Extrasynaptic δGABAA receptors mediate resistance to migraine-like phenotype in rats.

BACKGROUND: GABA, a key inhibitory neurotransmitter, has synaptic and extrasynaptic receptors on the postsynaptic neuron. Background GABA, which spills over from the synaptic cleft, acts on extrasynaptic delta subunit containing GABAA receptors. The role of extrasynaptic GABAergic input in migraine is unknown. We investigated the susceptibility to valid migraine-provoking substances with clinically relevant behavioral readouts in Genetic Absence Epilepsy of Rats Strasbourg (GAERS), in which the GABAergic tonus was altered. Subsequently, we screened relevant GABAergic mechanisms in Wistar rats by pharmacological means to identify the mechanisms. METHODS: Wistar and GAERS rats were administered nitroglycerin (10 mg/kg) or levcromakalim (1 mg/kg). Mechanical allodynia and photophobia were assessed using von Frey monofilaments and a dark-light box. Effects of GAT-1 blocker tiagabine (5 mg/kg), GABAB receptor agonist baclofen (2 mg/kg), synaptic GABAA receptor agonist diazepam (1 mg/kg), extrasynaptic GABAA receptor agonists gaboxadol (4 mg/kg), and muscimol (0.75 mg/kg), T-type calcium channel blocker ethosuximide (100 mg/kg) or synaptic GABAA receptor antagonist flumazenil (15 mg/kg) on levcromakalim-induced migraine phenotype were screened. RESULTS: Unlike Wistar rats, GAERS exhibited no reduction in mechanical pain thresholds or light aversion following nitroglycerin or levcromakalim injection. Ethosuximide did not reverse the resistant phenotype in GAERS, excluding the role of T-type calcium channel dysfunction in this phenomenon. Tiagabine prevented levcromakalim-induced mechanical allodynia in Wistar rats, suggesting a key role in enhanced GABA spillover. Baclofen did not alleviate mechanical allodynia. Diazepam failed to mitigate levcromakalim-induced migraine phenotype. Additionally, the resistant phenotype in GAERS was not affected by flumazenil. Extrasynaptic GABAA receptor agonists gaboxadol and muscimol inhibited periorbital allodynia in Wistar rats. CONCLUSION: Our study introduced a rat strain resistant to migraine-provoking agents and signified a critical involvement of extrasynaptic δGABAergic receptors. Extrasynaptic δ GABAA receptors, by mediating constant background inhibition on the excitability of neurons, stand as a novel drug target with a therapeutic potential in migraine.

Infrared- and white-light retinal sensitivity in glaucomatous neuropathy.

Glaucoma causes irreversible neuropathy, which, untreated, may lead to blindness. In this case-control study, we measured two-photon infrared (IR) light sensitivity in glaucomatous eyes to propose a new method to quantify the visual loss. In total, 64 patients were recruited with an equal distribution between glaucoma and control groups. Retinal sensitivity to IR light was assessed using a two-photon excitation device. A fundus-driven microperimeter was used to measure retinal sensitivity to visible light. The retinal nerve fiber layer (RNFL) thickness was quantified automatically with optical coherence tomography. The IR sensitivity of glaucoma and control eyes differed significantly (P = .003): 9.8 (6.5 to 13.1) dB vs. 10.9 (8.2 to 13.0) dB. Although in the visible-light microperimetry, retinal sensitivity was decreased in glaucoma (17.0, range: 6.9 to 20.0 dB) compared to the controls (17.7, range: 11.6 to 20.0 dB), this difference did not reach the significance level. A significant thinning of the RNFL in the glaucoma group was observed (P < .001). IR sensitivity significantly correlated with the RNFL in three of the four assessed quadrants instead of only one in visible-light microperimetry. Although further research is needed, this proof-of-concept study suggests that IR-light sensitivity can be used to support the detection of glaucomatous neuropathy.

Migraine and light: A narrative review.

