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Bjarne K Madsen,1 Karen Søgaard,2,3 Lars L Andersen,4 Jørgen Skotte,4 Birte Tornøe,5 Rigmor H Jensen1 1Danish Headache Center, Department of Neurology, University of Copenhagen, Rigshospitalet-Glostrup, Glostrup, 2Institute of Sports Science and Clinical Biomechanics, Physical Activity and Health in Work Life University of Southern Denmark, Odense, 3Department of Clinical research, University of Southern Denmark, Odense, 4National Research Centre for the Working Environment, Copenhagen, Denmark; 5Department of Health Sciences, Lund University, Lund, Sweden Introduction: Muscle pain has been associated with reduced maximal muscle strength, and reduced rate of force development (RFD). Strength training (ST) has shown an effect in not only normalizing muscle function but also reducing neck muscle pain.Aim: The aims of this study were to compare muscle function in terms of strength, force steadiness in neck flexion, as well as extension, and rate of RFD of the shoulder in tension-type headache (TTH) patients and healthy controls and to examine the correlation to tenderness. Furthermore, the aim of the study was to examine the effect of ST on neck and shoulder functions in TTH patients.Participants and methods: In all, 60 TTH patients and 30 sex- and age-matched healthy controls were included for a case–control comparison. The 60 patients with TTH were randomized into an ST and an ergonomic and posture correction (EP) control group. The ST group trained for 10 weeks with elastic bands.Results: TTH patients had a lower extension force steadiness with a significant 15% higher coefficient of variation (CoV) compared to healthy controls (p=0.047). A significantly lower RFD (25%) was noted in the TTH group than in the healthy controls (p=0.031). A significant (p

Keira A Markey,1 Maria Uldall,2 Hannah Botfield,1 Liam D Cato,1 Mohammed A L Miah,1 Ghaniah Hassan-Smith,1 Rigmor H Jensen,2 Ana M Gonzalez,1 Alexandra J Sinclair1 1Neurometabolism, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK; 2Danish Headache Center, Clinic of Neurology, Rigshospitalet-Glostrup, University of Copenhagen, Glostrup, Denmark Abstract: Idiopathic intracranial hypertension (IIH) results in raised intracranial pressure (ICP) leading to papilledema, visual dysfunction, and headaches. Obese females of reproductive age are predominantly affected, but the underlying pathological mechanisms behind IIH remain unknown. This review provides an overview of pathogenic factors that could result in IIH with particular focus on hormones and the impact of obesity, including its role in neuroendocrine signaling and driving inflammation. Despite occurring almost exclusively in obese women, there have been a few studies evaluating the mechanisms by which hormones and adipokines exert their effects on ICP regulation in IIH. Research involving 11ß-hydroxysteroid dehydrogenase type 1, a modulator of glucocorticoids, suggests a potential role in IIH. Improved understanding of the complex interplay between adipose signaling factors such as adipokines, steroid hormones, and ICP regulation may be key to the understanding and future management of IIH. Keywords: 11beta-hydroxysteroid dehydrogenase type 1, steroid and adipokines, obesity, leptin

The glycophorin A (GPA) assay is a human mutation assay that is potentially useful for large epidemiological studies. The assay is rapid and requires a minimal amount of blood, which can be stored before analysis. The data presented here were collected from workers exposed to styrene in a boat manufacturing plant. This study was the first to apply the GPA assay to an occupationally exposed population. Subjects with a mean styrene exposure of 30 ppm had a higher frequency of GPA N phi variant cells than subjects with mean exposure of 1 ppm, but the subjects differed in respect to smoking and age distribution. Results indicate that the original 1-W-1 version of the assay may not be suitable for studies of small numbers of exposed subjects due to variability and artifacts. The newer BR6 version, however, has much lower variability and shows promise for use in the occupational setting.

Background: Treatment outcomes of patients who had received T-PEMF as an augmenting therapy at Aalborg University Hospital, Aalborg, Denmark, was evaluated., Methods: Patients diagnosed with unipolar depression or bipolar disorder who had received a self-administered 8-week T-PEMF series between November 2019 and April 2023 were included. Data were retrieved from the patients' records. The primary outcome was the Hamilton Rating Scale for Depression 17-item version (HAMD 17 ), both as a continuous measure and with proportions of response and remission reported., Results: A total of 57 patients (65.1 % females, 86.0 % unipolar depression, mean age, 48 ± 14 years) were included. Duration of current depressive episode was almost equally divided for <2 years (38.6 %), 2-5 years (38.6 %) and > 5 years (22.8 %). HAM-D 17 decreased significantly from baseline (20.8 (SD: 3.3)) to week 8 (14.5 (SD: 6.2), p < 0.001). An episode duration of 2-5 years was associated with lower odds of response on HAM-D 6 (adjusted OR = 0.15, 95 % CI: 0.03; 0.96, p < 0.05) and self-rated HAM-D 6 (adjusted OR = 0.09, 95 % CI: 0.01; 0.99, p = 0.05) when compared to an episode duration <2 years., Limitations: This study is limited by a lack of a control group, limited controlling of confounders, small sample sizes, and an attrition rate of 29.8 % for the primary outcome., Conclusion: T-PEMF reduced depressive symptoms in a real-world clinical setting including patients with both unipolar depression and bipolar disorder. Receiving T-PEMF within the first 2 years of the depressive episode was associated with an improved outcome., Competing Interests: Declaration of competing interest R.E.N. has, within the past 3 years, been an investigator for Compass Pharmaceuticals, Janssen-Cilag, Sage and Boehringer-Ingelheim for clinical trials; has received speaking fees from Lundbeck, Teva Pharmaceuticals, Janssen-Cilag and Otsuka Pharmaceuticals; and has acted as advisor to Lundbeck and Janssen-Cilag. R.H.J. and G.B. declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Idiopathic intracranial hypertension (IIH) is a neurometabolic disease with an increasing incidence. The pathophysiology is unknown, but improvement of diagnosis and management requires discovery of novel biomarkers. Our objective was to identify such candidate biomarkers in IIH, and secondarily, test for associations between identified metabolites and disease severity., Methods: This is a prospective case-control study with collection of cerebrospinal fluid (CSF), serum, and clinical data from new-onset, treatment-naïve patients with IIH (n = 60). Patients were included consecutively from 2 tertiary headache centers in Denmark, and age, sex, and body mass index (BMI) -matched healthy controls (n = 35) were recruited. Clinical data were retrieved at ocular remission (n = 55). Samples were analyzed using non-targeted mass spectrometry., Results: Serum sphingosine 1-phosphate (S1P), adenosine, and glutamate were 0.46-fold (q < 0.0001), 0.25-fold (q = 0.0048), and 0.44-fold (q < 