTC-T (40.4% vs 20.1% for IIH, P = .001). The mean illness duration was shorter for PTC-T (18.3 weeks vs 62.9 weeks for IIH, P <.0001). Recurrence rates were significantly different (4.0% for PTC-T vs 16.5% for IIH, P <.001). The frequency of surgical intervention was similar. Vision loss was uncommon but occurred with similar frequency. CONCLUSION: We identified significant clinical differences but also identified important similarities between the 2 groups. There appear to be nonobese patients who develop PTC-T, discontinue the antibiotic, and never develop PTCS again. There are other patients who develop PTC-T, discontinue the antibiotic, and later develop IIH. We conclude that PTC-T represents a spectrum of disease in susceptible individuals.

Young Adults With Anterior Ischemic Optic Neuropathy: A Multicenter Optic Disc Drusen Study.

PURPOSE: Optic disc drusen (ODD), present in 2% of the general population, have occasionally been reported in patients with nonarteritic anterior ischemic optic neuropathy (NA-AION). The purpose of this study was to examine the prevalence of ODD in young patients with NA-AION. DESIGN: Retrospective, cross-sectional multicenter study. METHODS: All patients with NA-AION 50 years old or younger, seen in neuro-ophthalmology clinics of the international ODDS (Optic Disc Drusen Studies) Consortium between April 1, 2017, and March 31, 2019, were identified. Patients were included if ODD were diagnosed by any method, or if ODD were excluded by enhanced-depth imaging optical coherence tomography (EDI-OCT) using ODDS Consortium guidelines. NA-AION eyes with ODD were termed "ODD-AION"; those without were termed "NODD-AION". RESULTS: A total of 65 patients (127 eyes) with NA-AION were included (mean 41 years old). Of the 74 eyes with NA-AION, 51% had ODD-AION, whereas 43% of fellow eyes without NA-AION had ODD (P = .36). No significant differences were found between ODD-AION and NODD-AION eyes in terms of Snellen best-corrected VA or perimetric mean deviation. According to EDI-OCT results, 28% of eyes with NODD-AION had peripapillary hyperreflective ovoid mass-like structures (PHOMS); 7% had hyperreflective lines, whereas 54% with ODD-AION had PHOMS; and 66% had hyperreflective lines (P = .006 and P < .001, respectively). CONCLUSIONS: Most of these young NA-AION patients had ODD. This indicates that ODD may be an independent risk factor for the development of NA-AION, at least in younger patients. This study suggests ODD-AION be recognized as a novel diagnosis.

Multirater Validation of Peripapillary Hyperreflective Ovoid Mass-like Structures (PHOMS).

Peripapillary hyperreflective ovoid mass-like structures (PHOMS) are a new retinal optical coherence tomography (OCT) finding. The Optic Disc Drusen Studies Consortium had made recommendations to distinguish PHOMS from true optic disc drusen (ODD) in 2018. While publications on PHOMS have increased since then, the accuracy of the definition of PHOMS and reliability of detection is unknown. In this multi-rater study, we demonstrate that the 2018 definition of PHOMS resulted in a poor multi-rater kappa of 0.356. We performed a Delphi consensus process to develop a consistent and refined definition of PHOMS with clear principles around the nature of PHOMS and how they differ from normal anatomy. Fifty explanatory teaching slides, provided as supplementary material, allowed our expert group of raters to achieve a good level of agreement (kappa 0.701, 50 OCT scans, 21 raters). We recommend adopting the refined definition for PHOMS.

Reduced Visual Quality of Life Associated with Migraine is Most Closely Correlated with Symptoms of Dry Eye.

BACKGROUND AND OBJECTIVE: Patients with migraine frequently report ocular or visual symptoms including aura, photophobia, and eye pain. Using validated instruments, our group previously reported that due to these symptoms, patients have marked reductions in visual quality of life. In chronic migraine, these reductions can be as substantial as those reported for other neuro-ophthalmic diseases such as multiple sclerosis with optic neuritis and idiopathic intracranial hypertension. Because the instruments take several different dimensions into account, we were unable to determine which ocular symptom(s) contributed to reduced visual quality of life. The purpose of this investigation was to attempt to determine which ocular symptom(s) were driving the observed reduction in visual quality of life. METHODS: We designed a cross-sectional survey-based study to assess visual quality of life, headache impact, aura, dry eye, and photophobia in migraine patients. Subjects were recruited from the Headache Clinic and General Neurology Clinic at a tertiary teaching hospital. Subjects completed validated questionnaires including: The visual functioning questionnaire-25 (VFQ-25), the headache impact test (HIT-6), the visual aura rating scale (VARS), the ocular surface disease index (OSDI), and the Utah photophobia score (UPSIS-17). Associations between VFQ-25 and OSDI, VFQ-25 and VARS, VFQ-25 and UPSIS-17, HIT-6 and OSDI, HIT-6 and VARS, and HIT-6 and UPSIS-17 were calculated. RESULTS: Of the 62 patients who completed all questionnaires, 17 had episodic migraine and 45 had chronic migraine. Twenty-three patients experienced aura and 39 did not report aura. The most striking correlations were observed between the VFQ-25 and the OSDI (-0.678; P < .001), between the HIT-6 and UPSIS-17 (0.489; P < .001), and between the HIT-6 and OSDI (0.453; P < .001). CONCLUSIONS: Dry eye seems to be the most important symptom that reduces visual quality of life and worsens headache impact. This symptom may be a form of allodynia, a well-known feature of chronic migraine. Photophobia appears to have modest effects on headache impact. In the future, we hope to determine whether treatment of dry eye symptoms can improve visual quality of life and reduce headache impact.