OBJECTIVE: In this narrative review, we summarize clinical and experimental data on the effect of light in migraine and discuss future prospects. BACKGROUND: Effective nonpharmacological treatment of hypersensitivity to light in migraine is an unmet clinical need. Current management strategies primarily consist of seeking a dark room and avoiding light exposure. Advances in the past 2 decades have improved our understanding of the underlying pathophysiology of how migraine is influenced by light. This may provide promising avenues for novel approaches in clinical management. METHODS: We searched MEDLINE for articles published from database inception up to September 1, 2021. We used the search term "migraine" with the search terms "light," "photophobia," "treatment," "trigger," "circadian rhythm," "environment," and/or "pathophysiology." RESULTS: Light is commonly reported as a trigger factor of migraine attacks, however, early manifestation of photophobia and false attribution is likely the actual cause based on data deriving from retrospective, prospective, and experimental studies. The most common photophobia symptoms in migraine are exacerbation of headache by light and abnormal sensitivity to light with the underlying neural pathways likely being dependent on ongoing activity in the trigeminovascular system. Clinical studies and experimental models have identified mediators of photophobia and uncovered narrow wavebands of the light spectrum that may reduce pain intensity during a migraine attack. Consequently, novel devices have undergone exploratory clinical trials with promising results. CONCLUSION: False attribution is likely the reason why light is commonly reported as a trigger factor of migraine attacks, and a prospective confirmation is required to prevent unnecessary avoidance. The observation that individuals with migraine are not equally photophobic to all wavebands of the light spectrum opens the potential for innovative pain management strategies. In this context, using human-centric lighting (also called integrative lighting) to mimic the natural daylight cycle and avoid harmful wavebands through modern technology may prove beneficial. Future research should identify direct and indirect consequences of light and other environmental factors in migraine to fill out knowledge gaps and enable evidence-based care strategies within institutions, work environments, and other settings.

Reflexive Eye Closure in Response to Cone and Melanopsin Stimulation: A Study of Implicit Measures of Light Sensitivity in Migraine.

BACKGROUND AND OBJECTIVES: To quantify interictal photophobia in migraine with and without aura using reflexive eye closure as an implicit measure of light sensitivity and to assess the contribution of melanopsin and cone signals to these responses. METHODS: Participants were screened to meet criteria for 1 of 3 groups: headache-free (HF) controls, migraine without aura (MO), and migraine with visual aura (MA). MO and MA participants were included if they endorsed ictal and interictal photophobia. Exclusion criteria included impaired vision, inability to collect usable pupillometry, and history of either head trauma or seizure. Participants viewed light pulses that selectively targeted melanopsin, the cones, or their combination during recording of orbicularis oculi EMG (OO-EMG) and blinking activity. RESULTS: We studied 20 participants in each group. MA and MO groups reported increased visual discomfort to light stimuli (discomfort rating, 400% contrast, MA: 4.84 [95% confidence interval 0.33, 9.35]; MO: 5.23 [0.96, 9.50]) as compared to HF controls (2.71 [0, 6.47]). Time course analysis of OO-EMG and blinking activity demonstrated that reflexive eye closure was tightly coupled to the light pulses. The MA group had greater OO-EMG and blinking activity in response to these stimuli (EMG activity, 400% contrast: 42.9%Δ [28.4, 57.4]; blink activity, 400% contrast: 11.2% [8.8, 13.6]) as compared to the MO (EMG activity, 400% contrast: 9.9%Δ [5.8, 14.0]; blink activity, 400% contrast: 4.7% [3.5, 5.9]) and HF control (EMG activity, 400% contrast: 13.2%Δ [7.1, 19.3]; blink activity, 400% contrast: 4.5% [3.1, 5.9]) groups. DISCUSSION: Our findings suggest that the intrinsically photosensitive retinal ganglion cells (ipRGCs), which integrate melanopsin and cone signals, provide the afferent input for light-induced reflexive eye closure in a photophobic state. Moreover, we find a dissociation between implicit and explicit measures of interictal photophobia depending on a history of visual aura in migraine. This implies distinct pathophysiology in forms of migraine, interacting with separate neural pathways by which the amplification of ipRGC signals elicits implicit and explicit signs of visual discomfort.

Hyperhomocysteinemia increases susceptibility to cortical spreading depression associated with photophobia, mechanical allodynia, and anxiety in rats.