0.0001) lower, respectively, in IIH. CSF stearoyl-lysophosphatidylcholine (LysoPC-18) and 2-palmitoyl-lysophosphatidylcholine (LysoPC-16) were 0.42 (q = 0.0025) and 0.37 (q < 0.001) -fold lower. LysoPC-18 was higher in patients with moderate-severe versus mild papilledema (p = 0.022). LysoPC-18 correlated positively with retinal nerve fiber layer thickness (p = 0.0012, r = 0.42) and inversely with mean deviation on automated perimetry (p = 0.01, r = -0.35). Higher baseline serum S1P (p = 0.018) and lower CSF LysoPC-16 (p = 0.003) were associated with optic nerve atrophy at ocular remission. Pathway analysis suggests dysregulated lipid metabolism and redox disturbances in new-onset IIH., Interpretation: We identify perturbed metabolism in new-onset IIH. S1P and LysoPC-16 demonstrate potential prognostic value due to association with subsequent optic nerve atrophy. This association between specific, differential metabolites and outcome provides substantial evidence for novel biomarkers of clinical significance that should be the focus of further targeted studies. ANN NEUROL 2024;96:595-607., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Importance: The magnetic resonance imaging (MRI) criteria currently used to diagnose idiopathic intracranial hypertension (IIH) are based on expert opinion and have limited accuracy. Additional neuroimaging signs have been proposed and used with contradictory results; thus, prospective evidence is needed to improve diagnostic accuracy., Objective: To provide evidence-based, accurate MRI signs for IIH diagnosis., Design, Setting, and Participants: This prospective cohort study was conducted from January 2018 to May 2021 with 3 validation cohorts at 2 Danish headache centers and with 3 independent international cohorts. Consecutive patients with suspected IIH were enrolled. Eligibility required the clinical suspicion of IIH, age 18 years or older, and written informed consent. The validation cohorts comprised patients with confirmed IIH from Austria and the US, and patients without IIH from the US. Data analysis was performed from December 2021 to August 2023., Exposure: Standardized diagnostic workup was performed to classify cases according to current criteria, and blinded evaluation of cerebral radiological diagnostics and papilledema was performed., Main Outcomes and Measures: The primary outcomes were MRI signs associated with IIH as assessed by univariate analyses. An MRI score estimating papilledema was calculated using machine learning. Internal validation of associations with lumbar puncture opening pressure and outcome and external validation of accuracy were performed in 3 cohorts., Results: Of 192 eligible patients (185 women [96.4%]; median [IQR] age, 28.0 [23.0-35.0] years), 110 were classified as having IIH, 4 as having probable IIH, and 1 as having suspected IIH without papilledema; 77 did not have IIH and served as controls, with corresponding age, sex, and weight. Papilledema at diagnosis was associated with perioptic subarachnoid space distension (56 patients [68.3%] vs 21 patients [41.2%]), posterior globe flattening (53 patients [66.3%] vs 10 patients [21.3%]), optic nerve disc protrusion (35 patients [30.4%] vs 2 patients [2.3%]), and transverse sinus venous stenosis (75 patients [79.8%] vs 29 patients [46.8%]). The papilledema-estimating MRI score showed optimal balance between sensitivity (49%) and specificity (87%) when 2 of the 3 latter signs were present and was associated with the lumbar puncture opening pressure and ophthalmological outcome. The score showed strong diagnostic accuracy in the external validation cohorts (587 patients; area under the receiver operating characteristic curve, 0.86) and outperformed the current (2013) diagnostic MRI criteria., Conclusions and Relevance: The findings of this cohort study of patients with IIH and controls suggest that an evidence-based MRI score including posterior globe flattening, optic nerve disc protrusion, and transverse sinus stenosis can estimate the presence of papilledema more accurately than the current diagnostic criteria.

Cluster headache, characterised by attacks of severe, recurrent, unilateral headache and ipsilateral cranial autonomic symptoms, remains a primary headache with an elusive pathophysiology. Recent advances have introduced effective treatments and broadened understanding of the clinical features of cluster headache. These features are similar in patients globally, but regional differences in prevalence and burden exist. International collaborations have led to identification of eight genetic loci associated with cluster headache. The pathophysiological mechanisms are still not fully understood but recent studies show that targeting the trigeminal autonomic reflex by neurostimulation, or targeting the neuropeptide calcitonin gene-related peptide (CGRP), might lessen the attack burden. The US Food and Drug Administration has approved galcanezumab, a monoclonal antibody targeting CGRP, as the first specific preventive treatment for episodic cluster headache. However, a preventive effect was not replicated in chronic cluster headache, and the European Medicines Agency did not approve galcanezumab, restricting its availability in Europe. Owing to the low prevalence of cluster headache, continued collaboration through multicentre clinical trials and data sharing will be imperative for further breakthroughs in understanding and management., Competing Interests: Declaration of interests ASP has received a restricted research grant (payment to their institution) and conference attendance from Lundbeck Pharma, and personal fees from Pfizer for teaching activities. NL has received a restricted research grant from Lundbeck Pharma (payment to their institution), a research grant from the Capital Region Research Foundation, support for conference attendance from Pfizer, and personal fees from teaching activities for general practitioners from Dagens Medicin and Pfizer (personal). PJG reports, over the past 36 months: grants from Celgene and Kallyope; personal fees from Aeon Biopharma, AbbVie, Amgen, eNeura, CoolTech, Dr Reddys, Eli Lilly, Epalex, Linpharma, Lundbeck, Novartis, Pfizer, Sanofi, Satsuma, Shiratronics, and Teva Pharmaceuticals; participation on a data and safety monitoring board for Aeon Biopharma and Man & Science; personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, and Vector Metric; fees for educational materials from CME Outfitters; publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate, and Wolters Kluwer; and a patent for magnetic stimulation for headache (WO2016090333 A1) assigned to eNeura, without fee. PJG is a board member of the American Headache Society, Migraine Trust, and Organisation for Understanding Cluster Headache. ACB reports honoraria for presentations from Novartis, Teva, and Lundbeck; and research funding from the Swedish Brain Foundation and the Mellby Gård Foundation. S-JW has received honoraria as a moderator from AbbVie, Biogen, Eli Lilly, Hava Biopharma, and Pfizer; has received consulting fees from AbbVie, Eli Lilly Taiwan, Percept, and Pfizer Taiwan; and has received research grants from the Taiwan branches of Eli Lilly, Lundbeck, Novartis, and Orient