Search

Background: Varied responses to acute migraine medications have been observed, with over one‐third (34.5%) of patients reporting insufficient headache relief. Sumatriptan‐naproxen sodium, a single, fixed‐dose combination tablet comprising sumatriptan 85 mg and naproxen sodium 500 mg, was developed with the rationale of targeting multiple putative mechanisms involved in the pathogenesis of migraine to optimise acute migraine care. Methods: A narrative review of clinical trials investigating sumatriptan‐naproxen sodium for both adults and adolescents was performed in March 2024. Results: Across a total of 14 clinical trials in nine publications, sumatriptan‐naproxen sodium offered greater efficacy for 2‐h pain freedom (14/14) and sustained pain‐free response up to 24 h (13/14) compared with monotherapy and/or placebo for both adult and adolescent study participants with an acceptable and well‐tolerated adverse effect profile. Clinical trial data also demonstrates the effectiveness of sumatriptan‐naproxen sodium in participants with allodynia, probable migraine, menstrual‐related migraine and those with poor responses to acute, non‐specific, migraine medication. Conclusions: Multi‐mechanistic therapeutic agents offer an opportunity to optimise acute medications by targeting multiple mediators involved in the pathogenesis of migraine. Sumatriptan‐naproxen sodium resulted in greater initial and sustained pain freedom, compared with either sumatriptan, naproxen‐sodium and/or placebo, for the treatment of single or multiple attacks of migraine across both adult and adolescent study populations. [ABSTRACT FROM AUTHOR]

Objective: Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those targeting calcitonin gene‐related peptide (CGRP). However, there remains a substantial need for further treatments for those unresponsive to current therapies. Targeting pituitary adenylate cyclase‐activating polypeptide (PACAP) as a possible therapeutic strategy in the primary headache disorders has gained interest over recent years. Methods: This review will summarize what we know about PACAP to date: its expression, receptors, roles in migraine and cluster headache biology, insights gained from preclinical and clinical models of migraine, and therapeutic scope. Results: PACAP shares homology with vasoactive intestinal polypeptide (VIP) and is one of several vasoactive neuropeptides along with CGRP and VIP, which has been implicated in migraine neurobiology. PACAP is widely expressed in areas of interest in migraine pathophysiology, such as the thalamus, trigeminal nucleus caudalis, and sphenopalatine ganglion. Preclinical evidence suggests a role for PACAP in trigeminovascular sensitization, while clinical evidence shows ictal release of PACAP in migraine and intravenous infusion of PACAP triggering attacks in susceptible individuals. PACAP leads to dural vasodilatation and secondary central phenomena via its binding to different G‐protein‐coupled receptors, and intracellular downstream effects through cyclic adenosine monophosphate (cAMP) and phosphokinase C (PKC). Targeting PACAP as a therapeutic strategy in headache has been explored using monoclonal antibodies developed against PACAP and against the PAC1 receptor, with initial positive results. Interpretation: Future clinical trials hold considerable promise for a new therapeutic approach using PACAP‐targeted therapies in both migraine and cluster headache. [ABSTRACT FROM AUTHOR]

Objective: To provide a position statement update from The American Headache Society specifically regarding therapies targeting calcitonin gene‐related peptide (CGRP) for the prevention of migraine. Background: All migraine preventive therapies previously considered to be first‐line treatments were developed for other indications and adopted later for migraine. Adherence to these therapies is often poor due to issues with efficacy and tolerability. Multiple new migraine‐specific therapies have been developed based on a broad foundation of pre‐clinical and clinical evidence showing that CGRP plays a key role in the pathogenesis of migraine. These CGRP‐targeting therapies have had a transformational impact on the management of migraine but are still not widely considered to be first‐line approaches. Methods: Evidence regarding migraine preventive therapies including primary and secondary endpoints from randomized placebo‐controlled clinical trials, post hoc analyses and open‐label extensions of these trials, and prospective and retrospective observational studies were collected from a variety of sources including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the Board of Directors of The American Headache Society to confirm consistency with clinical experience and to achieve consensus. Results: The evidence for the efficacy, tolerability, and safety of CGRP‐targeting migraine preventive therapies (the monoclonal antibodies: erenumab, fremanezumab, galcanezumab, and eptinezumab, and the gepants: rimegepant and atogepant) is substantial, and vastly exceeds that for any other preventive treatment approach. The evidence remains consistent across different individual CGRP‐targeting treatments and is corroborated by extensive "real‐world" clinical experience. The data indicates that the efficacy and tolerability of CGRP‐targeting therapies are equal to or greater than those of previous first‐line therapies and that serious adverse events associated with CGRP‐targeting therapies are rare. Conclusion: The CGRP‐targeting therapies should be considered as a first‐line approach for migraine prevention along with previous first‐line treatments without a requirement for prior failure of other classes of migraine preventive treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: Little is known of how cranial autonomic symptoms (CAS) in cluster headache and migraine may contribute to their severe headache phenotype. This strong association suggests the involvement of the cranial parasympathetic efferent pathway. To investigate its contribution, we studied the role of pituitary adenylate cyclase activating polypeptide‐38 (PACAP‐38), a potent sensory and parasympathetic neuropeptide, in modulating pre‐ and post‐ganglionic cranial parasympathetic projection neurons, and their influence on headache‐related trigeminal‐autonomic responses. Experimental Approach: Using PACAP‐38 and PACAP‐38 responsive receptor antagonists, electrophysiological, behavioural and facial neurovascular‐blood flow was measured in rats to probe trigeminal‐ and parasympathetic‐neuronal, periorbital thresholds and cranial‐autonomic outcomes, as they relate to primary headaches. Key Results: Sumatriptan attenuated the development of PACAP‐38 mediated activation and sensitization of trigeminocervical neurons and related periorbital allodynia. PACAP‐38 also caused activation and enhanced responses of dural‐responsive pre‐ganglionic pontine‐superior salivatory parasympathetic neurons. Further, the PACAP‐38 responsive receptor antagonists dissected a role of VPAC1 and PAC1 receptors in attenuating cranial‐autonomic and trigeminal‐neuronal responses to activation of the cranial parasympathetic projection, which requires post‐ganglionic parasympathetic neurotransmission. Conclusion and Implications: Given the prevailing view that sumatriptan acts to some degree via a peripheral mechanism, our data support that PACAP‐38 mediated receptor activation modulates headache‐related cranial‐autonomic and trigeminovascular responses via peripheral and central components of the cranial parasympathetic projection. This provides a mechanistic rationale for the association of CAS with more severe headache phenotypes in cluster headache and migraine, and supports the cranial parasympathetic projection as a potential novel locus for treatment by selectively targeting PACAP‐38 or PACAP‐38 responsive VPAC1/PAC1 receptors. [ABSTRACT FROM AUTHOR]

Objective: Neuropharmacological changes in visual snow syndrome (VSS) are poorly understood. We aimed to use receptor target maps combined with resting functional magnetic resonance imaging (fMRI) data to identify which neurotransmitters might modulate brain circuits involved in VSS. Methods: We used Receptor‐Enriched Analysis of Functional Connectivity by Targets (REACT) to estimate and compare the molecular‐enriched functional networks related to 5 neurotransmitter systems of patients with VSS (n = 24), healthy controls (HCs; n = 24), and migraine patients ([MIG], n = 25, 15 of whom had migraine with aura [MwA]). For REACT we used receptor density templates for the transporters of noradrenaline, dopamine, and serotonin, GABA‐A and NMDA receptors, as well as 5HT1B and 5HT2A receptors, and estimated the subject‐specific voxel‐wise maps of functional connectivity (FC). We then performed voxel‐wise comparisons of these maps among HCs, MIG, and VSS. Results: Patients with VSS had reduced FC in glutamatergic networks localized in the anterior cingulate cortex (ACC) compared to HCs and patients with migraine, and reduced FC in serotoninergic networks localized in the insula, temporal pole, and orbitofrontal cortex compared to controls, similar to patients with migraine with aura. Patients with VSS also showed reduced FC in 5HT2A‐enriched networks, largely localized in occipito‐temporo‐parietal association cortices. As revealed by subgroup analyses, these changes were independent of, and analogous to, those found in patients with migraine with aura. Interpretation: Our results show that glutamate and serotonin are involved in brain connectivity alterations in areas of the visual, salience, and limbic systems in VSS. Importantly, altered serotonergic connectivity is independent of migraine in VSS, and simultaneously comparable to that of migraine with aura, highlighting a shared biology between the disorders. ANN NEUROL 2023;94:873–884 [ABSTRACT FROM AUTHOR]

Background and Purpose: Cluster headache is a relatively rare, disabling primary headache disorder with a major impact on patients' quality of life. This work presents evidence‐based recommendations for the treatment of cluster headache derived from a systematic review of the literature and consensus among a panel of experts. Methods: The databases PubMed (Medline), Science Citation Index, and Cochrane Library were screened for studies on the efficacy of interventions (last access July 2022). The findings in these studies were evaluated according to the recommendations of the European Academy of Neurology, and the level of evidence was established using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Recommendations: For the acute treatment of cluster headache attacks, there is a strong recommendation for oxygen (100%) with a flow of at least 12 L/min over 15 min and 6 mg subcutaneous sumatriptan. Prophylaxis of cluster headache attacks with verapamil at a daily dose of at least 240 mg (maximum dose depends on efficacy and tolerability) is recommended. Corticosteroids are efficacious in cluster headache. To reach an effect, the use of at least 100 mg prednisone (or equivalent corticosteroid) given orally or at up to 500 mg iv per day over 5 days is recommended. Lithium, topiramate, and galcanezumab (only for episodic cluster headache) are recommended as alternative treatments. Noninvasive vagus nerve stimulation is efficacious in episodic but not chronic cluster headache. Greater occipital nerve block is recommended, but electrical stimulation of the greater occipital nerve is not recommended due to the side effect profile. [ABSTRACT FROM AUTHOR]

