Spreading depression is a neurophysiological phenomenon that is observed in the central nervous system of many species, from insects to humans. In essence, spreading depression is a slowly propagating wave of mass depolarization (that is, spreading depolarization), aptly termed a 'brain tsunami', which successively engulfs contiguous brain regions, causing transient neuronal hyperexcitability at its leading edge, followed by complete but reversible neuronal silence lasting minutes. This wave cannot be detected in routine scalp EEG recordings, which contributes to its under-recognized status as a disease biomarker. Here, we present an evidence-based view of spreading depression as a probable cause of characteristic neurological signs and symptoms in numerous neurological conditions. Although migraine aura is a widely recognized manifestation of spreading depression, the clinical signs and symptoms of spreading depressions arising from structural brain pathology have remained an orphan concept with no established name or place in clinical terminology. Therefore, clinicians have long used the term 'migraine aura' to describe the transient neurological manifestations of spreading depression that occur entirely outside of the context of a migraine attack. As migraine is a primary headache disorder not caused by known structural pathology, this terminology is not only erroneous but could also lead to serious misdiagnoses. Consequently, we advocate for the clinical adoption of the more specific mechanistic term spreading depression to describe these clinical episodes. We believe it is imperative to recognize spreading depression as a generic mechanism underlying certain inherited or acquired neurological deficits and to differentiate between structural and non-structural aetiologies, as is done in seizure disorders.

White matter hyperintensities (WMHs) are common MRI findings and established markers of cerebral small-vessel disease associated with stroke, cognitive decline, and vascular risk factors. Several studies have suggested that individuals with migraine, particularly migraine with aura (MA), may have an increased burden of WMHs compared with individuals without migraine. Early population-based studies and meta-analyses reported a higher prevalence of WMHs in migraine, whereas more recent large neuroimaging cohorts have reported conflicting findings or no association. Differences in study design, migraine ascertainment, MRI acquisition parameters, WMH quantification methods, and adjustment for vascular risk factors complicate interpretation of the existing literature. An updated systematic review focusing on methodologically comparable population-based cohorts is therefore warranted. The primary objective of this systematic review and meta-analysis is to determine whether adults with migraine have a higher prevalence or burden of WMHs on MRI than non-migraine controls. Secondary objectives include evaluating associations according to migraine subtype (MA vs. migraine without aura and episodic vs. chronic migraine), sex, WMH location, age, and MRI acquisition or WMH quantification methods, as well as examining longitudinal WMH progression where available. We will include population-based cross-sectional or longitudinal cohort studies of adults undergoing brain MRI with sequences suitable for WMH detection. Migraine exposure may be defined using International Classification of Headache Disorders criteria, structured interviews, validated questionnaires, physician diagnosis, or ICD codes. Controls must originate from the same source population. Searches will be conducted in PubMed/MEDLINE, EMBASE, Web of Science, and Scopus. Study selection, data extraction, and risk-of-bias assessment will be performed independently by two reviewers using Covidence, and risk of bias will be evaluated using the ROBINS-E tool. Because WMH burden is reported using heterogeneous metrics across studies, the primary synthesis will use a precision-weighted direction-of-effect approach, in which each study contributes the direction of the association, weighted by statistical precision. Where sufficiently comparable outcomes are available, random-effects meta-analysis will be performed. Sensitivity analyses will explore the influence of diagnostic criteria, MRI field strength, and confounder adjustment. This review will provide an updated and methodologically rigorous synthesis of the evidence on the association between migraine and WMHs.