Europharma. RF reports research grants from Bioprojet, Jazz Pharmaceuticals, Netherlands Brain Foundation, and ZonMW (fee for institution); educational honoraria from Novartis (fee for institution), Teva Pharmaceutical Industries, Bioprojet, and Lundbeck Pharma (personal fees); consultancy for AbbVie, Eli Lilly, and Takeda (fee for institution); and is a member of the cluster headache section of the Dutch Headache guidelines (unpaid). MB reports grant funding from the Will Erwin Headache Research Foundation; travel support for attending meetings from the American Headache Society; has served as a consultant for Lundbeck, Beckley Psytech, Praxis Precision Medicines, and PureTech Health; is a site investigator for a cluster headache clinical trial funded by Lundbeck; was a paid guest for a video podcast by the American Academy of Neurology, is a paid survey respondent for Doximetry, and is an unpaid member of the medical advisory board of Clusterbusters. S-JC was involved as a site investigator of a multicentre trial sponsored by Allergan, AbbVie, Hyundai Pharmaceutical, Ildong Pharmaceutical, Eli Lilly, Pfizer, and Lundbeck; and has received lecture fees or advisory honoraria from AbbVie Korea, Lundbeck, Eli Lilly Korea, SK Chemicals, Teva Pharmaceutical Industries, and Pfizer. MFPP reports consulting fees for AbbVie–Allergan, Ache, Eli Lilly, Eurofarma, Libbs, Lundbeck, Kenvue, Pfizer, Sanofi-Aventis, and Teva Pharmaceutical Industries; travel support from Teva; participation in advisory boards for AbbVie-Allergan, Eli Lilly, Pfizer, Kenvue, Eurofarma, and Sonofi-Aventis; and is president of the Brazilian Association for Cluster Headache and Migraine (unpaid). RHJ received a restricted research grant (for institution) for work on cluster headache from Lundbeck Pharma; received a research grant for treatment trial for idiopathic intracranial hypertension (for institution) from Novo Nordisk Foundation; is on an advisory board for Lundbeck Pharma and has received fees for participation on an advisory board (for institution); has received personal fees for educational and teaching activities from Pfizer, Teva Pharmaceutical Industries, Novartis, AbbVie, Lundbeck, and Eli Lilly; is chair of the Master of Headache Disorders at the University of Copenhagen, a director of the Danish Headache Center, and undertakes unpaid activities as a director of Lifting The Burden., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: Activation of adenosine triphosphate-sensitive potassium (K ATP ) channels has been implicated in triggering migraine attacks. However, whether the opening of these channels provoke cluster headache attacks remains undetermined. The hallmark of cluster headache is a distinct cyclical pattern of recurrent, severe headache episodes, succeeded by intervals of remission where no symptoms are present. In our study, we enrolled 41 participants: 10 with episodic cluster headaches during a bout, 15 in the attack-free remission period, and 17 diagnosed with chronic cluster headaches. Over 2 distinct experimental days, participants underwent a continuous 20-minute infusion of levcromakalim, a K ATP channel opener, or a placebo (isotonic saline), followed by a 90-minute observational period. The primary outcome was comparing the incidence of cluster headache attacks within the postinfusion observation period between the levcromakalim and placebo groups. Six of 10 participants (60%) with episodic cluster headaches in bout experienced attacks after levcromakalim infusion, vs just 1 of 10 (10%) with placebo ( P = 0.037). Among those in the remission phase, 1 of 15 participants (7%) reported attacks after levcromakalim, whereas none did postplacebo ( P = 0.50). In addition, 5 of 17 participants (29%) with chronic cluster headache had attacks after levcromakalim, in contrast to none after placebo ( P = 0.037). These findings demonstrate that K ATP channel activation can induce cluster headache attacks in participants with episodic cluster headaches in bout and chronic cluster headache, but not in those in the remission period. Our results underscore the potential utility of K ATP channel inhibitors as therapeutic agents for cluster headaches., (Copyright © 2023 International Association for the Study of Pain.)

Objective: Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear., Methods: We performed a prospective, case-controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone-binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age- and sex-matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations., Results: The mean fT/LH ratio was reduced by 35% (95% confidence interval [CI]: 21%-47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%-37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT) gene on chromosome 17), between fT and cluster headache was identified., Interpretation: Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT. ANN NEUROL 2024;95:1149-1161., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Cluster headache presents in an episodic and chronic form, between which patients can convert during the course of disease. We aimed to quantify the rate of cluster headache patients changing phenotype within one and five years and investigate the earlier proposed association between chronification and having side-shifting attacks., Methods: In total, 430 cluster headache patients well-characterized according to current International Classification of Headache Disorders criteria, who were all participants in a prior transition-study, were re-interviewed in an observational, retrospective, cross-sectional follow-up study design at the Danish Headache Center., Results: The transition rate for the whole cohort was 6.5% within one year and 19.8% within five years. The risk of becoming chronic if episodic was 4.0% within one year and 12.3% within five years. For conversion from chronic to episodic, the corresponding risk was 11.1% and 25.0%, respectively. Alterations in attack-side were reported in 32% of all chronic patients, generating an odds ratio of 2.24 of being chronic as opposed to episodic if experiencing side-shifting attacks., Conclusions: A higher transition rate since the original cross-sectional study demonstrates cluster headache as a non-static condition. Identifying a risk of transition within one and five years, based on current phenotype along with high odds of being chronic when experiencing a shift of attack-side, offers a valuable clinical compass in the dialogue with the patient., Competing Interests: Declaration of conflicting interestsMarie-Louise Kulas Søborg is a previous sub-investigator in trials for Lundbeck. Anja Sofie Petersen is a previous sub-investigator in trials for Lundbeck and received personal fees for teaching from Pfizer. Nunu Lund has received a restricted grant from Region Hovedstadens forskningsfond and Lundbeck and has given lectures for Pfizer and Dagens Medicin. Mads Christian Johannes Barløse has no conflicts of interest to report. Rigmor Højland Jensen has served as principal investigator in studies sponsored by Eli Lily, Novartis, Autonomic Technologies (ATI) and Lundbeck and has given lectures for Eli-Lily, ATI, Lundbeck, Novartis, AbbVie, Pfizer and TEVA.

