Temporal Ordering of Biomarkers in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: The temporal ordering of biomarkers for cerebral amyloid angiopathy (CAA) is important for their use in trials and for the understanding of the pathological cascade of CAA. We investigated the presence and abnormality of the most common biomarkers in the largest (pre)symptomatic Dutch-type hereditary CAA (D-CAA) cohort to date. METHODS: We included cross-sectional data from participants with (pre)symptomatic D-CAA and controls without CAA. We investigated CAA-related cerebral small vessel disease markers on 3T-MRI, cerebrovascular reactivity with functional 7T-MRI (fMRI) and amyloid-ß40 and amyloid-ß42 levels in cerebrospinal fluid. We calculated frequencies and plotted biomarker abnormality according to age to form scatterplots. RESULTS: We included 68 participants with D-CAA (59% presymptomatic, mean age, 50 [range, 26-75] years; 53% women), 53 controls (mean age, 51 years; 42% women) for cerebrospinal fluid analysis and 36 controls (mean age, 53 years; 100% women) for fMRI analysis. Decreased cerebrospinal fluid amyloid-ß40 and amyloid-ß42 levels were the earliest biomarkers present: all D-CAA participants had lower levels of amyloid-ß40 and amyloid-ß42 compared with controls (youngest participant 30 years). Markers of nonhemorrhagic injury (>20 enlarged perivascular spaces in the centrum semiovale and white matter hyperintensities Fazekas score, ≥2, present in 83% [n=54]) and markers of impaired cerebrovascular reactivity (abnormal BOLD amplitude, time to peak and time to baseline, present in 56% [n=38]) were present from the age of 30 years. Finally, markers of hemorrhagic injury were present in 64% (n=41) and only appeared after the age of 41 years (first microbleeds and macrobleeds followed by cortical superficial siderosis). CONCLUSIONS: Our results suggest that amyloid biomarkers in cerebrospinal fluid are the first to become abnormal in CAA, followed by MRI biomarkers for cerebrovascular reactivity and nonhemorrhagic injury and lastly hemorrhagic injury. This temporal ordering probably reflects the pathological stages of CAA and should be taken into account when future therapeutic trials targeting specific stages are designed.

Cerebrospinal Fluid and Plasma Amine Profiles in Interictal Migraine.

OBJECTIVE: Impaired amine metabolism has been associated with the etiology of migraine, that is, why patients continue to get migraine attacks. However, evidence from cerebrospinal fluid (CSF) is lacking. Here, we evaluated individual amine levels, global amine profiles, and amine pathways in CSF and plasma of interictal migraine patients and healthy controls. METHODS: CSF and plasma were sampled between 8:30 am and 1:00 pm, randomly and interchangeably over the time span to avoid any diurnal and seasonal influences, from healthy volunteers and interictal migraine patients, matched for age, sex, and sampling time. The study was approved by the local medical ethics committee. Individual amines (n = 31), global amine profiles, and specific amine pathways were analyzed using a validated ultraperformance liquid chromatography mass spectrometry platform. RESULTS: We analyzed n = 99 participants with migraine with aura, n = 98 with migraine without aura, and n = 96 healthy volunteers. Univariate analysis with Bonferroni correction indicated that CSF L-arginine was reduced in migraine with aura (10.4%, p < 0.001) and without aura (5.0%, p = 0.03). False discovery rate-corrected CSF L-phenylalanine was also lower in migraine with aura (6.9%, p = 0.011) and without aura (8.1%, p = 0.001), p = 0.088 after Bonferroni correction. Multivariate analysis revealed that CSF global amine profiles were similar for both types of migraine (p = 0.64), but distinct from controls (p = 0.009). Global profile analyses were similar in plasma. The strongest associated pathways with migraine were related to L-arginine metabolism. INTERPRETATION: L-Arginine was decreased in the CSF (but not in plasma) of interictal patients with migraine with or without aura, and associated pathways were altered. This suggests that dysfunction of nitric oxide signaling is involved in susceptibility to getting migraine attacks. ANN NEUROL 2023;93:715-728.

