Hypersensitivity of Intrinsically Photosensitive Retinal Ganglion Cells in Migraine Induces Cortical Spreading Depression.

Migraine is a complex disorder characterized by episodes of moderate-to-severe, often unilateral headaches and generally accompanied by nausea, vomiting, and increased sensitivity to light (photophobia), sound (phonophobia), and smell (hyperosmia). Photophobia is considered the most bothersome symptom of migraine attacks. Although the underlying mechanism remains unclear, the intrinsically photosensitive retinal ganglion cells (ipRGCs) are considered to be involved in photophobia associated with migraine. In this study, we investigated the association between the sensitivity of ipRGCs and migraines and cortical spreading depression (CSD), which may trigger migraine attacks. The pupillary responses closely associated with the function of ipRGCs in patients with migraine who were irradiated with lights were evaluated. Blue (486 nm) light irradiation elicited a response from ipRGCs; however, red light (560 nm) had no such effect. Melanopsin, a photosensitive protein, phototransduces in ipRGCs following blue light stimulation. Hypersensitivity of ipRGCs was observed in patients with migraine. CSD was more easily induced with blue light than with incandescent light using a mouse CSD model. Moreover, CSD was suppressed, even in the presence of blue light, after injecting opsinamide, a melanopsin inhibitor. The hypersensitivity of ipRGCs in patients with migraine may induce CSD, resulting in migraine attacks.

Hyperactivity of the medial thalamus in patients with photophobia-associated migraine.

OBJECTIVE: To examine cerebral functional alterations associated with sensory processing in patients with migraine and constant photophobia. BACKGROUND: Migraine is a common headache disorder that presents with photophobia in many patients during attacks. Furthermore, some patients with migraine experience constant photophobia, even during headache-free intervals, leading to a compromised quality of life. METHODS: This prospective, case-control study included 40 patients with migraine (18 male and 22 female) who were recruited at an eye hospital and eye clinic. The patients were divided into two groups: migraine with photophobia group, consisting of 22 patients (10 male and 12 female) with constant photophobia, and migraine without photophobia group, consisting of 18 patients (eight male and 10 female) without constant photophobia. We used 18F-fluorodeoxyglucose and positron emission tomography to compare cerebral glucose metabolism between the two patient groups and 42 healthy participants (16 men and 26 women). RESULTS: Compared with the healthy group, both the migraine with photophobia and migraine without photophobia groups showed cerebral glucose hypermetabolism in the bilateral thalamus (p < 0.05, family-wise error-corrected). Moreover, the contrast of migraine with photophobia minus migraine without photophobia patients showed glucose hypermetabolism in the bilateral medial thalamus (p < 0.05, family-wise error-corrected). CONCLUSIONS: The medial thalamus may be associated with the development of continuous photophobia in patients with migraine.

Psychometric Properties of the Persian Translation of the 12-Item Utah Photophobia Symptom Impact Scale Questionnaire.

To translate the the Utah Photophobia Symptom Impact Scale-12 questionnaire into Persian and assess the psychometric aspects to check its validity and reliability based on the Rasch modelling method. Translation and cultural adjustment of the English language UPSIS-12 questionnaire to Persian was undertaken. A total of 61 patients with complaints of photophobia participated in evaluating validity and reliability aspects. All the participants were asked to complete the Persian translation of the UPSIS-12 questionnaire. Rasch analyses of the survey items were conducted using WINSTEPS. All items fit the Rasch model. Point-measure correlation values varied from 0.41 to 0.77, providing a preliminary indication of adequate construct validity. All factor loadings were found more than 0.4. All items obtained infit and outfit mean square (MnSq) values of < 2.0. All participants except 5 had normal outfit values. Patients' abilities relative to the items' difficulty were analysed. Item difficulty was estimated and item characteristic curves were included. Sufficient unidimensionality, hierarchical order, and equal interval scoring were obtained. In conclusion, the Persian UPSIS-10 questionnaire has excellent psychometric properties and it will be valuable in both clinical practice and research. It will help Persian practitioners to assess their patients' photophobia.

Photophobia and Visual Triggers in Vestibular Migraine.