Background: Nurses work at headache centres throughout Europe, and their care for migraine patients is acknowledged. However, the specific roles and tasks of nursing vary, and a unified understanding is lacking, posing challenges to knowledge sharing and research., Objectives: Using an e-Delphi study method, the objective is to obtain healthcare professional headache experts' opinions on nursing-specific roles and tasks and combine this into consensus statements for nurse recommendations for migraine treatment., Methods: A three-round questionnaire study was conducted with nurses and neurologists from 18 specialised headache centres in 10 countries. In round 1, statements were compiled from a systematic examination of existing literature and expert opinions. In rounds 2 and 3, the experts rated the importance of statements (from round 1) on a 5-point Likert scale. Statements were analysed using a content analysis method, and the consensus of pre-defined statements was evaluated with gradually increased predetermined criteria using descriptive statistics., Results: Twenty-one experts, representing all 10 countries, participated. The predetermined consensus of ≥70% agreement was reached for 42 out of the initial 63 statements. These statements formed the final recommendations within two themes: "The nurses' roles and tasks in the clinical setting" and "The nurses' roles and tasks in educating patients and colleagues." The consensus level of statements was strong, with 40% receiving unanimous agreement (100%) and 97% achieving relatively high agreement (>80%)., Conclusion: Nursing plays a vital role with diverse tasks in migraine care. This study offers practical recommendations and a framework for nurses, equipping them with a clinical tool to enhance care and promote a coordinated approach to migraine treatment., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.V.R. has received honoraria from Lundbeck and Eli Lilly for Advisory Boards and written compendium; R.H.J. has received honoraria for lectures and patient leaflets from MSD, Berlin-Chemie Menarini, ATI, and Pfizer and participated in medical advisory boards for ATI and Electrocore and conducted clinical trials for Eli-Lilly and ATI; A.G. has received honoraria for lectures or consulting from AbbVie, Almirall, Biogen, BioMed, Curatis, EliLilly, Lundbeck, Neurolite, Novartis, TEVA/Mepha; S.L. received fees for attending advisory meetings, presentations and preparing presentation materials from AbbVie, TEVA, Eli Lilly, Tillots Pharma, Salvia and Novartis; M.S.M. is chair of the medical advisory board of the CSF Leak Association, serves on the advisory board for Abbott, AbbVie, Eli Lilly, Salvia, Lundbeck, Pfizer and TEVA, has received payment for the development of educational presentations from AbbVie, Eli Lilly, Lundbeck, TEVA and Pfizer; S.B.M. has received travel grants from Lundbeck, TEVA, AbbVie and for Advisory board for AbbVie, Lundbeck, Novartis, TEVA; M.H. received funding for travel and/or speaker honoraria from TEVA, Lundbeck and compensation for advisory service or producing educational material from TEVA, Lundbeck and Novartis; All other authors have declared no conflict of interests.

Background: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues., Methods: Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA., Results: Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands., Conclusion: These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Connar Westgate reports financial support was provided by Lundbeck Foundation. Rigmor Jensen reports financial support was provided by Lundbeck Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Idiopathic intracranial hypertension is a secondary headache disorder potentially causing visual loss. Neurofilament light chain is a candidate, prognostic biomarker, but further studies of neuronal biomarkers are needed. Our objective was to investigate neurofilament light chain in cerebrospinal fluid (cNfL) and plasma (pNfL), amyloid-beta 42 (Aβ-42), total-tau and phosphorylated-tau in cerebrospinal fluid in new-onset idiopathic intracranial hypertension., Methods: Prospective case-control study including new-onset idiopathic intracranial hypertension and age, sex and BMI matched controls. Biomarkers were compared between patients and controls and related to papilledema, visual fields and opening pressure., Results: We included 37 patients and 35 controls. Patients had higher age-adjusted cNfL (1.4 vs. 0.6 pg/mL, p-adjusted < 0.001), pNfL (0.5 vs. 0.3 pg/mL, p-adjusted < 0.001) and total-tau/Aβ-42 (0.12 vs. 0.11, p-adjusted = 0.039). Significant, positive linear correlations were found between cNfL, pNfL, total-tau/Aβ-42 and opening pressure. Patients with severe papilledema had elevated cNfL compared to mild-moderate papilledema (median cNfL: 4.3 pg/mL (3.7) versus 1.0 pg/mL (1.4), p-adjusted = 0.009). cNFL was inversely associated with perimetric mean deviation (r = -0.47, p-adjusted < 0.001)., Conclusions: cNfL, pNfL and total-tau/Aβ-42 were elevated in new-onset idiopathic intracranial hypertension. cNfL was associated with severity of papilledema and visual field defects at diagnosis. This indicates early axonal damage. Neurofilament light chain is a candidate biomarker for disease severity., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KS: No conflicts of interest. JJK: Received funding from the Lundbeck Foundation, Rigshospitalet-Glostrup and Odense University Hospital. RHJ: Paid lectures for Pfizer, Eli-Lilly, Merck, TEVA, Novartis, Lundbeck and Allergan. Investigator in clinical trials with Eli-Lilly, Novartis and Lundbeck; Director of Danish Headache Center, Lifting The Global Burden of Headache and Founder of Master of Headache Disorders at University of Copenhagen. Recived research funding from University of Copenhagen, Rigshospitalet, Lundbeck Foundation, The Medical Society in Copenhagen, NovoNordisk Foundation and Tryg Foundation. TP: No conflicts of interest. CSK: No conflicts of interest. SGH: No conflicts of interest. SMH: No conflicts of interest. EAW: Medical Advisory Board for StatuManu ICP ApS. Received research funding from Øjenforeningen (Fight for Sight, Denmark) and the Synoptik Foundation. LDM: No conflicts of interest. DB: Presentations (TEVA, Novartis, Pfizer), Travel Support (Allergan, TEVA, Pfizer, Abbvie), Advisory Boards (Novartis, Lilly, Teva, Lundbeck, Pfizer, Abbvie) and Participations in clinical trials (TEVA, Lundbeck, Novartis, Lilly, Novo Nordic Foundation) outside the submitted work (other headache disorders), receiving grants from Odense University Hospital and Rigshospitalet, University of Copenhagen during the conduction of the work.