Decreased Cerebrospinal Fluid Amyloid ß 38, 40, 42, and 43 Levels in Sporadic and Hereditary Cerebral Amyloid Angiopathy.

OBJECTIVE: Vascular amyloid ß (Aß) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides Aß38, Aß40, Aß42, and Aß43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimer disease (AD). METHODS: Aß peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD, and 37 controls), and a group of 22 patients with D-CAA and 54 controls. To determine the diagnostic accuracy, the area under the curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI). RESULTS: We found decreased levels of all Aß peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for Aß42 (AUC of sCAA vs controls for discovery: 0.90, 95% CI = 0.82-0.99; for validation: 0.94, 95% CI = 0.89-0.99) and Aß43 (AUC of sCAA vs controls for discovery: 0.95, 95% CI = 0.88-1.00; for validation: 0.91, 95% CI = 0.83-1.0). All Aß peptides except Aß43 were also decreased in sCAA compared to AD (CSF Aß38: AUC = 0.82, 95% CI = 0.71-0.93; CSF Aß40: AUC = 0.88, 95% CI = 0.80-0.96; CSF Aß42: AUC = 0.79, 95% CI = 0.66-0.92). INTERPRETATION: A combined biomarker panel of CSF Aß38, Aß40, Aß42, and Aß43 has potential to differentiate sCAA from AD and controls, and D-CAA from controls. ANN NEUROL 2023;93:1173-1186.

Guidelines of the International Headache Society for controlled trials of pharmacological preventive treatment for persistent post-traumatic headache attributed to mild traumatic brain injury.

BACKGROUND: Persistent headache attributed to traumatic injury to the head is divided into two subtypes, one attributed to moderate or severe traumatic injury and another attributed to mild traumatic injury (i.e., concussion). The latter is much more prevalent, in part because more than 90% of cases with traumatic brain injury are classified as mild. The pathophysiology of persistent post-traumatic headache is poorly understood and the underlying mechanisms are likely multifactorial. There is currently no approved treatment specifically for persistent post-traumatic headache, and management strategies rely on medications used for migraine or tension-type headache. Therefore, high-quality trials are urgently needed to support clinical decision-making and optimize management strategies. International guidelines can facilitate appropriate trial design and ensure the acquisition of high-quality data evaluating the efficacy, tolerability, and safety of available and novel pharmacological therapies for the preventive treatment of persistent post-traumatic headache. METHODS: The development of this guideline was based on a literature review of available studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, along with a review of previously published guidelines for controlled trials of preventive treatment for episodic and chronic migraine. The identified literature was critically appraised, and due to the scarcity of scientific evidence, recommendations were primarily based on the consensus of experts in the field. OBJECTIVE: To provide guidelines for designing state-of-the-art controlled clinical trials aimed at evaluating the effectiveness of preventive treatments for persistent post-traumatic headache attributed to mild traumatic brain injury.

Depression and treatment with anti-calcitonin gene related peptide (CGRP) (ligand or receptor) antibodies for migraine.

BACKGROUND AND PURPOSE: The aim was to evaluate the effect of anti-calcitonin gene related peptide (CGRP) (ligand or receptor) antibodies on depressive symptoms in subjects with migraine and to determine whether depressive symptoms predict treatment response. METHODS: Patients with migraine treated with erenumab and fremanezumab at the Leiden Headache Centre completed daily E-headache diaries. A control group was included. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Center for Epidemiological Studies Depression Scale (CES-D) questionnaires at baseline (T0) and after 3 months (T1). First, the effect of treatment on the reduction in HADS-D and CES-D scores was assessed, with reduction in depression scores as the dependent variable and reduction in monthly migraine days (MMD) and treatment with anti-CGRP medication as independent variables. Second, depression as a predictor of treatment response was investigated, using the absolute reduction in MMD as a dependent variable and age, gender, MMD, active depression, impact, stress and locus of control scores as independent variables. RESULTS: In total, n = 108 patients were treated with erenumab, n = 90 with fremanezumab and n = 68 were without active treatment. Treatment with anti-CGRP medication was positively associated with a reduction in the HADS-D (ß = 1.65, p = 0.01) compared to control, independent of MMD reduction. However, the same effect was not found for the CES-D (ß = 2.15, p = 0.21). Active depression predicted poorer response to erenumab (p = 0.02) but not to fremanezumab (p = 0.09). CONCLUSION: Anti-CGRP (ligand or receptor) monoclonals lead to improvement of depressive symptoms in individuals with migraine, independent of migraine reduction. Depression may predict treatment response to erenumab but not to fremanezumab.

