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Background: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and is considered a promising new migraine drug target. Although intravenous PACAP triggers migraine attacks and a recent phase II trial with a PACAP-inhibiting antibody showed efficacy in migraine prevention, targeting the PACAP receptor PAC1 alone has been unsuccessful. The present study investigated the role of three PACAP receptors (PAC1, VPAC1 and VPAC2) in inducing migraine-relevant hypersensitivity in mice., Methods: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (N total = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR., Results: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice., Conclusions: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment., (© 2024. The Author(s).)

Background: General practitioners (GPs) diagnose and manage a majority of headache patients seeking health care. With the aim to understand the potential for clinical improvement and educational needs, we performed a study to investigate Norwegian GPs knowledge about headache and its clinical management., Methods: We invited GPs from a random sample of 130 Norwegian continuous medical education (CME) groups to respond to an anonymous questionnaire survey., Results: 367 GPs responded to the survey (73% of invited CME groups, 7.6% of all GPs in Norway). Mean age was 46 (SD 11) years, with an average of 18 (SD 10) years of clinical experience. In general the national treatment recommendations were followed, while the International Classification of Headache Disorders and other international guidelines were rarely used. Overall, 80% (n = 292) of the GPs suggested adequate prophylactic medication for frequent episodic migraine, while 28% (n = 101) suggested adequate prophylactic medication for chronic tension-type headache (CTTH). Half (52%, n = 191)) of the respondents were aware that different types of acute headache medication can lead to medication-overuse headache (MOH), and 59% (n = 217) knew that prophylactic headache medication does not lead to MOH. GPs often used MRI in the diagnostic work-up. GPs reported that lack of good treatment options was a main barrier to more optimized treatment of headache patients., Conclusion: The knowledge of management of CTTH and MOH was moderate compared to migraine among Norwegian GPs., (© 2021. The Author(s).)

Background: Headache is a frequent symptom following COVID-19 immunization with a typical onset within days post-vaccination. Cases of cerebral venous thrombosis (CVT) have been reported in adenovirus vector-based COVID-19 vaccine recipients., Findings: We reviewed all vaccine related CVT published cases by April 30, 2021. We assessed demographic, clinical variables and the interval between the vaccination and onset of headache. We assessed whether the presence of headache was associated with higher probability of death or intracranial hemorrhage. We identified 77 cases of CVT after COVID-19 vaccination. Patients' age was below 60 years in 74/77 (95.8%) cases and 61/68 (89.7%) were women. Headache was described in 38/77 (49.4%) cases, and in 35/38 (92.1%) was associated with other symptoms. Multiple organ thrombosis was reported in 19/77 (24.7%) cases, intracranial hemorrhage in 33/77 (42.9%) cases and 19/77 (24.7%) patients died. The median time between vaccination and CVT-related headache onset was 8 (interquartile range 7.0-9.7) days. The presence of headache was associated with a higher odd of intracranial hemorrhage (OR 7.4; 95% CI: 2.7-20.8, p < 0.001), but not with death (OR: 0.51, 95% CI: 0.18-1.47, p = 0.213)., Conclusion: Delayed onset of headache following an adenovirus vector-based COVID-19 vaccine is associated with development of CVT. Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vaccine, should receive a thorough clinical evaluation and CVT must be ruled out., (© 2021. The Author(s).)