Background: Headache burden is substantial in idiopathic intracranial hypertension. The classification of idiopathic intracranial hypertension headache by the International Classification of Headache Disorders (ICHD) is an important tool for research and clinical purposes., Methods: We phenotyped headaches and tested sensitivity and specificity of the ICHD-3 criteria for idiopathic intracranial hypertension headache in a prospective cohort of patients suspected of idiopathic intracranial hypertension at two tertiary headache centers., Results: Sensitivity was 93% and specificity was 100% of ICHD-3 criteria for idiopathic intracranial hypertension-related headache validated in idiopathic intracranial hypertension ( n  = 140) and patients in whom idiopathic intracranial hypertension was suspected but disproven ( n =  103). The phenotype of new/worsened headaches related to idiopathic intracranial hypertension suspicion was equally migraine-like (p = 0.76) and tension-type-like (p = 0.08). Lumbar puncture opening pressure was higher ( p  < 0.0001) and pulsatile tinnitus more frequent ( p  < 0.0001) in idiopathic intracranial hypertension patients, but neither improved the applicability of the headache criteria, nor did papilledema., Conclusion: Headache phenotype is not distinct in idiopathic intracranial hypertension. ICHD-3 criteria for idiopathic intracranial hypertension headache are sensitive and specific, but simplicity can be improved without compromising accuracy. We propose that a new or worsened headache temporally related to active idiopathic intracranial hypertension is a sufficient criterion for idiopathic intracranial hypertension headache regardless of headache phenotype or accompanying symptoms, and that elements of idiopathic intracranial hypertension diagnostics (papilledema and opening pressure) be segregated from headache criteria. Trial Registration: ClinicalTrials.gov Identifier: NCT04032379., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: NSH received funding from the Novo Nordic Foundation during the conduction of the work and gave lectures for Pfizer, University of Southern Denmark, and University of Copenhagen. JJK received funding from the Lundbeck Foundation, Rigshospitalet-Glostrup, and Odense University hospital for the duration of the study. HMY received support from Abbvie for participation in non-related courses. RHJ gave lectures for Pfizer, Eli-Lilly, Merck, TEVA, Novartis, Lundbeck and Allergan; was investigator in clinical trials with Eli-Lilly, Novartis and Lundbeck. She is the Director of Danish Headache Center, Lifting The Global Burden of Headache and Founder of Master of Headache Disorders at University of Copenhagen and received research funding from University of Copenhagen, Rigshospitalet, Lundbeck Foundation, The Medical Society in Copenhagen, NovoNordisk Foundation and Tryg Foundation. DB gave lectures for TEVA, Novartis, Pfizer. Received travel support from Allergan, TEVA, Pfizer, Abbvie; was in advisory boards for Novartis, Lilly, Teva, Lundbeck, Pfizer, Abbvie and participated in clinical trials for TEVA, Lundbeck, Novartis, Lilly, Novo Nordic Foundation outside the submitted work. Received grants from Odense University Hospital and Rigshospitalet, University of Copenhagen during the conduction of the work.

Background: Idiopathic intracranial hypertension (IIH) occurs more frequently in obese females of childbearing age. A link between eating disorders and poor outcome has been suggested but remains unproven., Methods: This prospective field study at two tertiary headache centers included patients with clinically suspected IIH after standardized diagnostic work-up. Eating disorders were evaluated using validated questionnaires (EDQs). Primary outcome was the impact of eating disorders on IIH severity and outcome, secondary outcome was the prevalence and type of eating disorders in IIH compared to controls., Results: We screened 326 patients; 143 patients replied to the EDQs and were classified as 'IIH' or 'non-IIH' patients. The demographic profile of EDQ-respondents and non-respondents was similar. Presence of an eating disorder did not impact IIH severity (lumbar puncture opening pressure (p = 0.63), perimetric mean deviation (p = 0.18), papilledema (Frisén grad 1-3; p = 0.53)) nor IIH outcome (optic nerve atrophy (p = 0.6), impaired visual fields (p = 0.18)). Moreover, we found no differences in the prevalence and type of eating disorders when comparing IIH with non-IIH patients (p = 0.09)., Conclusion: Eating disorders did not affect IIH severity or outcome. We found the same prevalence and distribution pattern of eating disorders in IIH and non-IIH patients advocating against a direct link between IIH and eating disorders., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: T.W.: No conflicts of interest. J.L.: No conflicts of interest. M.B.L.: No conflicts of interest. N.S.H.: Received funding from the Novo Nordic Foundation (NNF20OC0065926) during the conduction of the work and gave lectures for Pfizer, University of Southern Denmark, and University of Copenhagen. J.J.K.: Received funding from the Lundbeck Foundation, Odense University Hospital and Rigshospitalet during the study. L.H.: No conflicts of interest. S.M.H.: Received grants from Fight for Sight, Denmark and the Synoptik Foundation. L.D.M.: No conflicts of interest. R.H.J.: Gave lectures for Pfizer, Eli-Lilly, ATI, Merck, TEVA, Novartis, Lundbeck and Allergan. Investigator in clinical trials with ATI, Eli-Lilly, Novartis and Lundbeck. Director of Danish Headache Center, Lifting The Global Burden of Headache and Founder of Master of Headache Disorders at University of Copenhagen. Recived research funding from University of Copenhagen, Rigshospitalet, ATI, Lundbeck Foundation, The Medical Society in Copenhagen, NovoNordisk Foundation and Tryg Foundation. D.B.: Participated in clinical trials and served with lectures as well as on advisory or speaker boards for Novartis, Eli Lilly, Lundbeck, Pfizer, Abbvie and Teva outside the submitted work (migraine). Received grants from Odense University Hospital and Rigshospitalet, University of Copenhagen during the conduct of the study.