Changes in Migraine Symptoms after Ischemic Stroke: A Cohort Study.

INTRODUCTION: Migraine symptoms are postulated to improve post-stroke. We aimed to determine post-stroke changes in patients with active migraine pre-stroke and explored the relation with stroke location and stroke-preventive medication use. METHODS: Patients with active migraine who had an ischemic stroke were retrieved from three research-cohorts between 2014 and 2021. By an interview, we retrospectively investigated first-year post-stroke changes for those ischemic stroke patients that suffered from migraine pre-stroke. Associations between change in migraine frequency/intensity/aura (decrease, no change, increase), stroke location (posterior location vs. other), and use of secondary stroke preventive medication were assessed by ordinal regression with adjustment for confounders. RESULTS: We included 78 patients (mean age 48 years, 86% women, 47% with aura). Change in migraine symptomatology was reported by 63 (81%) patients; 51 (81%) noticed a decrease in attack frequency (27 no attacks) and 12 (19%) an increase. Pain intensity change was reported by 18 (35%) patients (50% increase, 50% decrease). Aura symptomatology improved in 4 (11%). Reduced attack frequency was not related to posterior stroke (OR = 1.5, 95% CI: 0.6-3.9), or preventive medication (antiplatelets OR = 1.0, 95% CI: 0.2-3.7; coumarin OR = 2.7, 95% CI: 0.4-20.6). CONCLUSIONS: Most patients with active pre-stroke migraine experience improvement of their symptoms in the first year after ischemic stroke. This change does not seem to be related to secondary stroke preventive medication or posterior stroke location.

Parental influence on intracerebral hemorrhage onset in hereditary Dutch-type cerebral amyloid angiopathy.

Introduction Dutch-type cerebral amyloid angiopathy (D-CAA) is an autosomal dominant hereditary form of CAA causing intracerebral hemorrhage (ICH) and cognitive decline. The age of onset of ICH in D-CAA mutation carriers is strikingly variable and ranges from end thirties up to seventy years. We investigated the presence of genetic anticipation and assessed the influence of parental age at onset and sex on age of ICH onset in offspring. Methods We included (potential) D-CAA mutation-carriers from our prospective D-CAA family database. Participants were sent a questionnaire by mail and asked for the onset age of symptomatic ICH and the onset age of symptomatic ICH of their affected first-degree relative(s); their siblings and affected parent. We used a Cox regression model with the age of onset of the parent as covariate and the sex of the offspring as factor. Next we replaced the sex of the offspring with a factor with four levels: mother/daughter, mother/son, father/daughter and father/son. We used a random effect per household. Results A total of 66 respondents completed the questionnaire. Reported mean age of first symptomatic ICH was similar (both 52 years, p=0.87) for D-CAA parents (n=60) and their offspring (n=100). Offspring with a mother with D-CAA seemed to have an earlier ICH onset (50 years, SD±7) than offspring with a paternal inheritance (54 years, SD±6, p=0.03). There was no association between onset of first ICH of the parent and offspring after adding sex of the offspring to the Cox regression model: hazard ratio (HR) 0.99, 95%CI: 0.94 to 1.03, p=0.51. The interaction between parent's sex and child's sex was not significant (p=0.70). The results with and without random effect were essentially identical. Conclusion We found no indication for genetic anticipation in D-CAA in general, although maternal inheritance seemed to be associated with an earlier ICH onset.