Epidemiological data suggest that elevated homocysteine is associated with migraine with aura. However, how homocysteine contributes to migraine is still unclear. Here, we tested whether hyperhomocysteinemia (hHCY) promotes cortical spreading depression (CSD), a phenomenon underlying migraine with aura, and whether hHCY contributes to pain behavior. hHCY was induced by dietary methionine in female rats while the testing was performed on their 6-8week-old offspring. CSD and multiple unit activity (MUA) induced by KCl were recorded from the primary somatosensory cortex, S1, using multichannel electrodes. In hHCY rats, compared to control, we found: i) higher probability of CSD occurrence; ii) induction of CSD by lower concentrations of KCl; iii) faster horizontal propagation of CSD; iv) smaller CSD with longer duration; v) higher frequency of MUA at CSD onset along with slower reappearance. Rats with hHCY demonstrated high level of locomotor activity and grooming while spent less time in the central area of the open field, indicating anxiety. These animals showed light sensitivity and facial mechanical allodinia. Thus, hHCY acquired at birth promotes multiple features of migraine such as higher cortical excitability, mechanical allodynia, photophobia, and anxiety. Our results provide the first experimental explanation for the higher occurrence of migraine with aura in patients with hHCY.

Preictal state detection using prodromal symptoms: A machine learning approach.

A reliable identification of a high-risk state for upcoming seizures may allow for preemptive treatment and improve the quality of patients' lives. We evaluated the ability of prodromal symptoms to predict preictal states using a machine learning (ML) approach. Twenty-four patients with drug-resistant epilepsy were admitted for continuous video-electroencephalographic monitoring and filled out a daily four-point questionnaire on prodromal symptoms. Data were then classified into (1) a preictal group for questionnaires completed in a 24-h period prior to at least one seizure (n1  = 58) and (2) an interictal group for questionnaires completed in a 24-h period without seizures (n2  = 190). Our prediction model was based on a support vector machine classifier and compared to a Fisher's linear classifier. The combination of all the prodromal symptoms yielded a good prediction performance (area under the curve [AUC] = .72, 95% confidence interval [CI] = .61-.81). This performance was significantly enhanced by selecting a subset of the most relevant symptoms (AUC = .80, 95% CI = .69-.88). In comparison, the linear classifier systematically failed (AUCs < .6). Our findings indicate that the ML analysis of prodromal symptoms is a promising approach to identifying preictal states prior to seizures. This could pave the way for development of clinical strategies in seizure prevention and even a noninvasive alarm system.

Photophobia: shared pathophysiology underlying dry eye disease, migraine and traumatic brain injury leading to central neuroplasticity of the trigeminothalamic pathway.

BACKGROUND: Photophobia is a potentially debilitating symptom often found in dry eye disease (DE), migraine and traumatic brain injury (TBI). METHODS: We conducted a review of the literature via a PubMed search of English language articles with a focus on how photophobia may relate to a shared pathophysiology across DE, migraine and TBI. RESULTS: DE, migraine and TBI are common conditions in the general population, are often comorbid, and share photophobia as a symptom. Across the three conditions, neural dysregulation of peripheral and central nervous system components is implicated in photophobia in various animal models and in humans. Enhanced activity of the neuropeptide calcitonin gene-related peptide (CGRP) is closely linked to photophobia. Current therapies for photophobia include glasses which shield the eyes from specific wavelengths, botulinum toxin, and inhibition of CGRP and its receptor. Many individuals have persistent photophobia despite the use of these therapies, and thus, development of new therapies is needed. CONCLUSIONS: The presence of photophobia in DE, migraine and TBI suggests shared trigeminothalamic pathophysiologic mechanisms, as explained by central neuroplasticity and hypersensitivity mediated by neuropeptide CGRP. Treatment strategies which target neural pathways (ie, oral neuromodulators, transcutaneous nerve stimulation) should be considered in patients with persistent photophobia, specifically in individuals with DE whose symptoms are not controlled with traditional therapies.