Objective: To identify changes in regional cerebral blood flow (CBF) associated with premonitory symptoms (PS) of nitroglycerin (NTG)‐triggered migraine attacks. Background: PS could provide insights into attack initiation and alterations in neuronal function prior to headache onset. Methods: We undertook a functional imaging study using a double‐blind placebo‐controlled randomized approach in patients with migraine who spontaneously experienced PS, and in whom PS and migraine‐like headache could be induced by administration of NTG. All study visits took place in a dedicated clinical research facility housing a monitoring area with clinical beds next to a 3Tesla magnetic resonance imaging scanner. Fifty‐three patients with migraine were enrolled; imaging on at least one triggered visit was obtained from 25 patients, with 21 patients completing the entire imaging protocol including a placebo visit. Whole brain CBF maps were acquired using 3D pseudo‐continuous arterial spin labeling (3D pCASL). Results: The primary outcome was that patients with migraine not taking preventive treatment (n = 12) displayed significant increases in CBF in anterior cingulate cortex, caudate, midbrain, lentiform, amygdala and hippocampus (p < 0.05 family‐wise error‐corrected) during NTG‐induced PS. A separate region of interest analysis revealed significant CBF increases in the region of the hypothalamus (p = 0.006, effect size 0.77). Post hoc analyses revealed significant reductions in CBF over the occipital cortices in participants with a history of migraine with underlying aura (n = 14). Conclusions: We identified significant regional CBF changes associated with NTG‐induced PS, consistent with other investigations and with novel findings, withstanding statistical comparison against placebo. These findings were not present in patients who continually took preventive medication. Additional findings were identified only in participants who experience migraine with aura. Understanding this biological and treatment‐related heterogeneity is vital to evaluating functional imaging outcomes in migraine research. [ABSTRACT FROM AUTHOR]

Background and purpose: In the phase 3b, randomized, double‐blind, placebo‐controlled DELIVER clinical trial, eptinezumab reduced migraine frequency and headache in adults with two to four prior preventive treatment failures. Here, the effect of eptinezumab on coinciding patient‐reported outcomes is reported. Methods: Adults were randomized to receive eptinezumab 100, 300 mg or placebo intravenously at weeks 12 and 24. The EQ‐5D‐5L, measuring overall patient health, and the six‐item Headache Impact Test were completed every 4 weeks. The Patient Global Impression of Change was completed at weeks 4, 12 and 24. Patient‐identified most bothersome symptom and the Migraine‐Specific Quality of Life Questionnaire were administered at weeks 12 and 24. Results: Eptinezumab improved patient‐reported outcomes more than placebo, starting at week 4 and at all subsequent time points. By week 12, patients' overall health (EQ‐5D‐5L visual analog scale score) improved with eptinezumab treatment (difference from placebo in change from baseline: 100 mg, 5.1, 95% confidence interval [CI] 2.2, 8.1, p < 0.001; 300 mg, 7.5, 95% CI 4.5, 10.4, p < 0.0001). At week 12, eptinezumab improved headache‐related quality of life (difference from placebo in change from baseline in Headache Impact Test total score: 100 mg, −3.8, 95% CI −5.0, −2.5, p < 0.0001; 300 mg, −5.4, 95% CI −6.7, −4.2, p < 0.0001), including each Migraine‐Specific Quality of Life Questionnaire domain (p ≤ 0.0001, all comparisons). Over twice as many patients receiving eptinezumab than placebo reported much or very much improvement on the Patient Global Impression of Change and patient‐identified most bothersome symptom. Conclusion: Patients with two to four prior preventive treatment failures receiving eptinezumab versus placebo reported greater improvements in well‐being, quality of life and most bothersome symptoms compared to placebo. Trial registration: ClinicalTrials.gov identifier: NCT04418765; EudraCT identifier: 2019‐004497‐25. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to identify magnetic resonance imaging (MRI) biomarkers that differentiate migraine from cluster headache patients and imaging features that are shared. Methods: Clinical, functional, and structural MRI data were obtained from 20 migraineurs, 20 cluster headache patients, and 15 healthy controls. Support vector machine algorithms and a stepwise removal process were used to discriminate headache patients from controls, and subgroups of patients. Regional between‐group differences and association between imaging features and patients' clinical characteristics were also investigated. Results: The accuracy for classifying headache patients from controls was 80%. The classification accuracy for discrimination between migraine and controls was 89%, and for cluster headache and controls it was 98%. For distinguishing cluster headache from migraine patients, the MRI classifier yielded an accuracy of 78%, whereas MRI–clinical combined classification model achieved an accuracy of 99%. Bilateral hypothalamic and periaqueductal gray (PAG) functional networks were the most important MRI features in classifying migraine and cluster headache patients from controls. The left thalamic network was the most discriminative MRI feature in classifying migraine from cluster headache patients. Compared to migraine, cluster headache patients showed decreased functional interaction between the left thalamus and cortical areas mediating interoception and sensory integration. The presence of restlessness was the most important clinical feature in discriminating the two groups of patients. Interpretation: Functional biomarkers, including the hypothalamic and PAG networks, are shared by migraine and cluster headache patients. The thalamocortical pathway may be the neural substrate that differentiates migraine from cluster headache attacks with their distinct clinical features. ANN NEUROL 2023;93:729–742 [ABSTRACT FROM AUTHOR]

Objectives: To capture patients' perspectives on migraine‐related cognitive symptoms during pre‐headache, headache, post‐headache, and interictal periods. Background: Migraine‐related cognitive symptoms are reported by people with migraine both during and between attacks. Associated with disability, they are increasingly viewed as a priority target for treatment. The Migraine Clinical Outcome Assessment System (MiCOAS) project is focused on developing a patient‐centered core set of outcome measures for the evaluation of migraine treatments. The project focuses on incorporating the experience of people living with migraine and the outcomes most meaningful to them. This includes an examination of the presence and functional impact of migraine‐related cognitive symptoms and their perceived impact on quality of life and disability. Methods: Forty individuals with self‐reported medically diagnosed migraine were recruited via iterative purposeful sampling for semi‐structured qualitative interviews conducted using audio‐only web conferencing. Thematic content analysis was performed to identify key concepts around migraine‐related cognitive symptoms. Recruitment continued until concept saturation was achieved. Results: Participants described symptoms consistent with migraine‐related deficits in language/speech, sustained attention, executive function, and memory that manifest during pre‐headache (36/40 [90%] reported ≥1 cognitive feature), headache (35/40 [88%] reported ≥1 cognitive feature), post‐headache (27/40 [68%] reported ≥1 cognitive feature), and interictal periods (13/40 [33%] reported ≥1 cognitive feature). Among participants reporting cognitive symptoms during pre‐headache, 32/40 (81%) endorsed 2–5 cognitive symptoms. Findings were similar during the headache phase. Participants reported language/speech problems consistent with, for example, impairments in receptive language, expressive language, and articulation. Issues with sustained attention included fogginess, confusion/disorientation, and trouble with concentration/focus. Deficits in executive function included difficulty processing information and reduced capacity for planning and decision‐making. Memory issues were reported across all phases of the migraine attack. Conclusions: This patient‐level qualitative study suggests that cognitive symptoms are common for persons with migraine, particularly in the pre‐headache and headache phases. These findings highlight the importance of assessing and ameliorating these cognitive problems. [ABSTRACT FROM AUTHOR]

Objective: To assess the characteristics and associated disability of headache as an adverse event following vaccination. Background: According to clinical trials and post‐licensure surveillance, headache is a common symptom of vaccines, yet systematic investigations of post‐licensure reports of this adverse event are lacking. Methods: This was a retrospective database analysis study. We searched the Vaccine Adverse Events Reporting System (VAERS) database completed from July 1990 to June 2020 (a 30‐year period prior to the start of COVID‐19 pandemic) to identify reports of headache. We evaluated epidemiological features, including event characteristics, patient demographics, and vaccine type. Results: In those aged 3 years or older, headache was the fifth most reported adverse symptom, present in 8.1% (43,218/536,120) of all reports. Of headache reports, 96.3% (41,635/43,218) included the code "headache" not further specified. Migraine was coded in 1973 cases, although almost one‐third (12,467/41,808; 29.8%) of headache reports without a migraine code mention nausea or vomiting. The onset of symptoms was within 1 day of vaccination in over two‐thirds of cases. The majority of reports were classified as not serious; about one‐third involved emergency room or office visits. Of the 43,218 total headache reports, only a minority involved hospitalizations (2624; 6.1%) or permanent disability (1091; 2.5%), females accounted for 68.9% (29,771) and males for 29.5% (12,725), patients aged 6 to 59 years represented 67.3% (29,112), and over one‐third of cases were reported after herpes zoster (8665; 20.1%) and influenza (6748; 15.6%) vaccinations. Conclusion: In a national surveillance system, headache was a commonly reported post‐vaccination adverse event; a small subset of reports was considered serious. The development of standardized vaccine‐related case definitions could be useful for better evaluating headache as an adverse event during vaccine development, and may reduce vaccine hesitancy especially in headache‐prone individuals. [ABSTRACT FROM AUTHOR]