Validation of a photophobia symptom impact scale.

BACKGROUND: Routine assessment of photophobia in the clinical setting may underestimate the presence and severity of this condition. We aimed to develop and validate a questionnaire to improve evaluation of the impact of photophobia on activities of daily living, and to determine the relationship of this questionnaire to psychophysical assessment of light sensitivity thresholds. METHODS: We developed the 17-item Utah Photophobia Symptom Impact Scale (UPSIS-17) and compared its psychometric properties to the 8-item Korean Photophobia Questionnaire (KUMC-8). Ninety five subjects with or without light sensitivity completed both questionnaires; 72 also completed laboratory-based assessment of light sensitivity thresholds. We used Rasch analysis to evaluate instrument targeting, including internal consistency and reliability. Correlation analysis was used to assess the relationship between questionnaire scores and light sensitivity thresholds. RESULTS: We observed correlation between UPSIS-17 and KUMC-8, r = 0.72 (p < 0.0001). Higher UPSIS-17 scores correlated with light sensitivity thresholds, r = -0.42 (p < 0.0001), whereas KUMC-8 scores did not significantly correlate with light sensitivity thresholds, r = -0.21 (p = 0.072). UPSIS-17 showed better instrument targeting than KUMC-8 on Rasch analysis. Person-item maps allowed for identification of questions that could be removed without affecting questionnaire validity measures. CONCLUSION: This study resulted in a shortened, 12-item questionnaire. The UPSIS-12 retained significant correlation with both the KUMC-8 and light sensitivity thresholds, yielding a simpler tool for symptom assessment, while retaining validity. This expanded tool may be useful in clinical, as well as research settings, for collection of data about disability due to photophobia.

Patients With Migraine Have Substantial Reductions in Measures of Visual Quality of Life.

OBJECTIVE: Migraine is associated with several important visual symptoms, during both acute attacks and headache-free intervals. The purpose of this investigation was to use validated vision-related quality of life instruments to assess the effect of migraine on visual quality of life. BACKGROUND: Many migraineurs experience visual aura, increased photophobia during and between headache attacks, and increased symptoms of dry eye with structural changes in corneal nerve endings. Other visual symptoms associated with migraine include positive persistent visual phenomenon (visual snow) and transient vision changes. Previous research looking at the disability associated with migraine has shown that patient-reported quality of life data can be useful in determining the severity of disease burden. Recent published literature has suggested that visual symptoms related to migraine represent a proportionally minor burden to patients, compared to other manifestations of migraine, but no previous studies have assessed how migraine affects visual quality of life. METHODS: In this cross-sectional quantitative survey, visual quality of life in individuals with chronic and episodic migraine was assessed using the National Eye Institute Visual Function Questionnaire-25, and the 10-item National Eye Institute Visual Function Questionnaire-25 Neuro-Ophthalmic Supplement. Overall headache severity and impact was assessed using the Migraine-specific Quality of Life Questionnaire (Version 2.1) and the Headache Impact Test-6. Participants were recruited from Headache and Neuro-ophthalmology subspecialty clinics. The target sample size was 30 participants per subgroup. The results were compared to those from disease-free controls and to results from other neuro-ophthalmic disease quality of life studies. RESULTS: Among 29 participants with chronic migraine, vision-specific quality of life scores were all statistically significantly decreased compared to disease-free controls. The National Eye Institute Visual Function Questionnaire-25 median composite score was 85 for chronic migraineurs and 96 for controls (P < .001). The 10-item National Eye Institute Visual Function Questionnaire-25 Neuro-Ophthalmic Supplement median score was 72 for chronic migraineurs and 95 for controls (P < .001). Among 37 participants with episodic migraine, vision-specific quality of life scores were also decreased compared to disease-free controls. In the episodic migraine group, decreases in the National Eye Institute Visual Function Questionnaire-25 scores were not statistically significant (median score 91, P = .01 compared to the control group), but decreases in the 10-item National Eye Institute Visual Function Questionnaire-25 Neuro-Ophthalmic Supplement remained statistically significant (median score 85, P = .003 compared to the control group). Chronic migraineurs had decreased visual quality of life scores compared to those with episodic migraines. Participants with chronic migraine had visual quality of life scores that were as poor as those previously published for patients with other neuro-ophthalmic disorders such as multiple sclerosis, myasthenia gravis, and ischemic optic neuropathy. CONCLUSIONS: Visual quality of life is significantly adversely affected in migraine sufferers. In fact, patients with chronic migraine may have visual quality of life impacts that are as significant as those associated with other common neuro-ophthalmic disorders. Future studies of the overall disease burden in patients with migraine should include an evaluation of the effects on visual functioning.

Diffusion-Weighted Imaging and Post-contrast Enhancement in Differentiating Optic Neuritis and Non-arteritic Anterior Optic Neuropathy.

Non-arteritic anterior ischaemic optic neuropathy (NAION) and optic neuritis (ON) may be difficult to distinguish early in their disease courses. Our goal was to determine if specific magnetic resonance imaging characteristics differentiate acute NAION from ON. Neuroradiologists, masked to diagnosis, reviewed the diffusion-weighted imaging (DWI) and post-contrast enhancement (PCE) characteristics of the optic nerve in 140 eyes. PCE and DWI signals of the optic disc alone did not discriminate between NAION and ON. After taking age and sex into consideration, only DWI and PCE of the intraorbital segment of the optic nerve differentiated the two, with ON having the increased likelihood of these findings. Isolated PCE without DWI signal at the optic disc, however, was 100% specific for NAION. This may be the most specific way to radiographically differentiate between NAION and ON in the acute setting.