OBJECTIVE:To assess the prevalence, frequency, and characteristics of headache disorders in transgender individuals receiving gender-affirming hormone therapy (GAHT), and to explore the relationship between GAHT and headache pathophysiology. We hypothesized that estrogen-based GAHT would be associated with increased risk of headache, particularly migraine, whereas testosterone-based GAHT would be associated with reduced headache burden. BACKGROUND:Migraine is a highly disabling headache disorder that disproportionately affects cisgender women, with hormonal fluctuations playing a key role in its pathophysiology. Despite extensive research in cisgender populations, there is a gap in our understanding about the prevalence and characteristics of headache disorders, including migraine, in transgender and nonbinary individuals undergoing GAHT, and there is true urgency to fill this knowledge gap. METHODS:We conducted a cross-sectional, observational study using an anonymous online survey targeting transgender and nonbinary individuals in Argentina from October 2023 to February 2024. Eligible participants were aged ≥18 years and receiving GAHT. The validated Migraine Screen Questionnaire (MS-Q) was used to identify migraine-like headaches. Additional items assessed changes in headache characteristics associated with GAHT. RESULTS:Of 160 participants, 102 (63.7%; 95% confidence interval [CI] 56.1%-70.8%) reported experiencing headaches. Of these, 86.3% (number [n] = 88) were receiving testosterone, 11.8% (n = 12) estrogens, and 2.0% (n = 2) were receiving other GAHT. Only 24.5% (n = 24) reported a prior headache diagnosis, including 18 participants (17.6%; 95% CI 11.3%-26.2%) with migraine. Based on the MS-Q, 46.1% (n = 47) screened positive for migraine-like headaches. New headache or worsening of headache was more frequently reported by estrogen users (66.6%) compared to those using testosterone (27.2%). Improvement or resolution of headaches was reported by 26.1% of testosterone users compared to 8.3% of estrogen users. CONCLUSION:Estrogen-based GAHT was associated with a higher proportion of individuals reporting new or worsening headaches, whereas testosterone-based GAHT was more often associated with headache improvement. These associations underscore the need for further research into how GAHT modulates headache patterns, as well as the high rate of underdiagnosed headache disorders in this population.

Introduction Immune checkpoint inhibitors (ICIs) have become an important treatment option for selected cancer patients in recent years. In this overview of systematic reviews, we aim to present a comprehensive summary of the evidence on neurological immune-related adverse events (irAEs) in patients treated with ICIs.Methods and analysis The overview will follow the preferred reporting items for overview of reviews statement. All systematic reviews reporting on neurological irAEs in adult patients treated with ICIs will be included. We will search PubMed, EMBASE and Cochrane’s Database of Systematic Reviews. Two authors will independently screen studies and extract data, with disagreements resolved by discussion or a third reviewer. Methodological quality will be assessed using AMSTAR-2. We will assess overlap by identifying shared primary studies and summarising their frequency in a table. Data will be presented narratively and in tables; when possible, frequencies of neurological irAEs and weighted means, along with associated distributions, will be reported.Ethics and dissemination As this study involves secondary analysis of published literature and does not include primary data collection, ethical approval is not required. Findings will be disseminated through peer-reviewed publications.PROSPERO registration number CRD420251020892.

BACKGROUND AND OBJECTIVES:Migraine is a multifaceted primary headache disorder. In neuroimaging of migraine, fMRI has been used to elucidate pathophysiology or monitor treatment effects. The current literature, however, is highly heterogeneous regarding reported variables and methodologies. This begets a lack of comparability and complicates synthesis of results across studies. We developed a framework for standardized reporting of fMRI studies in migraine. METHODS:Experts on fMRI in migraine were identified from the literature and subjected to structured questionnaires in 2 iterations of 3 rounds according to the DELPHI method. A total of 157 statements across 17 reporting domains were rated on 5-point Likert scales (strong support to strong opposition). The first iteration covered demographic data, migraine-specific factors, medication, scan timing, healthy controls (HCs), participant sampling/recruiting, standardized forms, study preregistration, region of interest (ROI) analyses, validation data sets, data sharing, preprocessing documentation, and analysis software. The second iteration of the questionnaire covered scanner-related factors, sequence-related factors, physiology monitoring, and stimulation-related factors. Items showing strong consensus/consensus (≥90%/≥75% of participants indicating scores 4 or 5) were included as standard reporting items. RESULTS:All 3 rounds of the first/second iteration were completed by 29 and 26 researchers (age 46 ± 11 years; 38% female/age 46 ± 12 years; 44% female) from 23 and 21 institutions. Across both iterations, strong consensus and consensus was achieved for 34 (3 scanner-related factors, 9 sequence-related factors, 1 stimulation-related factor, 2 demographic factors, 7 migraine-specific factors, 2 medication-factors, 2 scan timing factors, 4 HC factors, 1 preregistration factor, 1 analysis software factor, and 2 ROI analyses factors) and 33 (1 scanner-related factors, 4 sequence related factors, 1 factor related to physiology monitoring, 1 stimulation-related factor, 3 demographic factors, 6 migraine-specific factors, 4 medication factors, 3 HC factors, 2 sampling factors, 1 standardized form, 1 preregistration factor, 1 data sharing factor, 2 analysis software factors, and 3 ROI analyses factors) items, respectively. From these, a checklist covering 63 items from 14 reporting domains was created. DISCUSSION:We present an expert-based framework for reporting standards in fMRI studies of migraine, which can be used for future studies to homogenize cohort characterization, fMRI acquisitions, and analysis protocols.