Background and purpose: Chronic migraine is a highly disabling primary headache disorder that is the most common diagnosis of patients seen at tertiary headache centres. Typical oral preventive therapies are associated with many limitations that impact their therapeutic utility. Erenumab was the first available calcitonin gene‐related peptide monoclonal antibody in the UK. It had proven efficacy in migraine prevention in clinical trials and limited real‐world data in tertiary settings. Methods: We audited our first 92 patients (n = 73 females) with severely disabling chronic migraine who were given monthly erenumab 70 mg sc for 6 months between December 2018 and December 2019. Results: At 3 months, monthly migraine days were significantly reduced by a median of 4 days, and all other variables also showed significant improvement. The improvement was not affected by baseline analgesic use status. More than half of our patients experienced a clinically meaningful improvement in migraine days. No serious adverse events were reported. Conclusions: Our real‐world data with erenumab demonstrate it is effective and well tolerated in managing patients with chronic migraine in a tertiary care setting. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical phenotype of patients with chronic migraine (CM) to patients with new daily persistent headache of the chronic migraine subtype (NDPH‐CM). Methods: A study was conducted of CM (n = 257) and NDPH‐CM (n = 76) from a tertiary headache center in the UK, and in the US of patients with daily CM (n = 60) and NDPH‐CM (n = 22). Results: From the UK cohort, the age of first headache onset was lower in CM (mean ± SD: 16 ± 12 years) than in NDPH‐CM (mean ± SD: 23 ± 14 years; p < 0.001). There was a greater number of associated migrainous symptoms in CM compared to NDPH‐CM (median and interquartile range: 6, 5–8 vs. 5, 4–7; p < 0.001). A family history of headache was more common in CM compared to NDPH‐CM (82%, 202/248, vs. 53%, 31/59; p < 0.001). In the US cohort there were no differences. Osmophobia (B = −1.08; p = 0.002) and older age at presentation to the clinic (B = −0.06; p = 0.001) were negative predictors of NDPH‐CM. Conclusion: NDPH‐CM is relatively less migrainous than CM in the UK cohort. Family history of headache is less common in NDPH‐CM, with negative predictors for NDPH‐CM including osmophobia and older age of presentation to the clinic. More work is required to understand the chronic migraine phenotype of new daily persistent headache. [ABSTRACT FROM AUTHOR]

Objective: To assess the utility of the novel patient‐identified (PI) most bothersome symptom (MBS) measure from PROMISE‐2, a phase 3 trial of eptinezumab for the preventive treatment of chronic migraine. Background: Relief of bothersome migraine symptoms can influence satisfaction with treatment and therapeutic persistence. Understanding the impact of preventive treatment on a PI‐MBS could improve clinical decision‐making. Methods: In PROMISE‐2, patients with chronic migraine received eptinezumab 100, 300 mg, or placebo administered intravenously every 12 weeks for up to 2 doses (n = 1072). PI‐MBS was an exploratory outcome requiring each patient to self‐report their MBS in response to an open‐ended question. At baseline and week 12, patients rated overall improvement in PI‐MBS. The relationships among PI‐MBS at week 12 and change in monthly migraine days (MMDs) from baseline to month 3 (weeks 9–12), Patient Global Impression of Change at week 12, and changes from baseline to week 12 in the 6‐item Headache Impact Test total, EuroQol 5‐dimensions 5‐levels visual analog scale, and 36‐item Short‐Form Health Survey component scores were assessed. Results: Treatment groups had similar baseline characteristics and reported a total of 23 unique PI‐MBS, most commonly light sensitivity (200/1072, 18.7%), nausea/vomiting (162/1072, 15.1%), and pain with activity (147/1072, 13.7%). Improvements in PI‐MBS at week 12 correlated with changes in MMDs (ρ = −0.49; p < 0.0001) and other patient‐reported outcomes. Controlling for changes in MMDs, PI‐MBS improvement predicted other patient‐reported outcomes in expected directions. The magnitude of the standardized mean differences between placebo and active treatment for PI‐MBS were 0.31 (p < 0.0001 vs. placebo) and 0.54 (p < 0.0001 vs. placebo) for eptinezumab 100 and 300 mg, respectively. Conclusions: Improvement in PI‐MBS at week 12 was associated with improvement in other patient‐reported outcome measures, and PI‐MBS may be an important patient‐centered measure of treatment benefits in patients with chronic migraine. [ABSTRACT FROM AUTHOR]

Objective: To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies. Background: Current guidelines for preventive treatment of CH are largely based on off‐label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995. Methods/Results: Randomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of "cluster headache," and manually reviewed. Cumulatively, there were 27 unique placebo‐controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo‐controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, the excruciating pain associated with CH demands a suitably limited baseline duration, rapid treatment efficacy onset, and poses a specific issue regarding duration of investigational treatment period and length of exposure to placebo. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges. Conclusions: Optimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH. [ABSTRACT FROM AUTHOR]

Background and Purpose: Lasmiditan is a novel selective 5‐HT1F receptor agonist, recently approved for acute treatment of migraine. 5‐HT1F receptors are widely expressed in the CNS and trigeminovascular system. Here, we have explored the therapeutic effects of 5‐HT1F receptor activation in preclinical models of migraine and cluster headache. Experimental Approach: Electrical stimulation of the dura mater or the superior salivatory nucleus in anaesthetised rats evoked trigeminovascular or trigeminal–autonomic reflex activation at the level of the trigeminocervical complex. Additionally, cranial autonomic manifestations in response to trigeminal–autonomic reflex activation were measured, via anterior choroidal blood flow alterations. These responses were then challenged with lasmiditan. We explored the tissue distribution of mRNA for 5‐HT1F receptors in human post‐mortem tissue and of several 5‐HT1 receptor subtypes in specific tissue beds. Key Results: Lasmiditan dose‐dependently reduced trigeminovascular activation in a preclinical model of migraine. Lasmiditan also reduced superior salivatory nucleus‐evoked activation of the trigeminal–autonomic reflex, but had no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5‐HT1F receptor in several structures relevant for migraine and cluster headache. Conclusion and Implications: Our data suggest that lasmiditan acts, at least in part, as an anti‐migraine agent by reducing trigeminovascular activation. Furthermore, our results highlight a clear action for lasmiditan in a preclinical model of cluster headache. Given the proven translational efficacy of this model, our data support the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc [ABSTRACT FROM AUTHOR]

Background and purpose: A large proportion of headache sufferers do not routinely seek medical care. App‐based technologies permit the collection of real‐world data over time and between countries that can help assess true burden of headache. This study used a mobile phone application to collect information on the real‐world burden of self‐diagnosed headache and to describe its impact on daily life in headache sufferers who do not routinely seek medical advice. Methods: This retrospective, non‐interventional, cross‐sectional study analysed self‐reported data from users of the 'Migraine Buddy' app. The main objective was to describe self‐reported characteristics of headache and migraine (triggers, duration, frequency), treatment patterns and impact on daily activity in headache sufferers from Australia, Brazil, France, Germany and Japan. Data including demographics, self‐diagnosed episode type (headache/migraine), duration, potential triggers and impact on daily activity are reported. All analyses were exploratory and performed per country. Results: Self‐reported data were collected from 60,474 users between August 2016 and August 2018. Approximately 90% of users were females; >60% were aged 24–45 years. Over one‐third of users reported having two to five episodes of headache or migraine per month; impact included impaired concentration, being slower and missing work or social activities. Variations across countries were observed; within countries, episode characteristics were very similar for self‐diagnosed headache versus migraine. Conclusions: Headache tracking was used to describe the experience, impact and self‐management approaches of migraine and headache sufferers in a real‐world setting. Headache disorders present a range of important issues for patients that deserve more study and reinforce the need for better approaches to management. [ABSTRACT FROM AUTHOR]