INTRODUCTION: Vestibular migraine (VM) is a prevalent vestibular disorder characterized by episodic vertigo. However, the relationship between photophobia and visual triggers in VM remains unexplored. We investigated the correlation of photophobia during the VM attack with interictal photosensitivity and visually triggering dizziness in patients with VM. METHODS: We enrolled patients diagnosed with VM, with or without photophobia, across seven specialized vertigo and headache clinics in China. Healthy individuals were also included as a control group. Using a cross-sectional survey design, we collected data related to light intensity and dizziness frequency triggered by flicker, glare, and eyestrain using the Headache Triggers Sensitivity and Avoidance Questionnaire. RESULTS: A total of 366 patients were recruited. The photosensitivity and frequency of dizziness induced by flicker, glare, and eyestrain observed in patients with VM and photophobia were significantly elevated compared with those in patients without photophobia and control participants (P < 0.001). A significant positive correlation was observed between photosensitivity levels and dizziness frequency triggered by flicker, glare, and eyestrain in patients with VM and photophobia (P < 0.001). CONCLUSIONS: This study unequivocally established a positive association of ictal photophobia with interictal photosensitivity and visually triggering dizziness, strongly advocating the need for further research on exposure-based therapies for managing VM. CLINICAL TRIALS REGISTRATION: ClinicalTrial.gov Identifier, NCT04939922, retrospectively registered, 14th June 2021.

A study to investigate the prevalence of headache disorders and migraine conducted using medical claims data and linked results from online surveys: post-hoc analysis of other headache disorders.

BACKGROUND: Surveys using questionnaires to collect epidemiologic data may be subject to misclassification. Here, we analyzed a headache questionnaire to evaluate which questions led to a classification other than migraine. METHODS: Anonymized surveys coupled with medical claims data from individuals 19-74 years old were obtained from DeSC Healthcare Inc. to examine proportions of patients with primary headache disorders (i.e.; migraine, tension-type headache, cluster headache, and "other headache disorders"). Six criteria that determined migraine were used to explore how people with other headache disorders responded to these questions. RESULTS: Among the 21480 respondents, 7331 (34.0%) reported having headaches. 691 (3.2%) respondents reported migraine, 1441 (6.7%) had tension-type headache, 21 (0.1%) had cluster headache, and 5208 (24.2%) reported other headache disorders. Responses of participants with other headache disorders were analyzed, and the top 3 criteria combined with "Symptoms associated with headache" were "Site of pain" (7.3%), "Headache changes in severity during daily activities" (6.4%), and the 3 criteria combined (8.8%). The symptoms associated with headache were "Stiff shoulders" (13.6%), "Stiff neck" (9.4%), or "Nausea or vomiting" (8.7%), Photophobia" (3.3%) and "Phonophobia" (2.5%). CONCLUSIONS: Prevalence of migraine as diagnosed by questionnaire was much lower than expected while the prevalence of "other headache" was higher than expected. We believe the reason for this observation was due to misclassification, and resulted from the failure of the questionnaire to identify some features of migraine that would have been revealed by clinical history taking. Questionnaires should, therefore, be carefully designed, and doctors should be educated, on how to ask questions and record information when conducting semi-structured interviews with patients, to obtain more precise information about their symptoms, including photophobia and phonophobia.

Clinical course of two siblings with potassium voltage-gated channel modifier subfamily V member 2 (KCNV2)-associated retinopathy.

BACKGROUND: KCNV2-associated retinopathy causes a phenotype reported as "cone dystrophy with nyctalopia and supernormal rod responses (CDSRR; OMIM# 610356)," featuring pathognomonic findings on electroretinography (ERG). Here, we report the clinical courses of two siblings with CDSRR. CASE REPORTS: Patient 1: A 3-year-old boy with intermittent exophoria was referred to our hospital. The patient's decimal best-corrected visual acuity (BCVA) at age 6 was 0.7 and 0.7 in the right and left eyes, respectively. Photophobia and night blindness were also observed. Because the ERG showed a delayed and supernormal b-wave with a "squaring (trough-flattened)" a-wave in the DA-30 ERG, and CDSRR was diagnosed. The patient's vision gradually worsened, and faint bilateral bull's eye maculopathy was observed at the age of 27 years, although the fundi were initially unremarkable. Genetic examination revealed a homozygous missense variant, c.529T > C (p.Cys177Arg), in the KCNV2 gene. Patient 2: The second patient was Patient 1's younger sister, who was brought to our hospital at 3 years of age. The patient presented with exotropia, mild nystagmus, photophobia, night blindness, and color vision abnormalities. The patients' decimal BCVA at age 13 was 0.6 and 0.4 in the right and left eyes, respectively, and BCVA gradually decreased until the age of 24 years. The fundi were unremarkable. The siblings had similar ERG findings and the same homozygous missense variant in the KCNV2 gene. CONCLUSIONS: The siblings had clinical findings typical of CDSRR. High-intense flash ERG is recommended for identifying pathognomonic "squaring" a-waves in patients with CDSRR.