Migraine aura - manifesting as transient, neurological disturbances - presents a complex and unresolved relationship with migraine headache. Cortical spreading depolarization (SD), recognized as the mechanism underlying aura symptoms, has been shown to trigger head pain through activation of trigeminal nociceptors in animal models. However, recent clinical data challenge the notion that aura causes migraine headache in patients. In this Essay, we critically examine the pathophysiology of migraine aura and migraine headache, exploring evidence from clinical observations, (genetic) mouse models, and pharmacological studies. We also discuss the role of SD, the trigeminovascular system, and the impact of pharmacological agents that both trigger and treat migraine attacks. Our essay highlights the complexities and conflicting data surrounding the interplay between aura and headache, emphasizing the need for further research to unravel this mystery and improve therapeutic strategies for individuals with migraine.

Background/Hypothesis Levcromakalim has previously been shown to induce attacks of migraine with aura in certain individuals. In this study, we tested the migraine-inducing effect of levcromakalim in a cohort of participants with migraine aura without headache.Methods In a double-blind, randomized, placebo-controlled cross-over study, eight adult participants with migraine with aura received intravenous infusions of levcromakalim and saline. Headache, aura and associated symptoms were evaluated for 24 h following administration of the study drug. The primary endpoint was occurrence of migraine-like attacks with or without aura in the 24-h observation period.Results Five participants (62.5%) developed migraine of any type following levcromakalim compared with three participants (37.5%) following placebo. No participants developed aura following levcromakalim.Conclusion/Interpretation Our findings suggest that the aura-inducing effect of levcromakalim is likely not based on direct induction of cortical spreading depression but may involve activation of the trigeminovascular system. This hypothesis should be further explored in future studies.ClinicalTrials.gov identifier NCT04905654

Background/Hypothesis Experimental provocation studies have yielded important insights in migraine pathophysiology. Levcromakalim has been previously shown to induce migraine-like attacks with and without aura. In this study, we aim to further explore the migraine aura-inducing potential of levcromakalim. Methods In a double-blind, randomized, placebo-controlled cross-over study, 27 adult participants with migraine with aura received intravenous infusions of levcromakalim and saline. Headache, aura and associated symptoms were evaluated for 24 hours following administration of the study drug. The primary endpoint was occurrence of migraine-like attacks with or without aura in the 24-hour observation period. Results Thirteen participants developed migraine-like attacks on the active day only (P = 0.0098), and four participants developed aura on the active day only (P = 0.68). The median time to onset of migraine-like headache was three hours, and the median time to onset of aura was 27.5 minutes. Conclusion/Interpretation Our findings affirm the potent migraine-inducing effect of levcromakalim. We observed a lower induction-rate of migraine aura than previously reported. Further studies are warranted to identify predictors of migraine aura following levcromakalim. ClinicalTrials.gov identifier NCT04905654