Summary: Obstructive sleep apnea is linked to cardiovascular disease, metabolic disorders and dementia. The precise nature of the association between respiratory events in obstructive sleep apnea, cortical or subcortical arousals, and cognitive, autonomic and oxidative stress consequences remains incompletely elucidated. Previous studies have aimed to understand the relationship between obstructive sleep apnea and arousal patterns, as defined by the cyclic alternating pattern, but results have been inconsistent, in part likely due to the presence of associated comorbidities. To better define this relationship, we analysed cyclic alternating patterns in patients with obstructive sleep apnea without any additional comorbidities. We identified 18 adult male, non‐obese subjects with obstructive sleep apnea and no other comorbidities or medication history, who underwent whole‐night electroencephalography and polysomnography. Cyclic alternating pattern analysis was performed and verified by certified somnologists. Pairwise linear regression analysis demonstrated an inverse relationship between obstructive sleep apnea severity and cyclic alternating pattern subtype A1, and a direct correlation with cyclic alternating pattern subtype A3. Cyclic alternating pattern subtypes A1 prevail in milder obstructive sleep apnea phenotype, whilst cyclic alternating pattern subtypes A2 and A3 overcome among moderate‐to‐severe obstructive sleep apnea patients. The milder obstructive sleep apnea group also presented higher sleep efficiency, and increased percentages of non‐rapid eye movement stage 3 and rapid eye movement sleep, as well as longer cyclic alternating pattern sequences in N3, while severe obstructive sleep apnea patients spent more time in lighter sleep stages. These results imply/suggest a balance between cyclic alternating pattern's adaptive and maladaptive arousal processes in obstructive sleep apnea of differing severities. In milder obstructive sleep apnea (apnea–hypopnea index < 20), sleep continuity may be reinforced by cyclic alternating pattern subtype A1, whereas in more severe obstructive sleep apnea, decompensation of these sleep‐stabilizing mechanisms may occur and more intrusive cyclic alternating pattern fluctuations disrupt sleep circuitry. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether the 15‐day threshold of headache days per month adequately reflects substantial differences in disability across the full spectrum of migraine. Background: The monthly frequency of headache days defines migraine subtypes and has crucial implications for epidemiological and clinical research as well as access to care. Methods: The patients with migraine (N = 836) who participated in the American Registry for Migraine Research, which is a multicenter, longitudinal patient registry, between February 2016 and March 2020, were divided into four groups based on monthly headache frequency: Group 1 (0–7 headache days/month, n = 286), Group 2 (8–14 headache days/month, n = 180), Group 3 (15–23 headache days/month, n = 153), Group 4 (≥24 headache days/month, n = 217). Disability (MIDAS), Pain intensity (NRS), Work Productivity and Activity Impairment (WPAI), Pain Interference (PROMIS‐PI), Patient Health Questionnaire‐4 (PHQ‐4), and General Anxiety Disorder‐7 (GAD‐7) scores were compared. Results: Mean (standard deviation [SD]) age was 46 (13) years (87.9% [735/836] female). The proportion of patients in each group was as follows: Group 1 (34.2% [286/836]), Group 2 (21.5% [180/836]), Group 3 (18.3% [153/836]), and Group 4 (26.0% [217/836]). There were significant relationships with increasing disability, lost productive time, and pain interference in higher headache frequency categories. There were no significant differences between Group 2 and Group 3 for most measures (NRS, all WPAI scores, PROMIS‐PI, GAD‐7, and PHQ‐4), although MIDAS scores differed (median [interquartile range (IQR)]; 38 [20–58] vs. 55 [30–90], p < 0.001). Patients in Group 1 had significantly lower MIDAS (median [IQR];16 [7–30], p < 0.001), WPAI‐% total active impairment (mean (SD): Group 1 [30.9 (26.8)] vs. Group 2 [39.2 (24.5), p = 0.017], vs. Group 3 [45.9 (24.1), p < 0.001], vs. Group 4 [55.3 (23.0), p < 0.001], and PROMIS‐PI‐T score (Group 1 [60.3 (7.3)] vs. Group 2 [62.6 (6.4), p = 0.008], vs. Group 3 [64.6 (5.6), p < 0.001], vs. Group 4 [66.8 (5.9), p < 0.001]) compared to all other groups. Patients in Group 4 had significantly higher MIDAS (median (IQR): Group 4 [90 (52–138)] vs. Group 1 [16 (7–30), p < 0.001], vs. Group 2 [38 (20–58), p < 0.001], vs. Group 3 [55 (30–90), p < 0.001], WPAI‐%Presenteeism (Group 4 [50.4 (24.4)] vs. Group 1 [28.8 (24.9), p < 0.001], vs. Group 2 [34.9 (22.3), p < 0.001], vs. Group 3 [40.9 (22.3), p = 0.048], WPAI‐% total work productivity impairment (Group 4 [55.9 (26.1)] vs. Group 1 [32.1 (37.6), p < 0.001], vs. Group 2 [38.3 (24.0), p < 0.001], vs. Group 3 [44.6 (24.4), p = 0.019]), and WPAI‐%Total activity impairment (Group 4 [55.3 (23.0)] vs. Group 1 [30.9 (26.8), p < 0.001], vs. Group 2 [39.2 (24.5), p < 0.001], vs. Group 3 [45.9 (24.1), p = 0.025]) scores compared with all other groups. Conclusion: Our data suggest that the use of a 15 headache day/month threshold to distinguish episodic and chronic migraine does not capture the burden of illness nor reflect the treatment needs of patients. These results have important implications for future refinements in the classification of migraine. [ABSTRACT FROM AUTHOR]

This document is a reply to a letter from Lansbergen et al. regarding the European Academy of Neurology guidelines on the treatment of cluster headache. The authors discuss the issue of occipital nerve stimulation and sphenopalatine ganglion stimulation in the treatment of chronic cluster headache. They refer interested readers to the GRADE system, which is used by the European Academy of Neurology. The authors acknowledge that local experience with the device may influence assessment of adverse events. The document is authored by Arne May, Stefan Evers, and Peter J. Goadsby. [Extracted from the article]

Background and purpose: Although erenumab has demonstrated significant reduction in migraine frequency and improved quality of life in studies lasting 3 to 12 months, little is known about long‐term therapy. Methods: This study was an open‐label, 5‐year treatment phase following a 12‐week, double‐blind, placebo‐controlled trial in adults with episodic migraine. Patients initially received open‐label erenumab 70 mg, which increased to 140 mg following a protocol amendment. Efficacy analyses included change from baseline in monthly migraine days (MMDs), monthly acute migraine‐specific medication (AMSM) days, and health‐related quality of life. Results: Of 383 patients enrolled, 250 switched to 140 mg; 215 (56.1%) completed open‐label treatment. Mean (standard error) change in MMDs from baseline of 8.7 (0.2) days was −5.3 (0.3) days; an average reduction of 62.3% at year 5. Among patients using AMSM at baseline (6.3 [2.8] treatment days), mean change in monthly AMSM days was −4.4 (0.3) days at the end of 5 years. Patient‐reported outcomes indicated stable improvements in disability, headache impact, and migraine‐specific quality of life. Exposure‐adjusted patient incidence rates of adverse events (AEs) were 123.0/100 patient‐years; AEs were most frequently nasopharyngitis, upper respiratory tract infection, and influenza. Serious AEs (SAEs) reported by 49 patients (3.8/100 patient‐years) were mostly single occurrence. Two fatal adverse events were reported. There were no increases in incidence of AEs, SAEs, or AEs leading to treatment discontinuation over 5 years of exposure. Conclusions: Treatment with erenumab was associated with reductions in migraine frequency and improvements in health‐related quality of life that were maintained for at least 5 years. No new safety signals were observed. [ABSTRACT FROM AUTHOR]

Background: Indomethacin is a nonsteroidal anti‐inflammatory drug whose mechanism of action in certain types of headache disorders remains unknown. The so‐called indomethacin‐responsive headache disorders consist of a group of conditions with a very different presentation that have a particularly good response to indomethacin. The response is so distinct as to be used in the definition of two: hemicrania continua and paroxysmal hemicrania. Methods: This is a narrative literature review. PubMed and the Cochrane databases were used for the literature search. Results: We review the main pharmacokinetic and pharmacodynamics properties of indomethacin useful for daily practice. The proposed mechanisms of action of indomethacin in the responsive headache disorders, including its effect on cerebral blood flow and intracranial pressure, with special attention to nitrergic mechanisms, are covered. The current evidence for its use in primary headache disorders, such as some trigeminal autonomic cephalalgias, cough, hypnic, exertional or sexual headache, and migraine will be covered, as well as its indication for secondary headaches, such as those of posttraumatic origin. Conclusion: Increasing understanding of the mechanism(s) of action of indomethacin will enhance our understanding of the complex pathophysiology that might be shared by indomethacin‐sensitive headache disorders. [ABSTRACT FROM AUTHOR]

Here we investigate brain functional connectivity in patients with visual snow syndrome (VSS). Our main objective was to understand more about the underlying pathophysiology of this neurological syndrome. Twenty‐four patients with VSS and an equal number of gender and age‐matched healthy volunteers attended MRI sessions in which whole‐brain maps of functional connectivity were acquired under two conditions: at rest while watching a blank screen and during a visual paradigm consisting of a visual‐snow like stimulus. Eight unilateral seed regions were selected a priori based on previous observations and hypotheses; four seeds were placed in key anatomical areas of the visual pathways and the remaining were derived from a pre‐existing functional analysis. The between‐group analysis showed that patients with VSS had hyper and hypoconnectivity between key visual areas and the rest of the brain, both in the resting state and during a visual stimulation, compared with controls. We found altered connectivity internally within the visual network; between the thalamus/basal ganglia and the lingual gyrus; between the visual motion network and both the default mode and attentional networks. Further, patients with VSS presented decreased connectivity during external sensory input within the salience network, and between V5 and precuneus. Our results suggest that VSS is characterised by a widespread disturbance in the functional connectivity of several brain systems. This dysfunction involves the pre‐cortical and cortical visual pathways, the visual motion network, the attentional networks and finally the salience network; further, it represents evidence of ongoing alterations both at rest and during visual stimulus processing. [ABSTRACT FROM AUTHOR]

Objective: To determine the potential efficacy of ubrogepant for acute treatment of migraine based on historical experience with triptans. Background: Although triptans have improved migraine treatment, their efficacy and tolerability may limit their utility in some individuals. Ubrogepant is a small‐molecule, oral calcitonin gene–related peptide receptor antagonist approved by the Food and Drug Administration for acute treatment of migraine in adults. Methods: This post hoc analysis of pooled data from the pivotal trials ACHIEVE I and II, identically designed, randomized, double‐blind, phase 3, single‐attack trials of ubrogepant in adults with a history of migraine with/without aura, examined the efficacy and tolerability of ubrogepant 50 mg versus placebo based on participants' historical experience with triptans: triptan responder, triptan‐insufficient responder, and triptan naïve. Co‐primary efficacy endpoints were pain freedom and absence of most bothersome migraine‐associated symptom (MBS) 2 h post initial dose. Adverse events (AEs) within historical triptan experience subgroups were evaluated. Results: In the pooled analysis population (n = 1799), 682 (placebo, n = 350; ubrogepant 50 mg, n = 332), 451 (placebo, n = 223; ubrogepant, n = 228), and 666 (placebo, n = 339; ubrogepant, n = 327) participants were triptan responders, triptan‐insufficient responders, and triptan‐naïve, respectively. Response rates on co‐primary efficacy endpoints were higher for ubrogepant versus placebo across all groups. Treatment‐by‐subgroup interaction p values based on odds ratios for pain freedom (p = 0.290) and absence of MBS (p = 0.705) indicated no significant impact of historical triptan experience on ubrogepant efficacy. AE incidence for ubrogepant did not differ appreciably across historical triptan experience subgroups. Conclusions: Ubrogepant efficacy and tolerability did not differ for the acute treatment of migraine in participants classified as triptan responders, triptan‐insufficient responders, and triptan‐naïve based on their historical experience with triptans. [ABSTRACT FROM AUTHOR]