Photophobia is associated with lower sleep quality in individuals with migraine: results from the American Registry for Migraine Research (ARMR).

BACKGROUND: Patients with migraine often have poor sleep quality between and during migraine attacks. Furthermore, extensive research has identified photophobia as the most common and most bothersome symptom in individuals with migraine, second only to headache. Seeking the comfort of darkness is a common strategy for managing pain during an attack and preventing its recurrence between episodes. Given the well-established effects of daily light exposure on circadian activity rhythms and sleep quality, this study aimed to investigate the relationship between photophobia symptoms and sleep quality in a cohort of patients with migraine. METHODS: A cross-sectional observational study was conducted using existing data extracted from the American Registry for Migraine Research (ARMR). Participants with a migraine diagnosis who had completed the baseline questionnaires (Photosensitivity Assessment Questionnaire (PAQ), Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-2 (PHQ-2)), and selected questions of the ARMR Sleep questionnaire were included. Models were created to describe the relationship of photophobia and photophilia with various sleep facets, including sleep quality (SQ), sleep disturbance (SDis), sleep onset latency (SOL), sleep-related impairments (SRI), and insomnia. Each model was controlled for age, sex, headache frequency, anxiety, and depression. RESULTS: A total of 852 patients meeting the inclusion criteria were included in the analysis (mean age (SD) = 49.8 (13.9), 86.6% (n = 738) female). Those with photophobia exhibited significantly poorer sleep quality compared to patients without photophobia (p < 0.001). Photophobia scores were associated with SQ (p < 0.001), SDis (p < 0.001), SOL (p = 0.011), SRI (p = 0.020), and insomnia (p = 0.005) after controlling for age, sex, headache frequency, depression, and anxiety, signifying that higher levels of photophobia were associated with worse sleep-related outcomes. Conversely, photophilia scores were associated with better sleep-related outcomes for SQ (p < 0.007), SOL (p = 0.010), and insomnia (p = 0.014). CONCLUSION: Results suggest that photophobia is a significant predictor of poor sleep quality and sleep disturbances in migraine. These results underscore the necessity for comprehensive and systematic investigations into the intricate interplay between photophobia and sleep to enhance our understanding and develop tailored solutions for individuals with migraine.

Visual snow syndrome in patients with migraine: widening the clinical spectrum of the syndrome with permanent and episodic manifestations.

PURPOSE: Migraine is the comorbidity most frequently associated with visual snow syndrome (VSS), but the prevalence of VSS in patients with migraine (PWM) has not been studied. Our objective was to evaluate the frequency of VSS in PWM and to analyze if symptoms of VSS happened in a permanent or episodic manner (eVSS) in this population. METHODS: We conducted a multicenter observational cross-sectional study. PWM was recruited from headache units, and a survey about the presence of visual snow symptoms was administered. The frequency and characteristics of patients that met current VSS criteria were analyzed. Demographic and clinical features of patients with VSS, eVSS, and PWM with no visual snow were compared. RESULTS: A total of 217 PWM were included. Seventeen patients (7.8%) met the VSS criteria. VSS patients had visual aura more frequently (58.8% vs. 31%; p = 0.019) and a higher MIDAS score (96.6 vs. 47.7; p = 0.014). Fifty-eight PWM (26.7%) showed visual snow and associated features in an episodic way and were classified as eVSS. Patients with VSS showed a tendency towards a higher frequency of visual symptoms than patients with eVSS (p > 0.05). No statistically significant differences in sociodemographic characteristics and comorbid conditions were found between VSS and eVSS. CONCLUSION: The prevalence of VSS in PWM may be higher than that described for the general population. Some PWM may present similar visual symptoms to patients with VSS but in an episodic manner. Our study reinforces the observation that the clinical spectrum of visual snow is likely to be broader than previously described.