Substance use in a Dutch migraine cohort compared with the general population.

OBJECTIVE: To evaluate self-reported substance user profiles for individuals with migraine and compare these to the general population. BACKGROUND: There is increasing attention to lifestyle influences such as substance use as presumed migraine triggers. METHODS: Data on substance use were collected by survey in a large migraine cohort and from the biannual survey in the general Dutch population for substances. A representative cohort of Dutch patients with migraine (n = 5176) and the Dutch general population (n = 8370) was included. Patients with migraine were subdivided into episodic (EM) and chronic migraine (CM). Substance consumption was compared between the general population and patients with migraine, and between migraine subgroups after standardization for sex and level of education. RESULTS: Included patients with migraine were 83.4% female (4319/5176) and had a mean (standard deviation) age of 44.8 (11.3) years. Patients with migraine reported less illicit drug use (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.42-0.55; p < 0.001), less current and lifetime smoking (OR 0.60, 95% CI 0.55-0.65; p < 0.001 and OR 0.75, 95% CI 0.71-0.79; p < 0.001), and less current alcohol consumption (OR 0.66, 95% CI 0.62-0.70; p < 0.001) compared with the general population. Prevalence of substance use was compared between CM and EM participants and showed higher illicit drug use (OR 1.73, 95% CI 1.11-2.69; p = 0.011), higher current smoking (OR 1.61, 95% CI 1.22-2.11; p < 0.001) but less alcohol use (OR 0.54, 95% CI 0.43-0.68; p < 0.001) for participants with CM compared with EM. No differences were found for a history of smoking (OR 1.18, 95% CI 0.92-1.50, p = 0.19). CONCLUSIONS: Individuals with migraine are less likely to use illicit drugs, smoke, or drink alcohol compared with the general population. Patients with CM less often consume alcohol, while they more often use illicit drugs and smoke compared to those with EM.

Translating the Cluster Headache Quality of Life Questionnaire (CHQ) from English to Dutch with the TRAPD method.

OBJECTIVE: Cluster headache is associated with a decreased quality of life (QoL). The increased focus on patient-reported outcome measures (PROMS) has led to the creation of a tailored Cluster Headache Quality of Life scale (CHQ). Our objective was to create and authenticate a Dutch version of the CHQ (CHQ-D). METHODS: The TRAPD model (Translation, Review, Adjudication, Pretesting, Documentation) was used to translate the CHQ from English to Dutch and ensure cross-cultural adaption. Pre-testing was performed in n = 31 participants, and validity was in a new sample of n = 40 participants who completed the CHQ twice at a 2-day interval. Intraclass correlation coefficient (ICC) and Cronbach's alpha were used to assess the validity and reproducibility of the CHQ-D. RESULTS: To produce the CHQ-D, we made five modifications based on pretesting. Participants finished the questionnaire in a median time of 10 min (IQR:10.0, 17.5) and 90% within 20 min. The majority of participants (74.2%) did not find it burdensome at all. The reliability of the CHQ-D was excellent (Cronbach's alpha: 0.94; ICC: 0.94). CONCLUSION: The CHQ-D is a valid and practical instrument for QoL in individuals with cluster headache. We aim to use CHQ-D as PROM in clinical research in the Netherlands to enforce international collaborations and comparisons of studies.

Iatrogenic Cerebral Amyloid Angiopathy Post Neurosurgery: Frequency, Clinical Profile, Radiological Features, and Outcome.