Background/Objective: To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials. Method: A systematic literature review, following a prespecified (but unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, was conducted to understand endpoints and outcomes used in acute migraine clinical trials. Predefined terms were searched in PubMed to locate clinical trials assessing acute migraine treatments. Final database search was conducted on October 28, 2019. Identified publications were reviewed against established inclusion and exclusion criteria to determine eligibility. Data related to general trial design characteristics, sample characteristics, and outcomes and endpoints reported in each publication were extracted from eligible publications. Descriptive summaries of design features, sample characteristics, and the endpoints and outcomes employed across publications were constructed. Outcomes are presented within four broad categories: (a) pain‐related outcomes (pain relief, pain freedom, etc.), (b) associated symptoms (nausea, photophobia, etc.), (c) disability/impairment/impact, (d) patient‐reported outcome measures (PROMs, general health and migraine/headache‐specific). Endpoint types were categorized within three broad categories: (a) change from baseline, (b) fixed timepoint, and (c) responder definitions (e.g., 50% reduction). This review focuses on a subset of recent (1998 or later) randomized and blinded publications evaluating drugs or medical devices. Results: Of 1567 publications found through the initial search and reference section reviews, 705 met criteria and were included for data extraction. Inter‐rater agreement kappas for the descriptive variables extracted had an average kappa estimate of 0.86. The more recent, randomized and blinded pharmaceutical and medical device article subset includes 451 publications (451/705, 63.9%). The outcomes and endpoints varied substantially across trials, ranging from pain relief or freedom, freedom from or relief of migraine‐associated symptoms, use of acute or rescue medication, and various other PROMs, including measures of satisfaction and quality of life. Within the recent randomized and blinded article subset, most articles examined ≥1 pain‐related outcome (430/451, 95.3%). Of the publications that examined pain, outcomes most often used were pain relief (310/430, 72.1%), pain freedom (279/430, 64.9%), and headache recurrence (202/43,051, 47.0%) or rescue medication use (278/430, 64.9%). Associated symptoms such as nausea, photophobia, and phonophobia were more frequently measured (299/451, 66.3%) compared to most bothersome associated symptom (16/451, 3.5%), as it is a new addition to regulatory guidance. Over one‐third of eligible publications examined disability/impairment (186/451, 41.2%) or ≥1 PROM (159/451, 35.3%). The definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of "responders" to treatment based on wide variety of "responder definitions") also differed substantially across publications. Conclusion: Acute migraine clinical trials exhibit a large amount of variability in outcomes and endpoints used, in addition to the variability in how outcomes and endpoints were used from trial‐to‐trial. There were some common elements across trials that align with guidance from the International Headache Society, the Food and Drug Administration and other regulatory agencies (e.g., assessing pain and associated symptoms, 2‐hour post‐treatment). Other aspects of acute migraine clinical trial design did not follow guidance. For example, multi‐item PROMs intended to measure constructs (e.g., scales) are rarely used, the use of pain‐related outcomes is inconsistent, some associated symptom assessments are idiosyncratic, and the timing of the assessment of primary endpoints is variable. The development of a core set of outcomes and endpoints for acute migraine clinical trials that are patient‐centered and statistically robust could improve the conduct of individual trials, facilitate cross‐trial comparisons, and better support informed treatment decisions by healthcare professionals and patients. [ABSTRACT FROM AUTHOR]

Background: Over the last six decades (earliest included publication from 1959), clinical trials of migraine preventive treatments have led to the regulatory approval of many medications and devices. Despite similar clinical goals, the outcomes and endpoints used in these trials are broad and not well standardized. Objective: To describe results from a systematic literature review focused on outcomes and endpoints used in preventive migraine clinical trials. Method: A systematic literature review, following a pre‐specified (unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, was conducted to characterize the endpoints and outcomes used in preventive migraine clinical trials. Predetermined terms were searched in PubMed on October 28, 2019. Data related to trial design, subject characteristics, outcomes, and endpoints reported in each publication were extracted. Descriptive summaries of these features were tabulated for the recent subset of publications, published during or after 1988, that were randomized, blinded, and focused on pharmacological or device therapies for the preventive treatment of migraine. Results: The initial literature search identified 1506 publications, of which 757 publications were eligible for data extraction. Of specific clinical interest were the recent subset of 268 articles (268/757, 35.4%) fulfilling the targeted criteria. Results showed that the outcomes used to define endpoints varied substantially across publications. For example, in the recent subset of publications, 68.7% (184/268) of the publications examined ≥1 migraine‐specific outcome, 39.6% (106/268) examined ≥1 headache‐specific outcome, 50.7% (136/268) examined ≥1 acute/rescue medication use outcome, 40.3% (108/268) examined ≥1 headache‐related patient‐reported outcome measure (PROM), and 22.0% (59/268) examined ≥1 non‐headache‐specific PROM. Furthermore, the definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of "responders" to treatment based on wide variety of "responder definitions") also differed across publications. Conclusion: Publications from clinical trials of preventive migraine pharmacologic and device treatments differed in terms of study design, endpoint definitions, and how endpoints and outcomes were measured. Although there were common outcomes and endpoints used across publications, no clear "standardized" set of endpoints and outcomes emerged. The inconsistencies in endpoints and outcomes within this literature suggest that the development of a uniform set of outcomes and endpoints could improve the clinical meaningfulness of clinical trial results, facilitate cross‐trial comparisons and better inform patient care. This standard set of outcomes and endpoints should be statistically robust and informed by the priorities of various stakeholders, most importantly, the needs and preferences of people living with migraine. [ABSTRACT FROM AUTHOR]

Objective: To understand the changes in functional connectivity between brain areas of potential importance in migraine during different phases of the attack. Background: Migraine is a symptomatically heterogeneous disorder. Understanding the possible changes in brain function and, therefore, neurobiology during different phases of the migraine attack is important in developing disease biomarkers and advancing therapeutics. Design: Randomized, double‐blind, placebo‐controlled, multi‐visit experimental study. Methods: Subjects aged 18‐50 years with migraine with and without aura (≤22 headache days per month) were recruited from across the UK using advertising, from both population and hospital clinic samples (n = 53). Consented subjects were randomized to a 0.5 µg/kg/min nitroglycerin infusion or to placebo over 20 minutes across different study visits, during the period February 2015‐July 2017.* All subjects were exposed to a nitroglycerin infusion at least on 1 occasion at screening.** For those subjects who consented to participate in imaging visits (n = 25), structural T1, T2 and FLAIR sequences and resting state blood oxygen level dependant contrast (rsBOLD) time series, using a multiecho EPI sequence, were conducted over 30‐40 minutes at baseline and rsBOLD during premonitory symptoms and migraine headache on a 3T General Electric MR750 MRI scanner. For the placebo visit, the imaging was conducted at the same times following infusion in the absence of symptoms. Results: Montreal Neurological Institute (MNI) coordinates were used to characterize identified brain areas of connectivity change. Using repeated measures ANOVA models with time (visit number) and trigger substance (nitroglycerin/placebo) as factors, significant positive functional coupling was found between the thalami bilaterally and the right precuneus and cuneus regions during the nitroglycerin‐triggered premonitory phase (T = 3.23, peak connectivity change at [−6, −68, 40] for left thalamus, P = 0.012 and [−4, −68, 40] for right thalamus, P = 0.019). The nitroglycerin‐triggered premonitory phase was associated with a change in the direction of connectivity from positive to negative between the pons and the limbic lobe (T = 3.47, peak connectivity change at [2, 8, 50], P < 0.001). The headache phase of the nitroglycerin‐triggered migraine attack was associated with ongoing negative functional coupling between the pons and the cingulate and frontal cortices, and positive functional coupling between the pons and the cerebellar tonsils and medulla (T = 3.47, peak connectivity change at [−8, −52, −58], P = 0.007). Conclusions: Understanding the functional reorganization between subcortical and cortical brain areas in different phases of the migraine attack provides novel insights into the abnormal sensory processing and integration during migraine, as well as functional correlation with clinical symptoms displayed during each phase. [*Correction added on July 22, 2020 after first online publication: This sentence was revised from, "Consented subjects had a 0.5 μg/kg/min nitroglycerin infusion...".] [**Correction added on July 22, 2020 after first online publication: This sentence was revised from, "... at least on 1 occasion at screening."] [ABSTRACT FROM AUTHOR]

Background and Purpose: There is a major unmet need to develop new therapies for migraine. We have previously demonstrated the therapeutic potential of the acid-sensing ion channel (ASIC) blockade in migraine, via an ASIC1 mechanism. ASIC3 is expressed in the trigeminal ganglion and its response is potentiated by NO that can trigger migraine attacks in patients. Thus we sought to explore the potential therapeutic effect of ASIC3 blockade in migraine.Experimental Approach: To investigate this, we utilised validated electrophysiological and behavioural rodent preclinical models. In rats, ASIC3 blockade using APETx2 (50 or 100 μg·kg-1 , i.v.) was measured by using durovascular and NO-evoked trigeminal nociceptive responses along with cortical spreading depression models. In mice, we sought to determine if periorbital mechanical sensitivity, induced by acute nitroglycerin (10 mg·kg-1 , i.p.), was attenuated by APETx2 (230 μg·kg-1 , i.p.), as well as latent sensitisation induced by bright light stress in a chronic nitroglycerin model.Key Results: Here, we show that the ASIC3 blocker APETx2 inhibits durovascular-evoked and NO-induced sensitisation of trigeminal nociceptive responses in rats. In agreement, acute and chronic periorbital mechanosensitivity induced in mice by nitroglycerin and subsequent bright light stress-evoked latent sensitivity as a model of chronic migraine are all reversed by APETx2.Conclusion and Implications: These results support the development of specific ASIC3 or combined ASIC1/3 blockers for migraine-related pain and point to a potential role for ASIC-dependent NO-mediated attack triggering. This has key implications for migraine, given the major unmet need for novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Objective: To investigate the pathophysiology of visual snow (VS), through a combined functional neuroimaging and magnetic resonance spectroscopy (1H‐MRS) approach. Methods: We applied a functional MRI block‐design protocol studying the responses to a visual stimulation mimicking VS, in combination with 1H‐MRS over the right lingual gyrus, in 24 patients with VS compared to an equal number of age‐ and gender‐matched healthy controls. Results: We found reduced BOLD responses to the visual stimulus with respect to baseline in VS patients compared to controls, in the left (k = 291; P = 0.025; peak MNI coordinate [‐34 12 ‐6]) and right (k = 100; P = 0.003; peak MNI coordinate [44 14 ‐2]) anterior insula. Our spectroscopy analysis revealed a significant increase in lactate concentrations in patients with respect to controls (0.66 ± 0.9 mmol/L vs. 0.07 ± 0.2 mmol/L; P < 0.001) in the right lingual gyrus. In this area, there was a significant negative correlation between lactate concentrations and BOLD responses to visual stimulation (P = 0.004; r = −0.42), which was dependent on belonging to the patient group. Interpretation: As shown by our BOLD analysis, VS is characterized by a difference in bilateral insular responses to a visual stimulus mimicking VS itself, which could be due to disruptions within the salience network. Our results also suggest that patients with VS have a localized disturbance in extrastriate anaerobic metabolism, which may in turn cause a decreased metabolic reserve for the regular processing of visual stimuli. [ABSTRACT FROM AUTHOR]