Síndrome de nieve visual y su relación con la migraña / Visual snow syndrome and its relationship with migraine

Introducción El síndrome de nieve visual (SNV) es un trastorno del sistema nervioso central que implica la visión de forma constante de pequeños puntos blancos y negros en la totalidad del campo visual. Desarrollo El SNV puede presentarse desde la infancia hasta la tercera edad, siendo más frecuente en jóvenes y sin diferencia entre géneros. En sus criterios diagnósticos se incluye la presencia de nieve visual, pero también otros fenómenos visuales como palinopsia, fotofobia, nictalopía y otros fenómenos visuales persistentes. La fisiopatología del SNV es desconocida, pero se postulan como mecanismos la hiperexcitabilidad del córtex visual y una disfunción en el procesamiento visual de orden superior. La prevalencia de migraña en los pacientes con SNV es alta en comparación con la población general y cuando se presentan conjuntamente los síntomas son más severos. No se dispone de un tratamiento eficaz, pero el fármaco con mejores resultados es la lamotrigina, recomendándose únicamente en casos seleccionados con alta limitación funcional. Conclusiones El síndrome de nieve visual es una entidad poco conocida e infradiagnosticada, pero el creciente número de investigaciones durante los últimos años ha permitido definir unos criterios diagnósticos y acercarnos a su fisiopatología. Es una entidad íntimamente relacionada con la migraña, con solapamiento de síntomas y probablemente mecanismos fisiopatológicos comunes. (AU)

Introduction Visual snow syndrome (VSS) is a central nervous system disorder that consists of the constant perception of small black and white dots throughout the entire visual field. Development VSS can present from infancy to old age, with greater prevalence in the young population, and shows no difference between sexes. The diagnostic criteria include the presence of visual snow and such other visual phenomena as palinopsia, photophobia, nyctalopia, and other persistent visual phenomena. The pathophysiology of VSS is unknown, but hyperexcitability of the visual cortex and a dysfunction in higher-order visual processing are postulated as potential mechanisms. The prevalence of migraine among patients with VSS is high, compared to the general population, and symptoms are more severe in patients presenting both conditions. No effective treatment is available, but the drug with the best results is lamotrigine, which is recommended only in selected cases with severe functional limitation. Conclusions VSS is a little-known and underdiagnosed entity, but the increasing number of studies in recent years has made it possible to establish diagnostic criteria and begin studying its pathophysiology. This entity is closely related to migraine, with overlapping symptoms and probably shared pathophysiological mechanisms. (AU)

Self-Restricted Diet in Pediatric Autism Leading to Vitamin A Deficiency and Severe Photophobia.

In developed countries, vitamin A deficiency (VAD) remains rare but is a leading cause of global blindness. We describe the case of a 10-year-old girl with autism spectrum disorder (ASD) initially presenting mild VAD symptoms, escalating to severe photophobia and reluctance to leave a darkened room due to a self-restricted diet of fast-food french fries. A timely examination revealed severe VAD and vitamin A supplementation resolved her symptoms in three weeks. This case highlights the challenge of obtaining accurate patient history in ASD, emphasizing the need for routine dietary discussions and micronutrient testing, especially at ages nine and 13 when the United States Department of Agriculture (USDA) recommends increased vitamin A intake. Early intervention can prevent micronutrient deficiencies in pediatric patients, particularly those with ASD.

Individualized spectral filters alleviate persistent photophobia, headaches and migraines in active duty military and Veterans following brain trauma.