Background: Tension-type headache (TTH) has been ranked the second most prevalent health condition worldwide. Non-pharmacological treatments for TTH are widely used as a supplement or an alternative to medical treatment. However, the evidence for their effects are limited. Therefore, the aim of this study was to review the evidence for manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education as treatments for TTH on the effect of headache frequency and quality of life., Methods: A systematic literature search was conducted from February to July 2020 for clinical guidelines, systematic reviews, and individual randomised controlled trials (RCT). The primary outcomes measured were days with headache and quality of life at the end of treatment along with a number of secondary outcomes. Meta-analyses were performed on eligible RCTs and pooled estimates of effects were calculated using the random-effect model. The overall certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation approach (GRADE). In addition, patient preferences were included in the evaluation., Results: In all, 13 RCTs were included. Acupuncture might have positive effects on both primary outcomes. Supervised physical activity might have a positive effect on pain intensity at the end of treatment and headache frequency at follow-up. Manual joint mobilisation techniques might have a positive effect on headache frequency and quality of life at follow-up. Psychological treatment might have a positive effect on stress symptoms at the end of treatment. No relevant RCTs were identified for patient education. The overall certainty of evidence was downgraded to low and very low. No serious adverse events were reported. A consensus recommendation was made for patient education and weak recommendations for the other interventions., Conclusion: Based on identified benefits, certainty of evidence, and patient preferences, manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture, and patient education can be considered as non-pharmacological treatment approaches for TTH. Some positive effects were shown on headache frequency, quality of life, pain intensity and stress symptoms. Few studies and low sample sizes posed a challenge in drawing solid conclusions. Therefore, high-quality RCTs are warranted., (© 2021. The Author(s).)

Background: The Covid-19 pandemic is causing changes in delivery of medical care worldwide. It is not known how the management of headache patients was affected by the lockdown during the pandemic. The aim of the present study was to investigate how the initial phase of the Covid-19 pandemic affected the hospital management of headache in Denmark and Norway., Methods: All neurological departments in Denmark (n = 14) and Norway (n = 18) were invited to a questionnaire survey. The study focused on the lockdown and all questions were answered in regard to the period between March 12th and April 15th, 2020., Results: The responder rate was 91% (29/32). Of the neurological departments 86% changed their headache practice during the lockdown. The most common change was a shift to more telephone consultations (86%). Video consultations were offered by 45%. The number of new headache referrals decreased. Only 36% administered botulinum toxin A treatment according to usual schemes. Sixty% reported that fewer patients were admitted for in-hospital emergency diagnostics and treatment. Among departments conducting headache research 57% had to halt ongoing projects. Overall, 54% reported that the standard of care was worse for headache patients during the pandemic., Conclusion: Hospital-based headache care and research was impacted in Denmark and Norway during the initial phase of the Covid-19-pandemic.

Background: Previous studies found an association between migraine and dementia, which are two leading causes of disability. However, these studies did not differentiate between migraine types and did not investigate all prevalent dementia subtypes. The main objective of this national register-based study was to investigate whether migraine was a risk factor for dementia. Additionally, we explored potential differences in dementia risk for migraine with and without aura., Methods: We obtained data on birth cohorts born between 1935 and 1956 (n = 1,657,890) from Danish national registers. Individuals registered with migraine before age 59 (n = 18,135) were matched (1:5) on sex and birthdate with individuals without migraine (n = 1,378,346). Migraine was defined by International Classification of Diseases (ICD) diagnoses and dementia was defined by ICD diagnoses and anti-dementia medication. After matching, 62,578 individuals were eligible for analysis. For the statistical analyses, we used Cox regression models and adjusted for socio-demographic factors and several psychiatric and somatic morbidities., Results: During a median follow-up time of 6.9 (IQR: 3.6-11.2) years, 207 individuals with migraine developed dementia. Compared with individuals without migraine, we found a 50% higher rate of dementia among individuals with migraine (HR = 1.50; 95% CI: 1.28-1.76). Individuals without aura had a 19% higher rate of dementia (HR = 1.19; 95% CI: 0.84-1.70), and individuals with aura had a two times higher rate of dementia (HR = 2.11; 95% CI: 1.48-3.00)., Conclusions: Our findings support the hypothesis that migraine is a midlife risk factor for dementia in later life. The higher rate of dementia in individuals with a hospital-based diagnosis of migraine with aura emphasizes the need for studies on pathological mechanisms and potential preventative measures. Furthermore, given that only hospital-based migraine diagnoses were included in this study, future research should also investigate migraine cases derived from the primary healthcare system to include less severe migraine cases.