Migraine affects over a billion people worldwide in any year and is the second most common cause of years lost due to disability. Not "just a headache", morbidity washes though society and carries a substantial economic and social cost. Understanding of migraine pathophysiology has progressed significantly. Animal models and functional neuroimaging have yielded significant insight into brain structures that mediate migraine symptoms. The role of small peptides as neurotransmitters within this network has been elucidated, allowing the generation of novel therapeutic approaches that have been validated by randomised placebo-controlled trials. Migraine is underdiagnosed and undertreated. Treatment of migraine should be proactive. An acute and, when indicated, preventive strategy should be formulated with the patient. Comorbid medication overuse must be supportively managed. Migraine-specific medications are making their way from bench to bedside. They promise an improved safety profile and ease of use in comparison to older, repurposed medications. Devices promise a non-drug alternative should patients prefer. The migraine understanding and treatment landscape is changing rapidly. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusion To explore hidden Markov models (HMMs) as an approach for defining clinically meaningful headache‐frequency‐based groups in migraine.Monthly headache frequency in patients with migraine is known to vary over time. This variation has not been completely characterized and is not well accounted for in the classification of individuals as having chronic or episodic migraine, a diagnosis with potentially significant impacts on the individual. This study investigated variation in reported headache frequency in a migraine population and proposed a model for classifying individuals by frequency while accounting for natural variation.The American Registry for Migraine Research (ARMR) was a longitudinal multisite study of United States adults with migraine. Study participants completed quarterly questionnaires and daily headache diaries. A series of HMMs were fit to monthly headache frequency data calculated from the diary data of ARMR.Changes in monthly headache frequency tended to be small, with 47% of transitions resulting in a change of 0 or 1 day. A substantial portion (24%) of months reflected daily headache with individuals ever reporting daily headache likely to consistently report daily headache. An HMM with four states with mean monthly headache frequency emissions of 3.52 (95% Prediction Interval [PI] 0–8), 10.10 (95% PI 4–17), 20.29 (95% PI 12–28), and constant 28 days/month had the best fit of the models tested. Of sequential month‐to‐month headache frequency transitions, 12% were across the 15‐headache days chronic migraine cutoff. Under the HMM, 38.7% of those transitions involved a change in the HMM state, and the remaining 61.3% of the time, a change in chronic migraine classification was not accompanied by a change in the HMM state.A divide between the second and third states of this model aligns most strongly with the current episodic/chronic distinction, although there is a meaningful overlap between the states that supports the need for flexibility. An HMM has appealing properties for classifying individuals according to their headache frequency while accounting for natural variation in frequency. This empirically derived model may provide an informative classification approach that is more stable than the use of a single cutoff value. [ABSTRACT FROM AUTHOR]

Experimental and clinical studies suggest that the low‐affinity N‐methyl‐d‐aspartate (NMDA) receptor open‐channel blockers Mg2+ and memantine are effective in reducing trigeminal nociceptive activation. The aim of this study was to investigate the apparent effectiveness of these channel blockers using a model of trigeminal activation in vivo. Rats were anaesthetized before electrically stimulating the dura mater adjacent the middle meningeal artery. Neurons responding to stimulation were recorded extracellularly using electrophysiological methods. l‐Glutamate or NMDA, and Mg2+, memantine, or sodium controls were applied locally using microiontophoresis. Microiontophoretic application of Mg2+ or memantine into the trigeminocervical complex inhibited mechanically and electrically stimulated craniovascular afferents,  and l‐glutamate or NMDA‐evoked neuronal activity at the second‐order trigeminal synapse of craniovascular afferents. By contrast, intravenous administration of MgSO4 (100 mg/kg) or memantine (10 mg/kg) did not significantly affect electrically stimulated afferent‐evoked activity within the trigeminocervical complex. The Mg2+ and memantine concentrations achieved after systemic administration may not effectively inhibit activation of the trigeminocervical complex, perhaps providing an explanation for the relatively poor efficacy of these NMDA receptor open‐channel blockers for headache treatment in clinical studies. Nevertheless, the present results suggest blocking of NMDA‐receptor open channels inhibits nociceptive activation of the trigeminocervical complex. Further exploration of such channel blockers as a therapeutic strategy for primary head pain is warranted. [ABSTRACT FROM AUTHOR]

Objective: To review and highlight current literature on emerging acute migraine treatments, focusing on CGRP receptor antagonists, gepants, and 5‐HT1F receptor agonists (ditans). Background: Current acute migraine therapy consists of nonspecific analgesia and triptans. Limitations to these medicines, including lack of efficacy in many patients, side effects and the contraindication of triptans in patients with cardiovascular disease, suggest that there is an unmet need for new treatments. Studies of serotonin pharmacology led to the development of triptans, 5‐HT1B/1D receptor agonists, some of which have actions at the 5‐HT1F receptor. Exploration of the role of calcitonin gene‐related peptide (CGRP) has resulted in the development of CGRP receptor antagonists. Method: The authors performed a literature search of Pubmed and Cochrane databases as well as reviewed abstracts presented at meetings: American Headache Society, American Academy of Neurology, European Headache Federation and the Migraine Trust International Symposium, as well as on‐line sources. The authors briefly detail the relevant migraine pathophysiology pertaining to 5‐HT1F receptor and the CGRP pathway relevant to acute therapies. Recent clinical trials of acute therapies in which 5‐HT1F receptor agonists or CGRP receptor antagonists were studied are summarized. Results: Two 5‐HT1F receptor agonists have reached phase II clinical trials. One, lasmiditan, has completed 2 phase III clinical trials, demonstrating a significant effect for pain freedom and most bothersome symptom at 2 hours. Among the 6 gepants tested for the acute treatment of migraine to date, after issues for some of hepatic safety or efficacy, 2 CGRP receptor antagonists, rimegepant and ubrogepant, have completed phase III trials showing efficacy and safety. Conclusion: Current available therapies have either been nonspecific or had important limitations, including in patients with cardiovascular risk factors. Phase III clinical trials of lasmiditan, rimegepant and ubrogepant all met their primary endpoints, so the options for migraine‐targeted acute therapy will likely soon increase. [ABSTRACT FROM AUTHOR]

Background: Infant colic, or excessive crying in an otherwise healthy infant, is common, although the cause(s) are not known. This study aimed to determine whether parental migraine is associated with infant colic. Methods: This was a cross‐sectional online survey study of biological parents of 4‐8 week olds in the United States during February and March 2017 and October 2017‐April 2018. Parents self‐reported information about their and their infant's health using validated instruments wherever possible. Parents were recruited using social media advertisements and completed the survey online. Migraine was identified with a validated screener using modified International Classification of Headache Disorders 3rd edition criteria. Parental depression and anxiety were screened with the Patient Health Questionnaire‐2 (PHQ‐2) and Generalized Anxiety Disorder Scale‐2 (GAD‐2). Parental seasonal allergies and asthma were assessed by self‐report. Infant colic was determined based on parental response to the question, "Has your baby cried for at least 3 hours on at least 3 days in the last week?" Results: A total of 1,715 surveys were completed over 2 recruitment periods; 1,419 formed the analysis set. Eight hundred twenty‐seven were completed by biological mothers and 592 by biological fathers. Mean (SD) maternal age: 28.9 (5.1) years; 33.5% had migraine/probable migraine. Maternal migraine was associated with increased odds of infant colic: OR 1.7 (1.3‐2.4). Among mothers with migraine, headache frequency ≥15 days/month was associated with higher risk of infant colic (OR 2.5 (1.2‐5.3)); and anxiety was borderline associated (OR 1.7 (1.0‐2.9)). Mean (SD) paternal age was 31.6 (4.5) years; 20.8% had migraine/probable migraine. Paternal migraine was not associated with infant colic: OR 1.0 (0.7‐1.5). Fathers with depression (OR 2.4 (1.4‐4.3)) or anxiety (OR 1.7 (1.1‐2.7)) were more likely to have a baby with colic but having a girl infant was protective: (OR 0.7 (0.5‐0.97)). Conclusions: Mothers with migraine are more likely to have a baby with colic, while fathers with migraine are not. Further research is needed to determine the mechanisms underlying these findings. In the meantime, clinicians may wish to counsel parents with a maternal history of migraine about the increased possibility of having a colicky infant and provide resources and education about infant crying. [ABSTRACT FROM AUTHOR]