THE LOSS OF INFRARED LIGHT SENSITIVITY OF PHOTORECEPTOR CELLS MEASURED WITH TWO-PHOTON EXCITATION AS AN INDICATOR OF DIABETIC RETINOPATHY: A Pilot Study.

PURPOSE: Human photoreceptors are sensitive to infrared light (IR). This sensitivity can be used as a novel indicator of retinal function. Diabetic retinopathy patients were assessed using in vivo two-photon excitation and compared their scotopic IR threshold with that of healthy patients. METHODS: Sixty-two participants, 28 healthy and 34 with diabetic retinopathy, underwent a comprehensive eye examination, where visual acuity and contrast sensitivity were assessed. Infrared thresholds were measured in the fovea and parafovea following 30-minute dark adaptation. A two-photon excitation device was used with integrated pulsed laser light (1,045 nm) for sensitivity testing and scanning laser ophthalmoscopy for fundus imaging. RESULTS: The mean Snellen visual acuity of diabetic patients (6/7.7) was worse than that of the healthy patients (6/5.5), which was significantly different (P < 0.001). Disease patients had decreased contrast sensitivity, especially at 6 and 18 cycles/degree. The mean retinal sensitivity to IR light in eyes with diabetic retinopathy (11.6 ± 2.0 dB) was significantly (P < 0.001) lower than that in normal eyes (15.5 ± 1.3 dB). CONCLUSION: Compared with healthy control subjects, the IR light sensitivity of diabetic patients was significantly impaired. Two-photon measurements can be used in the assessment of retinal disease, but further studies are needed to validate IR light stimulation in various stages of diabetic retinopathy.

Tolerance to Light of Patients Suffering From Infectious Keratitis.

PURPOSE: With very photophobic patients, the advantages of red or near infrared light to develop new ophthalmology imaging devices seem obvious: no or little glare, possibility of long signal integration, no phototoxicity, and lesser autofluorescence of ocular tissues. Nevertheless, in this range, the shortest possible wavelength facilitates signal detection. The aim of this study was, thus, to determine the maximal irradiance tolerated with 6 wavelengths: 2 red, 2 far red, and 1 near infrared lights to determine the shortest wavelength well tolerated by patients, in comparison with the standard cobalt blue light of ophthalmology slitlamp. METHODS: An interventional, monocentric, single-group assignment study was conducted on 30 eyes of 30 patients with infectious keratitis. Thanks to a customized machine, the photophobic eye was exposed to the 6 lights with increasing intensity. The patients switched off the light when the discomfort was too elevated. The maximal cumulative irradiance possible at 482, 650, 675, 700, 750, and 800 nm were 171, 689, 759, 862, 920, and 889 mW/cm, respectively. RESULTS: The maximal cumulative irradiance tolerated by patients increased significantly with wavelength (P < 0.001), but the difference was not significant between each increment: red at 675 nm gave a significantly higher cumulative irradiance than blue at 482 nm; red at 700 nm did not provide significant gain compared with 675 nm; and far red at 750 nm still provided additional gain compared with 700 nm, but no significant gain was observed between 750 and 800 nm. The shortest wavelengths were stopped more quickly, and more than 50% of patients reached the maximum irradiance delivered by the source at 750 and 800 nm. CONCLUSIONS: We demonstrate that a light source at 750 and 800 nm can be used for ophthalmic imaging with good tolerance in photophobic patients. CLINICAL TRIAL REGISTRATION: NCT03586505.

Connections between intrinsically photosensitive retinal ganglion cells and TBI symptoms.

The majority of patients with traumatic brain injury (TBI) are classified as having a mild TBI. Despite being categorized as mild, these individuals report ongoing and complex symptoms, which negatively affect their ability to complete activities of daily living and overall quality of life. Some of the major symptoms include anxiety, depression, sleep problems, headaches, light sensitivity, and difficulty reading. The root cause for these symptoms is under investigation by many in the field. Of interest, several of these symptoms such as headaches, ocular pain, light sensitivity, and sleep disturbances may overlap and share underlying circuitry influenced by the intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells are light sensing, but non-image forming, and they influence corneal function, pupillary constriction, and circadian rhythm. In this review, we discuss these symptoms and propose a role of the ipRGCs as at least one underlying and unifying cause for such symptoms.