Background: The role of calcitonin gene-related peptide (CGRP) in the cyclic pattern of cluster headache is unclear. To acquire biological insight and to comprehend why only episodic cluster headache responds to CGRP monoclonal antibodies, we examined whether plasma CGRP changes between disease states (i.e. bout, remission and chronic) and controls., Methods: The present study is a prospective case-control study. Participants with episodic cluster headache were sampled twice (bout and remission). Participants with chronic cluster headache and controls were sampled once. CGRP concentrations were measured in plasma with a validated radioimmunoassay., Results: Plasma was collected from 201 participants diagnosed with cluster headache according to the International Classification of Headache Disorders, 3rd edition, and from 100 age- and sex-matched controls. Overall, plasma CGRP levels were significantly lower in participants with cluster headache compared to controls ( p  < 0.05). In episodic cluster headache, CGRP levels were higher in bout than in remission (mean difference: 17.1 pmol/L, 95% confidence interval = 9.8-24.3, p  < 0.0001). CGRP levels in bout were not different from chronic cluster headache ( p  = 0.266)., Conclusions: Plasma CGRP is unsuitable as a diagnostic biomarker of cluster headache or its disease states. The identified reduced CGRP levels suggest that CGRPs role in cluster headache is highly complex and future investigations are needed into the modulation of CGRP and its receptors., Competing Interests: Declaration of conflicting interestsASP reports being a sub-investigator in trials and received a restricted research grant from Lundbeck (payed to the institution), which manufactures Eptinezumab, a monoclonal antibody targeting CGRP under investigation as a preventive treatment for cluster headache. KM reports no disclosures. SLC reports no disclosures. MB reports no disclosures. NRJ reports no disclosures. LK reports no disclosures. RHJ reports lectures for Eli-Lilly, which manufactures Galcanezumab, a monoclonal antibody targeting CGRP and FDA approved as a preventive treatment for episodic cluster headache. RHJ also reports lectures, acting as an investigator in clinical trials and receiving funding in the form of a restricted and an unrestricted research grant (paid to the institution) from Lundbeck, which manufactures Eptinezumab, a monoclonal antibody targeting CGRP under investigation as a preventive treatment for cluster headache.

Background and Objectives: Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure without an identifiable cause that mostly affects obese persons of childbearing age. In this prospective case series, we have evaluated the overall outcome of pregnancy and birth in participants with IIH and their newborn children. We also provide a proposal for the management of pregnant persons with IIH., Methods: In this observational study, neuro-ophthalmological findings, the course of IIH-related symptoms, disease management, and pregnancy outcomes were evaluated. The participants were divided into 3 groups according to the course of the disease during pregnancy: stable, worsened, and new diagnosed. Furthermore, the type of delivery and outcome of newborn children such as gestational age, weight at birth, and the presence of asphyxia were compared between the groups., Results: We observed 47 pregnancies in 42 participants; 2 had spontaneous abortions. There were 19 (47%) participants in the stable, 18 (45%) in the worsened, and 3 (8%) in the new diagnosed groups, respectively. A relapse of IIH occurred in 2 (5%). Worsening of IIH-related symptoms was experienced by 18/37 (49%) participants: headache by 17/18 (94%), tinnitus by 11/18 (61%), and vision by 7/18 (39%) (mostly in the first and second trimester). In 8/18 (44%), the symptoms were transient or alleviated in the second and third trimester. Body mass index before and after pregnancy did not significantly differ among the groups. A total of 8 participants were treated with acetazolamide. The frequency of cesarean section was 17/40 (43%). Preterm delivery occurred in 22%. No increased risk of asphyxia was observed, and all infants, but one, were healthy., Discussion: Worsening of headache, tinnitus, and/or vision were experienced by half of pregnant participants with IIH, mostly transient in the first and second trimester, rarely required specific treatment, and were not identified as a relapse of IIH. There was no difference in gestational age and weight at birth in children among the groups, and no perinatal asphyxia was noted. Weight gain in the participants was not identified as a risk factor for relapse of IIH in pregnancy. The rate of cesarean and preterm delivery was higher than in the non-IIH population. A proposal for the management of IIH in pregnancy is provided., Competing Interests: V. Vukovic-Cvetkovic: lectures for Novartis, Merck, and MSD and investigator in clinical trials with Lundbeck and Allergan. D. Beier: advisory board of Pfizer, Lundbeck, AbbVie, Novartis, Eli Lilly and Company, and Teva and participation in clinical trials of Teva, Lundbeck, and Novartis. L. Buchgreitz: lecture for AbbVie/Allergan. J.J. Korsbæk: funding from Lundbeck of Candy Foundation. R. Jensen: lectures for Pfizer, Eli Lilly and Company, Merck, TEVA, Novartis, Lundbeck, and Allergan; investigator in clinical trials with Eli Lilly and Company, Novartis, and Lundbeck; director of Danish Headache Center and Lifting The Global Burden of Headache; founder of Master of Headache Disorders at the University of Copenhagen; and received research funding from the University of Copenhagen, Rigshospitalet, Lundbeck Foundation, The Medical Society in Copenhagen, The Capital Region, Novo Nordisk Foundation, and Tryg Foundation. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Introduction: Diabetic neuropathic pain (DNP) is a debilitating complication affecting 15-20% of people with diabetes and is a predictor of depression, poor sleep and decreased quality of life. Current pharmacological treatments are often insufficient and have significant side-effects. Subcutaneous or intradermal botulinumtoxin-A (BonT-A) is an effective and safe treatment for neuropathic pain but is limited by the need to cover the entire affected area with injections. For large cutaneous areas, infiltration of the sensory nerve supply with BonT-A could provide similar effects, with a single injection. We aim to investigate the safety, efficacy, and effects on quality of life, physical activity, depressive symptoms and activities of daily living of perineural injections of BonT-A in patients with DNP of both lower extremities., Methods: This study is a double-blind, randomised, placebo-controlled clinical trial. 