Objective: To identify natural subgroups of people with migraine based on profiles of comorbidities and concomitant conditions, hereafter referred to as comorbidities. Background: Migraine is a heterogeneous disease. Identifying natural subgroups (endophenotypes) may facilitate biological and genetic characterization and the development of personalized treatment. Methods: The Chronic Migraine Epidemiology and Outcomes Study is a prospective web‐based survey study designed to characterize the course of migraine and related comorbidities in a systematic US sample of people with migraine. Respondents were asked if they ever had a specific comorbidity and, if present, whether the comorbidity was confirmed/diagnosed by a “doctor”; 62 comorbidities were available for analysis. Latent class analysis (LCA) modeling determined the optimal number of classes and a parsimonious set of comorbidities. Results: Of the 12,810 respondents with migraine, 11,837 reported ≥1 comorbidity and were included in this analysis. After statistical analysis and clinical judgment reduced the number of comorbidities, we selected an 8‐class model based on 22 comorbidities. Each class had a distinct pattern summarized as follows: Class 1, Most Comorbidities; Class 2, Respiratory/Psychiatric; Class 3, Respiratory/Pain; Class 4, Respiratory; Class 5, Psychiatric; Class 6, Cardiovascular; Class 7, Pain; Class 8, Fewest Comorbidities. The distribution of individuals across models was variable, with one‐third of respondents in Class 8 (Fewest Comorbidities) and <10% in Class 1 (Most Comorbidities). Demographic and headache characteristics, not used in assigning class membership, varied across classes. For example, comparing Class 1 (Most Comorbidities) and Class 8 (Fewest Comorbidities), Class 1 had a greater proportion of individuals with severe disability (Migraine Disability Assessment grade IV; 48.1% vs 22.3% of overall individuals) and higher rates of allodynia (67.6% vs 47.0%), medication overuse (36.4% vs 15.0%), chronic migraine (23.1% vs 9.1%), and aura (40.1% vs 28.8%). Conclusions: LCA modeling identified 8 natural subgroups of persons with migraine based on comorbidity profiles. These classes show differences in demographic and headache features not used to form the classes. Subsequent research will assess prognostic and biologic differences among the classes. [ABSTRACT FROM AUTHOR]

Objective: To assess the feasibility, tolerability, and patient acceptability of single‐pulse transcranial magnetic stimulation (sTMS) for migraine prevention in adolescents in an open‐label pilot study. Background: Migraine is common in adolescents and can be disabling. Well tolerated preventative therapies that are safe and effective are needed. Methods: This was an open‐label prospective pilot feasibility study of sTMS for migraine prevention in adolescents aged 12‐17 years. Participants used sTMS twice daily in a preventative fashion, as well as additional pulses as needed acutely. A 4‐week baseline run‐in period (weeks 1‐4) was followed by a 12‐week treatment period. Feasibility was the primary outcome. Secondary outcomes included tolerability and acceptability, as well as the change in headache days, number of moderate/severe headache days, days of acute medication use, and PedMIDAS (headache disability) scores between the run‐in period (weeks 1‐4) and the third month of treatment (weeks 13‐16). Results: Twenty‐one participants enrolled. Nineteen completed the baseline run‐in, and 12 completed the study. Using sTMS proved feasible and acceptable with overall high compliance once treatment administration was streamlined. Initially, for preventive treatment, participants were asked to give 2 pulses, wait 15 minutes, then give 2 additional pulses twice daily. This 15‐minute delay proved challenging for adolescents, particularly on school days, and therefore was dropped. Study completion rate went from 4/13 (31%) to 7/8 (88%) once this change was made, P = .024. On average, participants used the device preventively between 22 and 24 days over a 28‐day block. There were no serious adverse events. Two participants reported mild discomfort with device use. Conclusion: sTMS appears to be a feasible, well‐tolerated, and acceptable nonpharmacologic preventive treatment for migraine in adolescents. In designing future trials of sTMS for migraine prevention in adolescents, streamlined treatment administration will be essential to minimize drop‐out. Efficacy needs to be assessed in a larger trial. [ABSTRACT FROM AUTHOR]

Objective To review current neuromodulation treatments available for migraine therapy, both in the acute and preventive setting. Methods The published literature was reviewed for studies reporting the effects of different neuromodulation strategies in migraine with and without aura. The use of non-invasive: single pulse transcranial magnetic stimulation, non-invasive vagal nerve stimulation, supraorbital nerve stimulation, and transcranial direct current stimulation, as well as invasive methods such as occipital nerve stimulation and sphenopalatine ganglion stimulation, are assessed. Results The available evidence shows that non-invasive techniques represent promising treatment strategies, whereas an invasive approach should only be used where patients are refractory to other preventives, including non-invasive methods. Conclusions Neuromodulation is emerging as an exciting approach to migraine therapy, especially in the context of failure of commonly used medicines or for patients who do not tolerate common side effects. More studies with appropriate blinding strategies are needed to confirm the results of these new treatment opportunities. [ABSTRACT FROM AUTHOR]

Visual disturbances in migraineurs, such as visual aura, are typically episodic, that is, associated with the headache attack, and overlaid by head pain and other symptoms that impact the patient. In some patients, however, visual symptoms are dominant due to frequency (migraine aura status), duration (persistent migraine aura and other persistent positive visual phenomena), or complexity (visual snow syndrome). These syndromes are more rare and challenging to classify in clinical practice resulting in a lack of systematic studies on pathophysiology and treatment. We aim at describing clinical features and pathophysiological concepts of typical migraine aura with a focus on cortical spreading depression and differentiation from non-typical migraine aura. Additionally, we discuss nomenclature and the specifics of migraine aura status, persistent migraine aura, persistent positive visual phenomena, visual snow, and other migrainous visual disturbances. The term migraine with prolonged aura might be a useful bridge between typical aura and persistent aura. Further studies would be necessary to assess whether a return of the classification category eventually helps diagnosing or treating patients more effectively. A practical approach is presented to help the treating physician to assign the correct diagnosis and to choose a medication for treatment that has been successful in case reports of these rare but disabling conditions. [ABSTRACT FROM AUTHOR]

Objective To provide a summary of knowledge about the use of melatonin in the treatment of primary headache disorders. Background Melatonin is secreted by the pineal gland; its production is regulated by the hypothalamus and increases during periods of darkness. Methods We undertook a narrative review of the literature on the role of melatonin in the treatment of primary headache disorders. Results There are randomized placebo-controlled trials examining melatonin for preventive treatment of migraine and cluster headache. For cluster headache, melatonin 10 mg was superior to placebo. For migraine, a randomized placebo-controlled trial of melatonin 3 mg (immediate release) was positive, though an underpowered trial of melatonin 2 mg (sustained release) was negative. Uncontrolled studies, case series, and case reports cover melatonin's role in treating tension-type headache, hypnic headache, hemicrania continua, SUNCT/SUNA and primary stabbing headache. Conclusions Melatonin may be effective in treating several primary headache disorders, particularly cluster headache and migraine. Future research should focus on elucidating the underlying mechanisms of benefit of melatonin in different headache disorders, as well as clarifying optimal dosing and formulation. [ABSTRACT FROM AUTHOR]

Introduction Many patients suffering from migraine gain little relief from existing treatments partly because many existing acute and preventive therapies used in migraine have been adopted from other neurologic conditions such as depression or epilepsy. Here, we present data supporting a new migraine-specific target, the mGlu5 receptor. Methods We studied the effect of mGlu5 blockade using ADX10059, on neuronal firing in the trigeminocervical complex (TCC) and durovascular effects of nociceptive trigeminovascular activation in the anesthetized rat. The clinical potential of the mGlu5 mechanism was tested with ADX10059 orally in a double-blind placebo-controlled, parallel group, clinical trial. Results The negative allosteric mGlu5 modulator ADX10059 attenuated dural vasodilator responses to meningeal stimulation in a dose-dependent manner, comparable to naratriptan, while the N-methyl- d-aspartate receptor blocker MK-801 had no effect. ADX10059 reduced responses of trigeminocervical neurons to dural stimulation, most strikingly affecting their spontaneous firing rate. Immunostaining identified mGlu5 and not mGlu1a receptors in the TCC. The primary efficacy endpoint for the clinical trial, 2 h pain free, demonstrated a significant effect of ADX10059 375 mg, 17%, versus placebo, 5%. No serious adverse events were reported at the primary dose, with transient dizziness being the most common treatment-emergent event at 48%. Interpretation Our findings provide preclinical and clinical proof of concept establishing mGlu5 as a novel therapeutic target in the treatment of migraine. Although ADX10059 is unsuitable as a therapeutic candidate, because of hepatoxicity detected in a subsequent study, the data open a new direction for migraine research and therapy. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to compare the societal direct and indirect costs of chronic and episodic migraine in the United States. Background Episodic and chronic migraine are distinguished by the frequency of headache-days. Chronic migraine has a greater overall impact on quality of life than does episodic migraine. Individuals with chronic migraine also use more healthcare resources (resulting in higher direct costs) and experience greater decreases in productivity (resulting in higher indirect costs) than those with episodic migraine as shown in the American Migraine Prevalence and Prevention (AMPP) Study. Methods The International Burden of Migraine Study utilized a web-based questionnaire to elicit data on several topics related to the burden of migraine illness, including health resource utilization and productivity losses. Potential survey participants were identified by Synovate Healthcare (Chicago, IL, USA) from a pool of registered panelists from various countries. The panelists were screened online to determine eligibility and to identify individuals with migraine (episodic or chronic), based on reported symptoms. Participants from the United States were divided into episodic and chronic migraine groups, based on reported headache-day per month frequency. Direct and indirect costs were estimated by applying estimated unit costs to reported headache-related productivity losses and resource use. Costs were compared between participants with episodic and chronic migraine. Results Mean [standard deviation] total annual cost of headache among people with chronic migraine ($8243 [$10,646]) was over three times that of episodic migraine ($2649 [$4634], P < .001). Participants with chronic migraine had significantly greater direct medical costs ($4943 [$6382]) and indirect (lost productivity) costs ($3300 [$6907]) than did participants with episodic migraine (direct, $1705 [$3591]; indirect, $943 [$2084]) ( P < .001 for each). Unlike previous findings, direct medical costs constituted the majority of total headache-related costs for both chronic migraine (60.0%, $4943 of $8243) and episodic migraine (64.3%, $1705 of $2649) participants. A large portion of direct medical costs are attributable to pharmaceutical utilization among both chronic migraine (80%, $3925 of 4943) and episodic migraine (70%, $1196 of $1705) participants. Conclusion The results of this study build on previous results of the AMPP Study, demonstrating that headache-related direct, indirect, and total costs are significantly greater among individuals with chronic migraine than with episodic migraine in the United States. [ABSTRACT FROM AUTHOR]