Wavelength of light and photophobia in inherited retinal dystrophy.

Inherited retinal dystrophy (IRD) patients often experience photophobia. However, its mechanism has not been elucidated. This study aimed to investigate the main wavelength of light causing photophobia in IRD and difference among patients with different phenotypes. Forty-seven retinitis pigmentosa (RP) and 22 cone-rod dystrophy (CRD) patients were prospectively recruited. We designed two tinted glasses: short wavelength filtering (SWF) glasses and middle wavelength filtering (MWF) glasses. We classified photophobia into three types: (A) white out, (B) bright glare, and (C) ocular pain. Patients were asked to assign scores between one (not at all) and five (totally applicable) for each symptom with and without glasses. In patients with RP, photophobia was better relieved with SWF glasses {"white out" (p < 0.01) and "ocular pain" (p = 0.013)}. In CRD patients, there was no significant difference in the improvement wearing two glasses (p = 0.247-1.0). All RP patients who preferred MWF glasses had Bull's eye maculopathy. Meanwhile, only 15% of patients who preferred SWF glasses had the finding (p < 0.001). Photophobia is primarily caused by short wavelength light in many patients with IRD. However, the wavelength responsible for photophobia vary depending on the disease and probably vary according to the pathological condition.

The Influence of Photophobia on Postural Control in Patients With Migraine.

BACKGROUND: People with migraine exhibit postural control impairments. These patients also have an increased light sensitivity due to the disease, and it remains during the headache-free period. It is currently unknown if increased lighting levels can alter the balance control, especially in individuals with visual hypersensitivity, such as migraineurs. This study aimed to assess the balance and photophobia of women with migraine and non-headache controls under different light conditions. METHODS: This cross-sectional study consisted of 14 women with migraine (mean ± SD 30.6 ± 8.1 years old) and 14 women without any kind of headache (mean ± SD 27.2 ± 2.8 years old) screened from a tertiary headache clinical hospital and the local community. Quiet standing balance was evaluated during bipodal and unipodal support, under 3 light conditions: ambient (AMB) - 270 lx, visual discomfort threshold (VDT) - 400 lx, and intense visual discomfort (IVD) - 2000 lx. Sway area of the center of pressure was processed and compared between groups. The association of migraine with the risk of presenting a greater imbalance in the discomfort lighting conditions was verified. RESULTS: Compared to the non-headache controls, the migraine group presented greater sway area in bipodal stance under the 3 light conditions (mean difference (95% CI)): AMB 0.81 cm2 (0.19 to 1.43), P = .011; VDT 3.17 cm2 (0.74 to 5.60), P = .001; IVD 5.56 cm2 (2.75 to 8.37), P < .0001. Within-subject analysis showed increased sway area in bipodal stance among all lighting conditions for the migraine group only (mean difference (95% CI)): VDT-AMB 2.20 cm2 (0.23 to 4.18), P = .024; IVD-AMB 4.50 cm2 (2.38 to 6.62), P < .0001, IVD-VDT 2.29 cm2 (0.57 to 4.01), P = .005. The Prevalence Ratio (PR) analysis showed that migraine was associated with the risk of presenting greater imbalance in both bipodal and unipodal standing conditions for both VDT (PR value (95% CI) - bipodal: PR = 4.00 (1.02 to 15.59), P = .045; unipodal: PR = 4.00 (1.43 to 11.15), P = .008), and the IVD (bipodal: PR = 3.33 (1.13 to 9.58), P = .025; unipodal: PR = 5.50 (1.48 to 20.42), P = .010) lighting conditions. CONCLUSION: Photophobia might be a disturbing factor that worsens the balance of patients with migraine during the quiet standing posture.

Sensory Hypersensitivity Symptoms in Migraine With vs Without Aura: Results From the American Registry for Migraine Research.