BACKGROUND: Prion-like transmission of amyloid-ß through cadaveric dura, decades after neurosurgical procedures, has been hypothesized as an iatrogenic cause of cerebral amyloid angiopathy (CAA). We investigated new and previously described patients to assess the clinical profile, radiological features, and outcome of this presumed iatrogenic CAA-subtype (iCAA). METHODS: Patients were collected from our prospective lobar hemorrhage and CAA database (n=251) with patients presenting to our hospital between 2008 and 2022. In addition, we identified patients with iCAA from 2 other Dutch CAA-expertise hospitals and performed a systematic literature-search for previously described patients. We classified patients according to the previously proposed diagnostic criteria for iCAA, assessed clinical and radiological disease features, and calculated intracerebral hemorrhage (ICH)-recurrence rates. We evaluated the spatial colocalization of cadaveric dura placement and CAA-associated magnetic resonance imaging markers. RESULTS: We included 49 patients (74% men, mean age 43 years [range, 27-84]); 15 from our database (6% [95% CI, 3%-10%]; 45% of patients <55 years), 3 from the 2 other CAA-expertise hospitals, and 31 from the literature. We classified 43% (n=21; 1 newly identified patient) as probable and 57% (n=28) as possible iCAA. Patients presented with lobar ICH (57%), transient focal neurological episodes (12%), or seizures (8%). ICH-recurrence rate in the new patients (16/100 person-years [95% CI, 7-32], median follow-up 18 months) was lower than in the previously described patients (77/100 person-years [95% CI, 59-99], median follow-up 18 months). One patient had a 10 year interlude without ICH-recurrence. We identified no clear spatial relationship between dura placement and CAA-associated magnetic resonance imaging markers. During follow-up (median, 18 months), 20% of the patients developed transient focal neurological episodes and 20% cognitively declined. CONCLUSIONS: iCAA seems common in patients presenting with nonhereditary CAA under the age of 55. Clinical and radiological features are comparable with sCAA. After diagnosis, multiple ICH-recurrences but also long symptom-free intervals can occur. Harmonized registries are necessary to identify and understand this potentially underrecognized CAA-subtype.

Sex Differences in Onset and Progression of Cerebral Amyloid Angiopathy.

BACKGROUND: Cerebral Amyloid Angiopathy (CAA) disease course is highly variable even in hereditary forms. Sex may be a possible modifying factor. We investigated biological sex differences in clinical disease course and magnetic resonance imaging-markers in sporadic (sCAA) and Dutch-type hereditary CAA (D-CAA). METHODS: Patients with D-CAA and sCAA were included from hospital and research databases of the Leiden University Medical Center (2012-2020) and Massachusetts General Hospital (1994-2012). Key outcomes were: sex differences in symptomatic intracerebral hemorrhage (sICH) onset, recurrence and survival (analyzed using Kaplan Meier survival and regression analyses), and sex differences in magnetic resonance imaging-markers in D-CAA (explored using scatterplots), and in sCAA (investigated using regression analysis). RESULTS: We included 136 patients with D-CAA (mean age 57 years, 56% women, 64% with previous sICH) and 370 patients with sCAA (mean age 76 years, 51% women, all with previous sICH). Men and women with D-CAA did not differ for sICH onset (median age 54 in men and 56 in women [P=0.13]). Men with D-CAA had a slightly higher number of sICH compared with women (median 2 versus 1; adjusted RR, 1.5 [95% CI, 1.1-1.9]) and a shorter interval between the first and second sICH (median 1.8 years for men and 3.1 years for women, P=0.02). Men with sCAA had their first sICH at an earlier age (median 75 versus 78 years, respectively, P=0.003) and more lobar microbleeds (median 1 versus 0, P=0.022) compared with women with sCAA. No substantial differences were found in the other magnetic resonance imaging markers. Survival after first sICH was comparable between sexes for D-CAA (P=0.12) and sCAA (P=0.23). CONCLUSIONS: Men with CAA seem to have an earlier onset (sCAA) and more hemorrhagic disease course (sCAA and D-CAA) compared with women. Future studies are necessary to confirm these findings and determine the underlying role of sex-related factors.

Migraine genetics: Status and road forward.