Background: Single‐pulse transcranial magnetic stimulation (sTMS) is an emerging neuromodulation method reported to be useful in migraine. Despite a low propensity for side effects, some concern with its use in patients with cardiac pacemakers has been expressed. Case: We present a patient with chronic migraine with a cardiac pacemaker, who had tried unsuccessfully several migraine preventives with either poor efficacy or tolerability. With involvement of the cardiology team, we tested the effect of sTMS on her pacemaker and found it to be a safe and effective option for her. Conclusion: Having regard to the risk/benefit ratio of sTMS, its use in patients with disabling migraine in the presence of a cardiac pacemaker can be carefully evaluated and may represent a useful therapeutic option. [ABSTRACT FROM AUTHOR]

This review aims to understand the prevalence of premonitory symptoms in migraine, postulate their mechanisms, and compare these with functional imaging studies. A thorough literature review was conducted using Pub Med for prevalence studies of premonitory symptoms in migraine and functional imaging studies in the premonitory phase. The majority of studies have been retrospective reporting a prevalence of 7-88% for premonitory symptoms in migraine. Only one study has investigated premonitory symptoms prospectively and used preselected patients with recognized premonitory symptoms. The majority of patients were able to predict correctly the onset of migraine headache. Only one functional imaging study has been conducted in the premonitory phase that showed activation of posterolateral hypothalamus, midbrain tegmental area and substantia nigra, periaqueductal gray, dorsal pons, and various cortical areas including occipital, temporal, and prefrontal cortex. Subgroup analysis of patients with photophobia more than without photophobia in the premonitory phase showed activation of the occipital cortex. Comparison of patients with nausea more than without nausea in the premonitory phase showed activation in upper dorsal medulla and periaqueductal gray. Premonitory symptoms are common in migraine, although the true prevalence cannot be stated with certainty in the absence of prospective studies in unselected patients. Hypothalamic involvement can explain many of the premonitory symptoms. Activation of the the brainstem structures and hypothalamus before pain suggests a pivotal role of these structures in the pathogenesis of migraine. Hypersensitivity to light and occurrence of nausea in migraine is associated with activation of central brain structures involved in these pathways, and this can occur in the absence of pain. [ABSTRACT FROM AUTHOR]

Overview Trigeminal autonomic cephalalgias (TACs) are highly disabling primary headache disorders that involve severe unilateral head pain coupled with significant lateralized cranial autonomic features. Our understanding of these disorders and the development of novel and more effective treatments has been limited by the lack of a suitable animal model to explore their pathophysiology and screen prospective treatments. Discussion This review details the development of a novel preclinical model that demonstrates activation of both the trigeminovascular system and parasympathetic projections, thought to be responsible for the severe head pain and autonomic symptoms. Conclusion This model demonstrates a unique response to TAC specific treatments and highlights the importance of the cranial parasympathetic pathway to the pathophysiology of TACs and as a potential locus of action for treatments. The development of this model opens up opportunities to understand the pathophysiology of these disorders further, the likely involvement of the hypothalamus, as well as providing a preclinical model with which to screen novel compounds. [ABSTRACT FROM AUTHOR]

Pituitary adenylate cyclase activating peptide ( PACAP) is found in human trigeminocervical complex and can trigger migraine. PACAP levels were measured using a sensitive radioimmunoassay. Stimulation of the superior sagittal sinus ( SSS) in cat elevated PACAP levels in cranial blood. Patients with moderate or severe migraine headache had elevated PACAP in the external jugular vein during headache ( n = 15), that was reduced 1 h after treatment with sumatriptan 6 mg ( n = 11), and further reduced interictally ( n = 9). The data suggest PACAP, or its receptors, are a promising target for migraine therapeutics. [ABSTRACT FROM AUTHOR]

Background Crowned dens syndrome ( CDS) is a clinical-radiological entity characterized by acute attacks of neck pain with fever, rigidity, general signs of inflammation, and calcification of the periodontoid articular structures. Methods Case report with 42 months follow-up. Case description An 81-year-old man, who had never suffered from headache before July 2010, developed strictly left-sided headaches. The pain was restricted to the left side of the scalp and felt more intense in the frontal area. The intensity was moderate to high with a throbbing quality. The pain had an orthostatic component and was worsened by neck hyperextension and Valsalva maneuvers. Neurological and general examinations were normal, except for a reduced range of motion of the neck. He was prescribed indomethacin orally 25 mg t.i.d. and had a partial response. After a week, he was given a dosage of 50 mg t.i.d. with complete remission of the pain. Brain magnetic resonance imaging was normal, while an magnetic resonance imaging of the cervical spine showed a non-homogeneous mass behind the odontoid process of C2, narrowing the subarachnoid space in C1, stretching the posterior longitudinal ligament, and touching the left vertebral artery. A computed tomography scan showed calcification of the soft tissue around the odontoid process and a thickening of the left C2 root. After 4 months, the indomethacin dosage was reduced step-by-step. Indomethacin was discontinued in March 2012. Since then, the headache has not recurred. Discussion We here present the case of a patient with headache and radiological findings of crowned dens. However, the clinical presentation differed from previous CDS cases in the literature in that the pain was unilateral with frontal localization and throbbing quality, as well as an orthostatic component and lack of either fever or inflammatory signs. The differential diagnosis also includes a remitting form of hemicrania continua, presenting with an atypical presentation, with neuroimaging incidental finding of CDS. Conclusion This case widens the spectrum of the clinical presentation of crowned dens, a condition that should be kept in mind in cases of unilateral headache in older patients. [ABSTRACT FROM AUTHOR]

Objective To assess the relationship between the phenotype of the 'visual snow' syndrome, comorbid migraine, and typical migraine aura on a clinical basis and using functional brain imaging. Background Patients with 'visual snow' suffer from continuous TV-static-like tiny flickering dots in the entire visual field. Most patients describe a syndrome with additional visual symptoms of the following categories: palinopsia ('afterimages' and 'trailing'), entopic phenomena arising from the optic apparatus itself (floaters, blue field entoptic phenomenon, photopsia, self-light of the eye), photophobia, nyctalopia (impaired night vision), as well as the non-visual symptom tinnitus. The high prevalence of migraine and typical migraine aura in this population has led to the assumption that 'visual snow' is caused by persistent migraine aura. Due to the lack of objective measures, alternative diagnoses are malingering or a psychogenic disorder. Methods (1) The prevalence of additional visual symptoms, tinnitus, and comorbid migraine as well as typical migraine aura was assessed in a prospective semi-structured telephone interview of patients with 'visual snow.' Correlations were calculated using standard statistics with P < .05 being considered statistically significant. (2) Areas with increased brain metabolism in a group of 'visual snow' patients in comparison to healthy controls were identified using [18 F]-2-fluoro-2-deoxy-D-glucose positron emission tomography and statistical parametric mapping (SPM8 with whole brain analysis; statistical significance was defined by P < .001 uncorrected for multiple comparisons). Results (1) Of 120 patients with 'visual snow,' 70 patients also had migraine and 37 had typical migraine aura. Having comorbid migraine was associated with an increased likelihood of having palinopsia (odds ratio [ OR] 2.8; P = .04 for 'afterimages' and OR 2.6; P = .01 for 'trailing'), spontaneous photopsia ( OR 2.9; P = .004), photophobia ( OR 3.2; P = .005), nyctalopia ( OR 2.7; P = .01), and tinnitus ( OR 2.9; P = .006). Typical migraine aura was associated with an increased likelihood of spontaneous photopsia ( OR 2.4; P = .04). (2) After adjusting for typical migraine aura, comparison of 17 'visual snow' patients with 17 age and gender matched controls showed brain hypermetabolism in the right lingual gyrus (Montreal Neurological Institute coordinates 16-78-5; kE = 101; ZE = 3.41; P < .001) and the left cerebellar anterior lobe adjacent to the left lingual gyrus (Montreal Neurological Institute coordinates -12-62-9; kE = 152; ZE = 3.28; P = .001). Conclusions -Comorbid migraine aggravates the clinical phenotype of the 'visual snow' syndrome by worsening some of the additional visual symptoms and tinnitus. This might bias studies on 'visual snow' by migraineurs offering study participation more likely than non-migraineurs due to a more severe clinical presentation. The independence of entoptic phenomena from comorbid migraine indicates 'visual snow' is the main determinant. The hypermetabolic lingual gyrus confirms a brain dysfunction in patients with 'visual snow.' The metabolic pattern differs from interictal migraine with some similarities to migrainous photophobia. The findings support the view that 'visual snow,' migraine, and typical migraine aura are distinct syndromes with shared pathophysiological mechanisms that need to be addressed in order to develop rational treatment strategies for this disabling condition. [ABSTRACT FROM AUTHOR]