BACKGROUND AND OBJECTIVES: Migraine with aura (MwA) is associated with increased brain hyper-responsiveness to visual stimuli and increased visual network connectivity relative to migraine without aura (MwoA). Despite this, prior studies have provided conflicting results regarding whether MwA is associated with higher photophobia symptom scores compared to MwoA. The relationships between MwA and other types of sensory hypersensitivity, such as phonophobia and cutaneous allodynia (CA), have not been previously investigated. The purpose of this cross-sectional observational study was to investigate whether MwA is associated with greater symptoms of photophobia, phonophobia, and CA compared to MwoA. METHODS: This analysis included 321 migraine patients (146 MwA; 175 MwoA) who had been enrolled into the American Registry for Migraine Research. The diagnosis of either MwoA or MwA was determined by headache specialists using ICHD diagnostic criteria. Patients completed the Photosensitivity Assessment Questionnaire, the Hyperacusis Questionnaire, and the Allodynia Symptom Checklist. Mean or median values were compared between groups. Regression models were created to analyze the relationship between MwA with photophobia scores, hyperacusis scores, and the presence of interictal CA. RESULTS: Those with MwA had higher mean photophobia scores than those with MwoA (4.1 vs 3.0, P = .0003). MwA was positively associated with photophobia symptom severity (B = 0.50 [SE = 0.14], P = .0003), after controlling for age, patient sex, and headache frequency. Aura was not associated with hyperacusis symptom severity (B = 0.07 [SE = 0.08], P = .346) or the presence of interictal CA (OR 1.33 [95% CI 0.70-2.53], P = .381). CONCLUSION: MwA is associated with higher photophobia symptom scores compared to MwoA. Aura is not associated with greater hyperacusis or interictal allodynia scores. These findings complement prior imaging and neurophysiologic studies that demonstrated MwA to be associated with hyper-responsiveness of brain visual processing regions. The findings suggest that MwA is associated specifically with visual hypersensitivity, as opposed to being associated with a general hypersensitivity to multiple types of sensory stimuli.

Visual snow syndrome: A clinical and phenotypical description of 1,100 cases.

OBJECTIVE: To validate the current criteria of visual snow and to describe its common phenotype using a substantial clinical database. METHODS: We performed a web-based survey of patients with self-assessed visual snow (n = 1,104), with either the complete visual snow syndrome (n = 1,061) or visual snow without the syndrome (n = 43). We also describe a population of patients (n = 70) with possible hallucinogen persisting perception disorder who presented clinically with visual snow syndrome. RESULTS: The visual snow population had an average age of 29 years and had no sex prevalence. The disorder usually started in early life, and ≈40% of patients had symptoms for as long as they could remember. The most commonly experienced static was black and white. Floaters, afterimages, and photophobia were the most reported additional visual symptoms. A latent class analysis showed that visual snow does not present with specific clinical endophenotypes. Severity can be classified by the amount of visual symptoms experienced. Migraine and tinnitus had a very high prevalence and were independently associated with a more severe presentation of the syndrome. CONCLUSIONS: Clinical characteristics of visual snow did not differ from the previous cohort in the literature, supporting validity of the current criteria. Visual snow likely represents a clinical continuum, with different degrees of severity. On the severe end of the spectrum, it is more likely to present with its common comorbid conditions, migraine and tinnitus. Visual snow does not depend on the effect of psychotropic substances on the brain.

Electroretinographic abnormalities associated with pregabalin: a case report.

PURPOSE: Pregabalin binds to the α2-δ1/α2-δ2 subunits of the voltage-gated L-type calcium channel (LTCC), which is expressed in rod/cone photoreceptor terminals. The purpose of this report was to describe electroretinographic abnormalities associated with pregabalin treatment. CASE PRESENTATION: This is an observational case report. A 49-year-old female reported photophobia and night blindness in her left eye after 10 months of pregabalin administration. One month after the symptoms, ophthalmic examinations were performed, which revealed good visual acuity and no remarkable fundus findings. However, full-field electroretinography (ERG) of the left eye revealed a decreased b-wave in rod ERG, a slightly decreased a-wave and severely decreased b-wave (negative ERG) in bright flash ERG, decreased a- and b-waves in cone ERG, and decreased b-waves in 30-Hz flicker ERG. These findings are similar to those seen in incomplete congenital stationary night blindness, whereas the right eye ERG showed normal responses, except for a square a-wave in cone ERG. The ERG gradually improved from 1 to 12 months after discontinuing pregabalin. Finally, b-waves in bright flash ERG and cone ERG responses largely recovered, but b-waves in rod ERG and a-waves in bright flash ERG only partially recovered in the left eye. The square a-wave recovered to normal in the right eye. CONCLUSIONS: This is the first report to indicate that ERG abnormalities might be associated with pregabalin treatment. Our results suggest that pregabalin may affect LTCC function via the α2-δ1/α2-δ2 subunits, which leads to defective synaptic transmission from rod/cone photoreceptors to bipolar cells.