80 participants with moderate to severe DNP of both legs will be randomised 1:1 to receive injections of either 100 units incobotulinumtoxin-A or a saline placebo around each distal sciatic nerve for two cycles of 12 weeks. Average daily pain scores will be recorded once a day from 1 week prior to the first treatment and through the entire study period. Primary outcomes are differences between groups in daily and weekly mean pain scores. Secondary outcomes are levels of physical activity, depression scores, health-related quality of life, activities of daily living, sensory profiles and motor function, recorded at baseline, 4, 12, 16 and 24 weeks. The use of rescue medication and adverse events will be recorded throughout the study period., Ethics and Dissemination: The study is approved by the Danish Committee on Health Research Ethics and the Danish Medicines Agency. EU-Clinical Trial Information System (EU: 2022-500727-68-01), clinicaltrials.gov (ID: NCT05623111). Results will be published in peer-reviewed journals in open-access formats and data made available in anonymised form., Trial Registration Number: NCT05623111., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To systematically investigate previously examined biomarkers in blood, urine, cerebrospinal fluid, tear fluid, and saliva of patients with cluster headache., Background: Cluster headache is a condition with extensive clinical challenges in terms of diagnosis and treatment. Identification of a biomarker with diagnostic implications or as a potential treatment target is highly warranted., Methods: We conducted a systematic review including peer reviewed full text of studies that measured biochemical compounds in either blood, urine, cerebrospinal fluid, tear fluid, or saliva of patients with cluster headache diagnosed after the implementation of the International Classification of Headache Disorders (1988) written in English, Danish, Swedish, or Norwegian. Inclusion required a minimum of five participants. The search was conducted in PubMed and EMBASE, in September 2022, and extracted data were screened by two authors. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews were followed. The Newcastle-Ottawa Scale was used to assess the risk of bias in case-controlled studies., Results: We included 40 studies involving 832 patients with cluster headache and 872 controls, evaluating 80 potential biomarkers. The risk of bias for case-controlled studies was a median of 6 (range: 3-8) and 20 studies out of 40 (50%) were of fair or good quality. Most studies were identified within three groups: hypothalamic-regulated hormones, inflammatory markers, and neuropeptides. Among the hypothalamic hormones, cortisol was the most frequently investigated (N = 7) and was elevated in cluster headache in most of the studies. The most frequently examined inflammatory marker was interleukin 1 (N = 3), but findings were divergent. Calcitonin gene-related peptide was the most investigated neuropeptide (N = 9) and all studies found increased levels during attacks., Conclusion: Biomarker findings have been inconsistent and widely non-specific for cluster headache, which explains why none of the previous studies succeeded in identifying a unique biomarker for cluster headache, but instead contributed to substantiating the underlying pathophysiologic mechanisms. Several of the examined biomarkers could hold promise as markers for disease activity but are unfit for a clear distinction from both controls and other headaches., (© 2023 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Objective: To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH)., Background: CCH is an excruciating and difficult-to-treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited., Methods: In this small open-label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow-up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose., Results: The treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow-up (p FWER  = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic-diencephalic FC correlated negatively with a percent change in attack frequency (p FWER  = 0.03, R = -0.81), implicating this neural pathway in treatment response., Conclusion: Our results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted., (© 2023 American Headache Society.)

Background and Purpose: Diseases of raised intracranial pressure (ICP) cause severe morbidity and mortality. Multiple drugs are utilised to lower ICP including acetazolamide and topiramate. However, the evidence for their use is unclear. We aimed to assess the ICP modulatory effects and molecular effects at the choroid plexus (CP) of acetazolamide and topiramate., Experimental Approach: Female rats were implanted with telemetric ICP probes for physiological, freely moving 24/7 ICP recordings. Randomised cross-over studies were performed, where rats received acute (24 h) high doses of acetazolamide and topiramate, and chronic (10 days) clinically equivalent doses of acetazolamide and topiramate, all via oral gavage. Cerebrospinal fluid (CSF) secretion assays, and RT-qPCR and western blots on in vitro and in vivo CP, were used to investigate drug actions., Key Results: We demonstrate that acetazolamide and topiramate achieved maximal ICP reduction within 120 min of administration, and in combination doubled the ICP reduction over a 24-h period. Chronic administration of acetazolamide or topiramate lowered ICP by 25%. Topiramate decreased CSF secretion by 40%. Chronic topiramate increased the gene expression of Slc12a2 and Slc4a10 and protein expression of the sodium-dependent chloride/bicarbonate exchanger (NCBE), whereas chronic acetazolamide did not affect the expression of assessed genes., Conclusions and Implications: Acetazolamide and topiramate are effective at lowering ICP at therapeutic levels. We provide the first evidence that topiramate lowers CSF secretion and that acetazolamide and topiramate may lower ICP via distinct molecular mechanisms. Thus, the combination of acetazolamide and topiramate may have utility for treating raised ICP., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: Two phase 3 galcanezumab trials were conducted in Europe and North America to analyze the reduction of weekly cluster headache (CH) attack frequency in populations with episodic and chronic CH. The current study aims to illustrate prospectively recorded baseline clinical data from these trials and to identify possible predictors of response., Methods: Patients (aged 18-65 years) met The International Classification of Headache Disorders 3rd edition-beta criteria for CH. Attacks were evaluated using an electronic headache diary for 7-day (episodic) or 14-day (chronic) eligibility assessments before patients were randomized 1:1 to monthly subcutaneous galcanezumab 300 mg or placebo., Results: Data were collected from 106 patients with episodic and 237 with chronic CH. Overall, the mean age [standard deviation] was 45.4 [11.0] years; patients were predominantly White (84.5%), male (75.8%), and European (77.6%). Patients with episodic CH reported 17.5 [10.0] attacks/week; patients with chronic CH reported 18.8 [10.2] attacks/week. The average pain severity score (range 0-4) was 2.5 [0.7] for episodic CH and 2.7 [0.7] for chronic CH. Higher attack frequency was a possible predictor of response to galcanezumab; potential negative predictors of response were greater attack severity and duration., Conclusion: This large dataset of patients with CH provides reliable systematically and prospectively collected information on disease characteristics. The analysis in episodic CH underscores potential predictors of response worth considering for future CH trial design., Clinical Trial Registration: ClinicalTrials.gov, identifiers: NCT02397473 and NCT02438826., Competing Interests: RJ reports speaker's fees from Novartis, ATI, Lundbeck, TEVA, and Allergan and institutional payments for clinical trials with Eli Lilly and Company, Lundbeck, and ATI. CT reports fees for advisory boards or speaker's fees for Allergan/AbbVie, Eli Lilly and Company, Dompé, Lundbeck, Novartis, and TEVA and institutional payments for clinical trials with Allergan/AbbVie, Eli Lilly and Company, Lundbeck, Novartis, and TEVA. TM, JB, CZ, YD, and JM are full-time employees of Eli Lilly and Company and/or one of its subsidiaries and are minority holders of company stock. SA reports no commercial or financial relationships that could be construed as a potential conflict of interest. At the time the study was conducted, SA was a full-time employee of Eli Lilly and Company, Indianapolis, IN, USA, and was a minority holder of company stock., (Copyright © 2023 Jensen, Tassorelli, Myers Oakes, Bardos, Zhou, Dong, Aurora and Martinez.)