BACKGROUND: Migraine is considered a multifactorial genetic disorder. Different platforms and methods are used to unravel the genetic basis of migraine. Initially, linkage analysis in multigenerational families followed by Sanger sequencing of protein-coding parts (exons) of genes in the genomic region shared by affected family members identified high-effect risk DNA mutations for rare Mendelian forms of migraine, foremost hemiplegic migraine. More recently, genome-wide association studies testing millions of DNA variants in large groups of patients and controls have proven successful in identifying many dozens of low-effect risk DNA variants for the more common forms of migraine with the number of associated DNA variants increasing steadily with larger sample sizes. Currently, next-generation sequencing, utilising whole exome and whole genome sequence data, and other omics data are being used to facilitate their functional interpretation and the discovery of additional risk factors. Various methods and analysis tools, such as genetic correlation and causality analysis, are used to further characterise genetic risk factors. FINDINGS: We describe recent findings in genome-wide association studies and next-generation sequencing analysis in migraine. We show that the combined results of the two most recent and most powerful migraine genome-wide association studies have identified a total of 178 LD-independent (r2 < 0.1) genome-wide significant single nucleotide polymorphisms (SNPs), of which 99 were unique to Hautakangas et al., 11 were unique to Choquet et al., and 68 were identified by both studies. When considering that Choquet et al. also identified three SNPs in a female-specific genome-wide association studies then these two recent studies identified 181 independent SNPs robustly associated with migraine. Cross-trait and causal analyses are beginning to identify and characterise specific biological factors that contribute to migraine risk and its comorbid conditions. CONCLUSION: This review provides a timely update and overview of recent genetic findings in migraine.

Neurological and psychiatric comorbidities of migraine: Concepts and future perspectives.

BACKGROUND: This narrative review aims to discuss several common neurological and psychiatric disorders that show comorbidity with migraine. Not only can we gain pathophysiological insights by studying these disorders, comorbidities also have important implications for treating migraine patients in clinical practice. METHODS: A literature search on PubMed and Embase was conducted with the keywords "comorbidity", "migraine disorders", "migraine with aura", "migraine without aura", "depression", "depressive disorders", "epilepsy", "stroke", "patent foramen ovale", "sleep wake disorders", "restless legs syndrome", "genetics", "therapeutics". RESULTS: Several common neurological and psychiatric disorders show comorbidity with migraine. Major depression and migraine show bidirectional causality and have shared genetic factors. Dysregulation of both hypothalamic and thalamic pathways have been implicated as a possibly cause. The increased risk of ischaemic stroke in migraine likely involves spreading depolarizations. Epilepsy is not only bidirectionally related to migraine, but is also co-occurring in monogenic migraine syndromes. Neuronal hyperexcitability is an important overlapping mechanism between these conditions. Hypothalamic dysfunction is suggested as the underlying mechanism for comorbidity between sleep disorders and migraine and might explain altered circadian timing in migraine. CONCLUSION: These comorbid conditions in migraine with distinct pathophysiological mechanisms have important implications for best treatment choices and may provide clues for future approaches.

Migraine with and without aura in relation to the menstrual cycle and other hormonal milestones: A prospective cohort study.

BACKGROUND: Previous studies showed that the perimenstrual window is associated with an increased susceptibility to migraine attacks without aura, but had conflicting results regarding attacks with aura. METHODS: We performed a longitudinal E-diary study among 526 premenopausal women with migraine. Differences in occurrence of perimenstrual migraine attacks between women with migraine with aura and without aura were assessed using a mixed effects logistic regression model. Additionally, participants completed a questionnaire about the influence of hormonal milestones on migraine frequency. RESULTS: Prevalence of menstrual migraine did not differ between women with migraine without aura and migraine with aura (59% versus 53%, p = 0.176). The increased risk of migraine attacks without aura during the perimenstrual window was similar for women with migraine without aura (OR[95%CI]:1.53 [1.44-1.62]) and those with migraine with aura (1.53 [1.44-1.62]). The perimenstrual window was not associated with increased risk of migraine aura attacks (1.08 [0.93-1.26], p = 0.314). Women with migraine with aura more often reported increased migraine frequency during pregnancy and breastfeeding compared to women with migraine without aura, but not during hormonal contraception use. CONCLUSION: Sex hormone levels seem to differently affect the trigeminovascular system (migraine headache) and the susceptibility to cortical spreading depolarization (aura). Exclusively migraine attacks without aura should be interpreted as perimenstrual attacks.