Craniofacial Autonomic Dysfunction in Migraine: Implications for Treatment and Prognosis.

BACKGROUND: Craniofacial autonomic signs and symptoms (CASS) are relatively underrecognized in the evaluation of migraine headache. Yet, these features provide insight into diagnostic criterion, therapeutic approaches, and overarching disease burden. EVIDENCE ACQUISITION: This review aims to summarize relevant literature evaluating autonomic dysfunction, with focus on CASS, in migraine through targeted literature searches in PubMed. Full articles of original data published between 1974 and 2019 were identified using MeSH terms with no search limits. RESULTS: Although CASS are typically clinically evaluated by subjective patient report, investigational measures of cranial autonomic function have identified marked distinctions between headache attack and attack-free intervals. The presence of CASS during an attack does not differ based on age, sex, or presence of aura. Unilateral CASS may be predictive of longer, more frequent, and/or severe attacks and often co-occur with sensory dysfunction such as allodynia and photophobia. Although limited research has been performed to evaluate targeted therapeutics for migraine with CASS, triptans and onabotulinumtoxinA may demonstrate greater effects in this group. CONCLUSIONS: Migraine remains a debilitating disorder with significant community-wide impacts, necessitating continued evaluation of contributing features. Consideration of CASS provides important insight into potential treatment approaches and the effectiveness of novel therapeutic interventions aimed at improving overall disease burden. However, further investigation is needed to fully understand primary craniofacial features in migraine, and how these might inform individualized treatment decisions.

Clinical and biochemical differences between hantavirus infection and leptospirosis: a retrospective analysis of a patient series in Belgium.

Objectives: Hantavirus infection and leptospirosis are infectious diseases transmitted by rodents. The clinical picture is nonspecific, often involving the kidneys but other organs can be affected too. Clinical and biochemical clues to make a difference between these two entities will be described.Methods: A retrospective analysis was performed on a database of patients presenting between January 2012 and September 2017 at the emergency department of the university hospital Leuven, Belgium. Patients were selected on the basis of a compatible clinical picture, biochemistry, and microbiological evidence. Presenting complaints and clinical examination were compared. Blood, taken at presentation, was used for hematological and biochemical analysis.Results: Sixteen patients with hantavirus infection and eight patients with leptospirosis were identified. All patients complained about general malaise and fever. Other frequent complaints were myalgia and a headache. Patients with leptospirosis often experienced photo- or sonophobia.Looking for neck stiffness and eye lesions might help to diagnose leptospirosis.Differences in biochemistry between viral and bacterial disease could be recognized; high C-reactive protein (CRP) and leukocytosis with left shift favor leptospirosis, elevated lactate dehydrogenase (LDH) favors viral infection. Abnormal liver function with raised total bilirubin is often seen in cases with leptospirosis.Conclusion: This study demonstrates some subtle clues that may help to differentiate between hantavirus infection and leptospirosis in patients presenting to a hospital in a nonendemic region of the world. Because of small number of patients, we could not identify significant clinical or biochemical tests. Serology remains the gold standard.

The American Registry for Migraine Research: Research Methods and Baseline Data for an Initial Patient Cohort.