PURPOSE: Consistent with association between photophobia and headache, growing evidence suggests an underlying causal relationship between light sensitivity and central pain. We investigated whether an intervention to regulate light sensitivity by filtering only wavelengths causing difficulties for the specific individual could alleviate headaches/migraines resulting from traumatic brain injury (TBI). METHODS: Secondary data analysis of a clinical database including N = 392 military personnel (97% men, 3% women), ranging in age from 20 to 51 years, diagnosed with TBI, persistent headaches/migraines, and light sensitivity. The average elapsed time from TBI diagnosis to intervention was 3 years. Headache/migraine severity, frequency, medication use, and difficulties related to daily functioning were assessed pre and 4-12 weeks post-intervention with individualized spectral filters. RESULTS: Monthly migraine frequency decreased significantly from an average of 14.8 to 1.9, with 74% reporting no migraines post-intervention. Prescription and over-the-counter medication use decreased by more than 70%. Individuals also reported significant improvement in light sensitivity, headaches/migraine severity, and physical and perceptual symptoms. CONCLUSIONS: Wearing individualized spectral filters was associated with symptom relief, increased subjective quality of reported health and well-being, and decreased objective medication use for TBI-related persistent headaches/migraines. These results support a suggested relationship between dysregulated light sensitivity and central regulation of pain.

Quantifying sensory thresholds along the migraine cycle: An exploratory longitudinal study.

BACKGROUND: To date, a number of studies on migraine have cross-sectionally evaluated sensory sensitivity with aversion thresholds/scores along the migraine cycle, reporting a decreased tolerance to sensory stimuli in different sensory modalities. Our hypothesis was that patients with migraine would exhibit heightened sensitivity to sound, light, touch and smell on days where they reported greater headache intensity. METHODS: This is an exploratory, longitudinal study, carried out over the course of 27 days. Aversion thresholds or scores to sound, light, touch and smell were quantified in six patients with migraine (11.33 ± 6.53 headache days/month). RESULTS: Patients reported an increased sensitivity to light (padj = 0.0297), touch (padj = 0.0077), and smell (padj = 0.0201) on days with higher headache intensity. However, a greater sensitivity to sound on days with higher headache intensity was only reported when anxiety levels were high (padj = 1.4e-06). Interestingly, variable levels of tolerance to bothersome light over time can also influence the correlation between light sensitivity and headache intensity (padj = 1.4e-06). CONCLUSIONS: Based on the present findings, future longitudinal studies evaluating sensory threshold changes along the migraine cycle in patients with migraine should account for the increased tolerance to bothersome light over time as well as the effect of anxiety on auditory sensitivity.

Outcome of combined cataract surgery and iris prosthesis implantation in iris melanoma patients previously treated with iridocyclectomy: A national retrospective non-comparative case series.

PURPOSE: To examine complications, visual outcomes, photic patient-reported symptoms, corneal morphology, IOL tilt, and intraocular pressure after implantation of an intraocular lens (IOL) and iris prosthesis (IP) following iridocyclectomy. METHODS: Patients with previous iridocyclectomy treated with an IOL and IP at the Copenhagen University Hospital Rigshospitalet between 2007 and 2018 were included in this national retrospective non-comparative case series. The assessment encompassed BCVA, PRO questionnaire, corneal topography, and anterior segment OCT. RESULTS: 45 patients were included. Eight of 45 patients were previously treated with ruthenium-106 brachytherapy in conjunction with iridocyclectomy. Six of 45 patients developed endothelial dysfunction four of whom had received ruthenium-106 brachytherapy. Five of 45 patients had subluxation of the IOL/IP complex due to incomplete zonula apparatus. BCVA improved for all patients after lens surgery. 26 patients participated in the invited follow-up examination. 19 of 26 (73%) reported none or mild photic symptoms after IP instalment. Five (19%) reported ongoing severe photic symptoms. The corneal astigmatism significantly increased after iridocyclectomy but did not change after lens surgery. CONCLUSIONS: Implantation of an IOL and IP is a safe procedure, alleviating photic symptoms in most patients. It comes with higher risk of complications due to a more demanding procedure and larger surgical traumas from previous treatments. Ruthenium-106 brachytherapy increases the complication risk. Corneal astigmatism is induced by iridocyclectomy but does not change after lens surgery.

Visual snow syndrome and its relationship with migraine.