Characterizing opioid use in a Dutch cohort with migraine.

BACKGROUND: There is lack of data on opioid (over)use for migraine in Europe. METHODS: We performed a cross-sectional study in a large Dutch cohort using a web-based questionnaire to assess opioid use in individuals with migraine. Primary outcome was to assess opioid use for the treatment of migraine attacks. As secondary outcomes we specified use of opioids (duration of use, type of opioids, prescriber) and compared between persons with episodic migraine versus chronic migraine. Descriptive statistics, unpaired T-tests, Chi-square and Mann-Whitney U tests were used. RESULTS: In total n = 3712 patients participated, 13% ever used opioids for headache. In opioid users, 27% did this for >1 month, and 11% for >1 year, and 2% without prescription. The majority of prescribing physicians were general practitioners (46%), followed by neurologists (35%), other specialists (9%), or emergency room doctors (8%). Opioids were used as acute treatment in 63%, in 16% as preventive treatment, and in 21% for both indications. Chronic migraine patients reported more opioid use compared with episodic migraine (22% versus 12%, p < 0.001), with also more prolonged use (>1 month: 34% chronic migraine versus 24% episodic migraine, p < 0.003). CONCLUSION: Opioid use is more frequent and prolonged in chronic migraine patients. Further education for both doctors and migraine subjects and providing multimodal pain management strategies are needed to reduce opioid use in persons with migraine.

Effect of COVID vaccination on monthly migraine days: a longitudinal cohort study.

BACKGROUND: This longitudinal cohort study aimed to investigate changes in migraine-related outcomes following COVID-19 infection and vaccination. METHODS: We identified 547 clinically diagnosed migraine patients from the Leiden Headache Center who kept a headache E-diary during the COVID-19 pandemic (February 2020 to August 2022). We sent a questionnaire to register their COVID-19 infection and/or vaccination dates. After applying inclusion criteria, n = 59 participants could be included in the infection analysis and n = 147 could be included in the vaccination analysis. Primary outcome was the change in monthly migraine days (MMD) between 1 month prior and 1 month post COVID-19 infection or vaccination. Secondary outcome variables were change in monthly headache days (MHD) and monthly acute medication days (MAMD). RESULTS: Vaccination against COVID-19 was associated with an increase in MMD (1.06; 95% confidence interval [CI] = 0.57-1.55; p < 0.001), MHD (1.52; 95% CI = 0.91-2.14; p < 0.001) and MAMD (0.72; 95% CI = 0.33-1.12; p < 0.001) in the first month post-vaccination. COVID-19 infection solely increased the number of MAMD (1.11; 95% CI = 0.10-1.62; p < 0.027), but no statistically significant differences in MMD or MHD were observed. CONCLUSIONS: Our findings imply that vaccination against COVID-19 is associated with an increase in migraine, indicating a possible role of inflammatory mediators in migraine pathophysiology.

Harassment in the headache field: a global web-based cross-sectional survey.