BACKGROUND: The American Registry for Migraine Research (ARMR) is a multicenter, prospective, longitudinal patient registry, biorepository, and neuroimaging repository that collects clinical data, electronic health record (EHR) data, blood samples, and brain imaging data from individuals with migraine or other headache types. In this manuscript, we outline ARMR research methods and report baseline data describing an initial cohort of ARMR participants. METHODS: Adults with any International Classification of Headache Disorders (ICHD) diagnosis were prospectively enrolled from one of the 8 participating headache specialty centers. At baseline, ARMR participants complete web-based questionnaires, clinicians enter the participant's ICHD diagnoses, an optional blood specimen is collected, and neuroimaging data are uploaded to the ARMR neuroimaging repository. Participants maintain the ARMR daily headache diary longitudinally and follow-up questionnaires are completed by participants every 3 months. EHR data are integrated into the ARMR database from a subset of ARMR sites. Herein, we describe the ARMR methodology and report the summary data from ARMR participants who had, from February 2016 to May 2019, completed at least 1 baseline questionnaire from which data are reported in this manuscript. Descriptive statistics are used to provide an overview of patient's sociodemographics, headache diagnoses, headache characteristics, most bothersome symptoms other than headache, headache-related disability, comorbidities, and treatments. RESULTS: Data were available from 996 ARMR participants, enrolled from Mayo Clinic Arizona, Dartmouth-Hitchcock Medical Center, University of Utah, University of Colorado, Thomas Jefferson University, University of Texas Health Science Center at Houston, Georgetown University Medical Center, and DENT Neurological Institute. Among ARMR participants, 86.7% (n = 864) were female and the mean age at the time of enrollment was 48.6 years (±13.9; range 18-84). The most common provider-reported diagnosis was chronic migraine (n = 622), followed by migraine without aura (n = 327), migraine with aura (n = 196), and medication overuse headache (n = 65). Average headache frequency was 19.1 ± 9.2 days per month (n = 751), with 68% reporting at least 15 headache days per month. Sensitivity to light was the most frequent (n = 222) most bothersome symptom overall, other than headache, but when present, cognitive dysfunction was most frequently (n = 157) the most bothersome symptom other than headache. Average migraine disability assessment (MIDAS) score was 52 ± 49 (n = 760), (very severe headache-related disability); however, 17% of the ARMR population had MIDAS scores suggesting "no" or "mild" disability. The most common non-headache health issues were allergies (n = 364), back pain (n = 296), neck pain (n = 296), depression (n = 292), and anxiety (n = 278). Nearly 85% (n = 695) of patients were using preventive medications and 24.7% were using non-medication preventive therapy (eg, vitamins and neuromodulation). The most common preventive medication classes were neurotoxins, anticonvulsants, antidepressants, vitamins/supplements, and anticalcitonin gene-related peptide ligand or receptor-targeted monoclonal antibodies. Nearly 90% (n = 734) of ARMR participants was taking medications to treat migraine attacks, with the most common classes being triptans, non-steroidal anti-inflammatory drugs, antiemetics, acetaminophen, and combination analgesics. CONCLUSIONS: ARMR is a source of real-world patient data, biospecimens, and brain neuroimaging data that provides comprehensive insight into patients with migraine and other headache types being seen in headache specialty clinics in the United States. ARMR data will allow for longitudinal and advanced analytics that are expected to lead to a better characterization of patient heterogeneity, healthcare resource utilization, identification of endophenotypes, factors that predict treatment outcomes and clinical course, and ultimately advance the field toward precision headache medicine.

Blue light activates pulvinar nuclei in longstanding idiopathic photophobia: A case report.

Numerous pathologies can contribute to photophobia. When considering light transduction alone, photophobia may be triggered through melanopsin pathways (non-image forming), rod and cone pathways (image-forming), or some combination of the two. We evaluated a 39 year old female patient with longstanding idiopathic photophobia that was exacerbated by blue light, and tested her by presenting visual stimuli in an event-related fMRI experiment. Analysis showed significantly greater activation in bilateral pulvinar nuclei, associated with the melanopsin intrinsically photosensitive retinal ganglion cell (ipRGC) visual pathway, and their activation is consistent with the patient's report that blue light differentially evoked photophobia. This appears to be the first demonstration of functional activation of the ipRGC pathway during photophobia in a patient.