Background: Resting-state functional connectivity (FC) MRI has widely been used to understand migraine pathophysiology and to identify an imaging marker of the disorder. Here, we review what we have learned from FC studies., Methods: We performed a literature search on the PubMed website for original articles reporting data obtained from conventional resting-state FC recording in migraine patients compared with healthy controls or during and outside of migraine attacks in the same patients., Results: We found 219 articles and included 28 in this review after screening for inclusion and exclusion criteria. Twenty-five studies compared migraine patients with healthy controls, whereas three studies investigated migraine patients during and outside of attacks. In the studies of interictal migraine more alterations of more than 20 FC networks (including amygdala, caudate nucleus, central executive, cerebellum, cuneus, dorsal attention network, default mode, executive control, fronto-parietal, hypothalamus, insula, neostriatum, nucleus accumbens, occipital lobe, periaqueductal grey, prefrontal cortex, salience, somatosensory cortex I, thalamus and visual) were reported. We found a poor level of reproducibility and no migraine specific pattern across these studies., Conclusion: Based on the findings in the present review, it seems very difficult to extract knowledge of migraine pathophysiology or to identify a biomarker of migraine. There is an unmet need of guidelines for resting-state FC studies in migraine, which promote the use of homogenous terminology, public availability of protocol and the a priori hypothesis in line with for instance randomized clinical trial guidelines.

Migraine is a major public health problem afflicting approximately 10% of the general population and is a leading cause of disability worldwide, yet our understanding of the basis mechanisms of migraine remains incomplete. About a third of migraine patients have attacks with aura, consisting of transient neurological symptoms that precede or accompany headache, or occur without headache. For patients, aura symptoms are alarming and may be transiently disabling. For clinicians and scientists, aura represents an intriguing neurophysiological event that may provide important insight into basic mechanisms of migraine. Several observations point toward important differences between migraine with and without aura. Compared with migraine without aura, migraine with aura has different heritability, greater association with different conditions including stroke, different alterations of brain structure and function as revealed by imaging studies. A number of studies also indicate that migraine with aura may respond differently to acute and preventive therapies as compared to migraine without aura. The purpose of this review is to provide an overview of these differences in treatment responses, and to discuss the possibility of different therapeutic strategies for migraine with vs. without aura.

Background: To review the distribution and function of K ATP channels, describe the use of K ATP channels openers in clinical trials and make the case that these channels may play a role in headache and migraine., Discussion: K ATP channels are widely present in the trigeminovascular system and play an important role in the regulation of tone in cerebral and meningeal arteries. Clinical trials using synthetic K ATP channel openers report headache as a prevalent-side effect in non-migraine sufferers, indicating that K ATP channel opening may cause headache, possibly due to vascular mechanisms. Whether K ATP channel openers can provoke migraine in migraine sufferers is not known., Conclusion: We suggest that K ATP channels may play an important role in migraine pathogenesis and could be a potential novel therapeutic anti-migraine target.

Triptans are effective and well tolerated in acute migraine management but their exact mechanism of action is still debated. Triptans might exert their antimigraine effect by reducing the levels of circulating calcitonin gene-related peptide (CGRP). To examine this question, we examined whether sumatriptan modulate the baseline CGRP levels in vivo, under conditions without trigeminovascular system activation. We sampled blood from the internal and external jugular, the cubital veins, and the radial artery before and after administration of subcutaneous sumatriptan in 16 healthy volunteers. Repeated-measure ANOVA showed no interaction between catheter and time of sampling and thus no significant difference in CGRP between the four catheters (P=0.75). CGRP did not change over time in the four compartments (P>0.05). The relative changes in CGRP between baseline and maximal sumatriptan concentration did not differ between the four vascular compartments (P=0.49). It was found that Sumatriptan did not change the levels of circulating CGRP in the intra or extracerebral circulation in healthy volunteers. This speaks against a direct CGRP-reducing effect of sumatriptan in vivo in humans when the trigemino vascular system is not activated.