Importance Triptans are contraindicated in patients with ischemic heart disease or previous myocardial infarction, and caution is advised when prescribing these drugs to patients with vascular risk factors. However, controlled observational studies have either shown no association or an apparent lower risk, possibly owing to a channeling of triptans to individuals at low risk of cardiovascular outcomes, and it remains unclear whether avoiding triptan treatment for these patients is meaningful. Objective To establish whether an association between triptans and ischemic events could be demonstrated using a self-controlled design because this type of design is robust to the previously mentioned type of confounding. Design, Setting, and Participants All people in nationwide Danish registries who were initiating triptans and all the ischemic events that they experienced were identified. A case-crossover design was used to estimate odds ratios (OR) for associations between first-ever triptan use and ischemic outcomes, comparing triptan exposure in the 2-week period up to the event with four 2-week reference periods. Data were obtained for the period January 1995 to August 2022. Included from the population of Denmark were individuals redeeming a prescription for any triptan and experiencing at least 1 of 3 predefined ischemic outcomes. No one was excluded. ExposureInitiation of any triptan. Main Outcomes and Measures Acute myocardial infarction, ischemic stroke, or nonspecified stroke. Results Identified were a total of 429 612 individuals (median [IQR] age, 38 [28-48] years; 325 687 female [75.8%]) who redeemed a first prescription for a triptan in the study period. Of these patients, 11 (0.003%) had a myocardial infarction with the first triptan prescription in either a focal or referent window (odds ratio [OR], 3.3; 95% CI, 1.0-10.9), 18 (0.004%) had ischemic stroke (OR, 3.2; 95% CI, 1.3-8.1), and 35 (0.008%) had ischemic/nonspecified stroke (OR, 3.0; 95% CI, 1.5-5.9). Case patients had a median age of approximately 60 years and had a high-risk cardiovascular profile. Conclusions and Relevance Results of this case-crossover study suggest that triptan initiation was associated with higher risk of ischemic stroke and myocardial infarction. For the individual patient with low background cardiovascular risk, the risk of an ischemic event after triptan initiation was very low.

IntroductionMigraine is a complex neurological disorder that affects a significant portion of the global population. As traditional pharmacological approaches often fall short in alleviating symptoms, the development of innovative therapies has garnered significant interest. This text aims to summarize the current pharmacological options for managing migraine and to explore the potential impact of novel therapies.Areas coveredWe focused on conventional treatments, emerging therapies, and novel compounds in clinical development, including therapies targeting the trigeminovascular system, cannabis-based therapies, hormonal and metabolic therapies, and other options. English peer-reviewed articles were searched in PubMed, Scopus, and ClinicalTrials.gov electronic databases.Expert opinionSeveral novel treatment options for migraine have become available in recent years. Emerging pharmacological therapies targeting the trigeminovascular system, cannabis-based therapies, hormonal and metabolic interventions, and other emerging treatment modalities, may prove to be valuable for the treatment of migraine. Further research, clinical trials, and substantiated evidence are necessary to validate the efficacy, safety, and long-term outcomes of these therapeutic options.

Introduction Visual disturbances are the most common symptoms of migraine aura. These symptoms can be described systematically by subdividing them into elementary visual symptoms. Since visual symptoms of migraine aura are not easy to describe verbally, we developed a collection of images illustrating previously reported elementary visual symptoms.Objectives To test a standardised visual migraine aura iconography in a large population of migraine with aura patients and to improve it based on the participants' feedback.Methods We created a set of images representing 25 elementary visual symptoms and a web-based survey where participants could report whether they recognised these images as part of their visual aura. Elementary visual symptoms could also be recognised via a corresponding text description or described in a free text by participants. Individuals with migraine aura recruited from four tertiary headache centres (in Switzerland, Denmark, Norway and Italy) were invited to complete the survey.Results Two hundred and fifteen participants completed the study (78.9% women, median age 36). They recognised a total of 1645 elementary visual symptoms from our predefined list. Of those, 1291 (78.4%) where recognised via standardised iconography images. A new type of elementary visual symptom was reported by one participant.Conclusion Most elementary visual symptoms experienced by participants were recognised via the standardised iconography. This tool can be useful for clinical as well as research purposes.