BACKGROUND: Matters of workplace harassment are an important issue. This issue needs to be recognized and studied to prevent occurrences. These important sensitive areas of effective workplace management are increasingly gaining more interest. We aimed to identify the prevalence of workplace sexual, verbal and physical harassment among headache professionals. METHODS: We adopted a cross­sectional exploratory survey approach with quantitative design. The survey was distributed electronically among headache healthcare and research professionals globally through the International Headache Society (IHS). RESULTS: Data were obtained from 579 respondents (55.3%; 320/579 women). A large percentage of respondents (46.6%; 270/579) had experienced harassment; specifically, 16.1% (93/578) reported sexual harassment, 40.4% (234/579) verbal harassment and 5.5% (32/579) physical harassment. Women were almost seven times more likely to experience sexual harassment compared to men (odds ratio = 6.8; 95% confidence interval = 3.5-13.2). Although women did also more frequently report other types of harassment, this was not statistically significant (odds ratio = 1.4; 95% confidence interval = 1.0-2.0). CONCLUSIONS: Lifetime exposure to workplace harassment is prevalent among headache professionals, especially in women. The present study uncovers a widespread issue and calls for strategies to be implemented for building a healthy and safe workplace environment.

Defining migraine days, based on longitudinal E-diary data.

BACKGROUND: There is a need for standardization of the definition of a migraine day for clinical and research purposes. METHODS: We prospectively compared different definitions of a migraine day with E-diary data of n = 1494 patients with migraine. We used a baseline definition based on migraine characteristics with a duration of ≥4 hours OR triptan intake (independently from its effect) OR (visual) aura lasting 5-60 minutes. RESULTS: Of all migraine days defined by triptan intake only, 66.2% had a duration <4 hours. Adjusting the headache duration criterion to ≥30 minutes led to a decrease in days defined by triptan intake only and resulted in a 5.4% increase in total migraine days (equals 0.45 migraine day increase in monthly migraine days). These additional migraine days had a median duration of 2.5 hours. CONCLUSION: We propose to define a migraine day as follows: 1) (a) headache duration ≥30 minutes; (b) matching ≥2 of four characteristics: unilateral, pulsating, moderate to severe pain, aggravation by or causing avoidance of routine physical activity; and (c) during headache ≥1 of the following: nausea and/or vomiting, photophobia and phonophobia or 2) (visual) aura duration 5-60 minutes or 3) a day with headache for which acute migraine-specific medication is used irrespective of its effect.

Headache attributed to SARS-CoV-2 infection, vaccination and the impact on primary headache disorders of the COVID-19 pandemic: A comprehensive review.

OBJECTIVE: The objective is to summarize the knowledge on the epidemiology, pathophysiology and management of secondary headache attributed to SARS-CoV-2 infection and vaccination; as well as to delineate their impact on primary headache disorders. METHODS: This is a narrative review of the literature regarding primary and secondary headache disorders in the setting of COVID-19 pandemic. We conducted a literature search in 2022 on PubMed, with the keywords "COVID 19" or "vaccine" and "headache" to assess the appropriateness of all published articles for their inclusion in the review. RESULTS: Headache is a common and sometimes difficult-to-treat symptom of both the acute and post-acute phase of SARS-CoV-2 infection. Different pathophysiological mechanisms may be involved, with the trigeminovascular system as a plausible target. Specific evidence-based effective therapeutic options are lacking at present. Headache attributed to SARS-CoV-2 vaccinations is also common, its pathophysiology being unclear. People with primary headache disorders experience headache in the acute phase of COVID-19 and after vaccination more commonly than the general population. Pandemic measures, forcing lifestyle changes, seemed to have had a positive impact on migraine, and changes in headache care (telemedicine) have been effectively introduced. CONCLUSIONS: The ongoing COVID-19 pandemic is a global challenge, having an impact on the development of secondary headaches, both in people with or without primary headaches. This has created opportunities to better understand and treat headache and to potentiate strategies to manage patients and ensure care.

Guidelines of the International Headache Society for Controlled Clinical Trials in Idiopathic Intracranial Hypertension.

The quality of clinical trials is essential to advance treatment, inform regulatory decisions and meta-analysis. With the increased incidence of idiopathic intracranial hypertension and the emergence of clinical trials for novel therapies in this condition, the International Headache Society Guidelines for Controlled Clinical Trials in Idiopathic Intracranial Hypertension aims to establish guidelines for designing state-of-the-art controlled clinical trials for idiopathic intracranial hypertension.