INTRODUCTION: Visual snow syndrome (VSS) is a central nervous system disorder that consists of the constant perception of small black and white dots throughout the entire visual field. DEVELOPMENT: VSS can present from infancy to old age, with greater prevalence in the young population, and shows no difference between sexes. The diagnostic criteria include the presence of visual snow and such other visual phenomena as palinopsia, photophobia, nyctalopia, and other persistent visual phenomena. The pathophysiology of VSS is unknown, but hyperexcitability of the visual cortex and a dysfunction in higher-order visual processing are postulated as potential mechanisms. The prevalence of migraine among patients with VSS is high, compared to the general population, and symptoms are more severe in patients presenting both conditions. No effective treatment is available, but the drug with the best results is lamotrigine, which is recommended only in selected cases with severe functional limitation. CONCLUSIONS: VSS is a little-known and underdiagnosed entity, but the increasing number of studies in recent years has made it possible to establish diagnostic criteria and begin studying its pathophysiology. This entity is closely related to migraine, with overlapping symptoms and probably shared pathophysiological mechanisms.

Pre- and post-headache phases of migraine: multi-country results from the CaMEO - International Study.

BACKGROUND: Individuals with migraine frequently experience pre- and post-headache symptoms. This analysis aimed to characterize the relative frequency and burden of pre- and post-headache symptoms in people with migraine using data collected through the Chronic Migraine Epidemiology and Outcomes - International Study. METHODS: This cross-sectional, observational, web-based survey was conducted in 2021-2022 in Canada, France, Germany, Japan, the United Kingdom, and the United States. Respondents who met modified International Classification of Headache Disorders, 3rd edition, criteria were offered the opportunity to participate. Information collected included migraine-related disability, depression/anxiety symptoms, cutaneous allodynia, activity limitations, and acute treatment optimization. Respondents indicated how often they had pre- or post-headache symptoms using a 5-point scale, ranging from 0 to 4, with a rating of 2 or higher classified as a pre- or post-headache symptom case. Modeling was used to examine relationships with monthly headache days (MHDs) and activity limitations during pre-headache and post-headache phases. RESULTS: Among a total of 14,492 respondents, pre-headache symptoms were reported by 66.9%, while post-headache symptoms were reported by 60.2%. Both pre-headache and post-headache symptoms were reported by 49.5% of respondents, only pre-headache by 17.4%, only post-headache by 10.7%, and neither pre- nor post-headache symptoms by 22.4%. Compared with respondents who experienced only pre- or post-headache symptoms, respondents who experienced both pre- and post-headache symptoms had the highest rates of 4-7, 8-14, and ≥ 15 monthly headache days (23.1%, 14.1%, and 10.9%, respectively). Of respondents with both pre- and post-headache symptoms, 58.5% reported moderate-to-severe disability, 47.7% reported clinically significant symptoms of depression, 49.0% reported clinically significant symptoms of anxiety, and 63.8% reported cutaneous allodynia with headache (ASC-12). Moderate-to-severe activity limitations were reported during the pre-headache (29.5%) and post-headache phases (27.2%). For all outcomes modeled, after controlling for covariates, having pre-headache symptoms, post-headache symptoms, or both were associated with worse outcomes than having neither. CONCLUSIONS: Pre- and post-headache phases of migraine are common, carry unrecognized burden, and may be a target for treatment.

Low pressure headache and cerebral fat embolism from a sacral fracture through a Tarlov cyst: a case report.

BACKGROUND: Here we report the only formally documented case in the United Kingdom, to our knowledge, of a cerebral fat embolism secondary to non-iatrogenic trauma through a Tarlov cyst. This case demonstrates the pathology clearly giving an excellent opportunity to demonstrate a rarely seen pathology as well as illustrating the importance of the patient history to guiding further management. CASE PRESENTATION: A middle-aged patient was admitted on the acute medical take complaining of severe headache with photophobia, having just returned after a skiing holiday. Computerised tomography scan of the head showed fat within the anterior horn of both lateral ventricles, and within the subarachnoid space. Re-discussion with the patient and subsequent MRI (Magnetic Resonance Imaging) of the spine identified the pathogenesis of her symptoms: a sacral insufficiency fracture through a Tarlov cyst, causing subarachnoid fat embolism and symptoms of a low-pressure headaches due to a dural leak. Patient was medically managed and discharged with planned follow-up. Due to the Coronavirus pandemic and resolution of the patient's symptoms, they declined further follow up imaging. CONCLUSIONS: The case demonstrates a rarely seen pathology as cause of a common presenting problem, headache. Emphasizing the importance of history taking and appropriate investigations in medical cases that do not conform to the usual diagnosis.