Background Several studies have applied resting-state functional MRI to examine whether functional brain connectivity is altered in migraine with aura patients. These studies had multiple limitations, including small sample sizes, and reported conflicting results. Here, we performed a large, cross-sectional brain imaging study to reproduce previous findings. Methods We recruited women aged 30–60 years from the nationwide Danish Twin Registry. Resting-state functional MRI of women with migraine with aura, their co-twins, and unrelated migraine-free twins was performed at a single centre. We carried out an extensive series of brain connectivity data analyses. Patients were compared to migraine-free controls and to co-twins. Results Comparisons were based on data from 160 patients, 30 co-twins, and 136 controls. Patients were similar to controls with regard to age, and several lifestyle characteristics. We replicated clear effects of age on resting-state networks. In contrast, we failed to detect any differences, and to replicate previously reported differences, in functional connectivity between migraine patients with aura and non-migraine controls or their co-twins in any of the analyses. Conclusion Given the large sample size and the unbiased population-based design of our study, we conclude that women with migraine with aura have normal resting-state brain connectivity outside of migraine attacks.

BACKGROUND:The connection between migraine aura and headache is poorly understood. Some patients experience migraine aura without headache, and patients with migraine aura with headache commonly experience milder headaches with age. The distance between the cerebral cortex and the overlying dura mater has been hypothesized to influence development of headache following aura. We tested this hypothesis by comparing approximated distances between visual cortical areas and overlying dura mater between female patients with migraine aura without headache and female patients with migraine aura with headache.METHODS:Twelve cases with migraine aura without headache and 45 age-matched controls with migraine aura with headache underwent 3.0 T MRI. We calculated average distances between the occipital lobes, between the calcarine sulci, and between the skull and visual areas V1, V2 and V3a. We also measured volumes of corticospinal fluid between the occipital lobes, between the calcarine sulci, and overlying visual areas V2 and V3a. We investigated the relationship between headache status, distances and corticospinal fluid volumes using conditional logistic regression.RESULTS:Distances between the occipital lobes, calcarine sulci and between the skull and V1, V2 and V3a did not differ between patients with migraine aura with headache and patients with migraine aura without headache. We found no differences in corticospinal fluid volumes between groups.CONCLUSION:We found no indication for a connection between visual migraine aura and headache based on cortico-cortical, cortex-to-skull distances, or corticospinal fluid volumes overlying visual cortical areas. Longitudinal studies with imaging sequences optimized for measuring the cortico-dural distance and a larger sample of patients are needed to further investigate the hypothesis.

ObjectiveThis systematic review provides a summary and evaluation of cases of migraine aura-like episodes elicited by sclerotherapy of veins of the lower extremities and discusses possible underlying mechanisms. BackgroundSclerotherapy is a commonly used treatment for varicose veins. Symptoms resembling migraine aura have been reported during and following sclerotherapy of the lower extremities, suggesting that sclerotherapy may elicit migraine aura. MethodsWe searched PubMed for articles reporting neurological complications that were transient and fully reversible following sclerotherapy treatment for varicose veins in the lower limbs. There were no restrictions regarding article language or publication date. Only original studies and case reports were included. Two authors independently reviewed included articles in detail. Data were extracted from each article, including details on symptoms, previous migraine history, sclerotherapy method, and the presence of a right-to-left cardiac shunt in patients. We evaluated whether episodes fulfilled modified International Classification of Headache Disorders, 3rd edition, criteria for 1.2 Migraine with aura or 1.5.2 Probable migraine with aura. ResultsThe search yielded 777 articles, 28 of which were included. Twenty-six articles reported 119 episodes of transient neurological symptoms in 34,500 sclerotherapy sessions. Two additional articles reported six episodes of transient neurological symptoms with no specification of the number of sessions. Of the 125 episodes, 119 involved transient visual disturbances, and eight met the modified criteria for Probable migraine with aura. In most episodes (98%), clinical information was insufficient to determine if the criteria were fulfilled. ConclusionsSymptoms that are clinically indistinguishable from migraine with aura attacks may occur following sclerotherapy, although this likely is rare. Microembolization through a right-to-left shunt triggering cortical spreading depolarization is a possible mechanism. Our findings are limited by infrequent specific assessments for neurological complications and a low level of detail in the description of symptoms in the available literature. Future prospective studies are needed to determine this phenomenon's incidence and underlying mechanisms.