Background: Female sex is a known risk factor of brain disorders with raised intracranial pressure (ICP) and sex hormones have been suggested to alter cerebrospinal fluid (CSF) dynamics, thus impairing ICP regulation in CSF disorders such as idiopathic intracranial hypertension (IIH). The choroid plexus (CP) is the tissue producing CSF and it has been hypothesized that altered hormonal composition could affect the activity of transporters involved in CSF secretion, thus affecting ICP. Therefore, we aimed to investigate if expression of various transporters involved in CSF secretion at CP were different between males and females and between females in different estrous cycle states. Steroid levels in serum was also investigated., Methods: Female and male rats were used to determine sex-differences in the genes encoding for the transporters Aqp1 and 4, NKCC1, NBCe2, NCBE; carbonic anhydrase enzymes II and III (CA), subunits of the Na + /K + -ATPase including Atp1a1, Atp1b1 and Fxyd1 at CP. The estrous cycle stage metestrus (MET) and estrous (ES) were determined before euthanasia. Serum and CP were collected and subjected to RT-qPCR analysis and western blots. Serum was used to measure steroid levels using liquid chromatography tandem mass spectrometry (LC-MS/MS)., Results: Significant differences in gene expression and steroid levels between males and ES females were found, while no differences were found between male and MET females. During ES, expression of Aqp1 was lower (p < 0.01) and NKCC1 was higher in females compared to males. CAII was lower while CAIII was higher in ES females (p < 0.0001). Gene expression of Atp1a1 was lower in ES compared to male (p = 0.0008). Several of these choroidal genes were also significantly different in MET compared to females in ES. Differences in gene expression during the estrus cycle were correlated to serum level of steroid hormones. Protein expression of AQP1 (p = 0.008) and CAII (p = 0.035) was reduced in ES females compared to males., Conclusions: This study demonstrates for the first time that expression at CP is sex-dependent and markedly affected by the estrous cycle in female rats. Further, expression was related to hormone levels in serum. This opens a completely new avenue for steroid regulation of the expression of CSF transporters and the close link to the understanding of CSF disorders such as IIH., (© 2023. The Author(s).)

Background: Chronic cluster headache (CCH) is a debilitating primary headache disorder. Occipital nerve stimulation (ONS) has shown the potential to reduce attack frequency, but the occipital paresthesia evoked by conventional (tonic) stimulation challenges a blinded comparison of active stimulation and placebo. Burst ONS offers paresthesia-free stimulation, enabling a blinded, placebo-controlled study. Identification of a feasible preoperative test would help select the best candidates for implantation. This study aims to explore ONS as a preventive treatment for CCH, comparing burst stimulation to tonic stimulation and placebo, and possibly identifying a potential preoperative predictor., Methods: An investigator-initiated, double-blinded, randomized, placebo-controlled trial is conducted, including 40 patients with CCH. Eligible patients complete a trial with the following elements: I) four weeks of baseline observation, II) 12 weeks of transcutaneous electrical nerve stimulation (TENS) of the occipital nerves, III) implantation of a full ONS system followed by 2 week grace period, IV) 12 weeks of blinded trial with 1:1 randomization to either placebo (deactivated ONS system) or burst (paresthesia-free) stimulation, and V) 12 weeks of tonic stimulation. The primary outcomes are the reduction in headache attack frequency with TENS and ONS and treatment safety. Secondary outcomes are treatment efficacy of burst versus tonic ONS, the feasibility of TENS as a predictor for ONS outcome, reduction in headache pain intensity (numeric rating scale), reduction in background headache, the patient's impression of change (PGIC), health-related quality of life (EuroQoL-5D), self-reported sleep quality, and symptoms of anxiety and depression (Hospital Anxiety and Depression Scale, HADS). Data on headache attack characteristics are registered weekly. Data on patient-reported outcomes are assessed after each trial phase., Discussion: The study design allows a comparison between burst ONS and placebo in refractory CCH and enables a comparison of the efficacy of burst and tonic ONS. It will provide information about the effect of burst ONS and explore whether the addition of this stimulation paradigm may improve stimulation protocols. TENS is evaluated as a feasible preoperative screening tool for ONS outcomes by comparing the effect of attack prevention of TENS and tonic ONS., Trial Registration: The study is registered at Clinicaltrials.gov (trial registration number NCT05023460, registration date 07-27-2023)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: Caffeine, a non-selective adenosine receptor (AR) antagonist, is the most consumed psychostimulant in the world. Caffeine has been suggested to regulate cerebrospinal fluid secretion and is known both to alleviate and to trigger headache; however, its effect on the regulation of intracranial pressure (ICP) is not known. Therefore, we aimed to investigate the effects of caffeine on ICP and nociceptive responses., Methods: Female Sprague-Dawley rats were implanted with a novel telemetric device for continuous ICP recordings, which allowed for continuous recordings in freely moving rats. A single dose of caffeine (30 or 120 mg/kg intraperitoneally) was given. In a second group (non-implanted), the acute effects of 30 mg/kg caffeine on periorbital threshold using Von Frey testing and spontaneous behavior were utilized using an automated behavioral registration platform (Laboratory, Animal, Behavior, Observation, Registration and Analysis System) in a randomized cross-over study. Quantitative polymerase chain reaction and immunofluorescence were used to localize ARs in the choroid plexus., Results: A single dose of 30 mg/kg caffeine lowered the ICP by 35% at 165 min after administration (saline: 0.16 ± 0.9 vs caffeine: -1.18 ± 0.9 ΔmmHg, p = 0.0098) and lasted up to 12 h. Administration of 120 mg/kg caffeine showed a faster onset of decrease in ICP within 15 min by 50% (p = 0.0018) and lasted up to 12 h. The periorbital pain thresholds were higher after 1 h (saline: 224.6 ± 15.1 vs caffeine: 289.5 ± 8.7 g, p = 0.005) and lasted up to 5 h. Caffeine-treated rats had increased locomotor activity, speed, and changed grooming behavior. Expression of AR 1 was found in the choroid plexus., Conclusions: This study demonstrates that caffeine has a lowering effect on ICP as an acute treatment. Interestingly, caffeine acutely caused an increased response in cephalic thresholds supporting hypoalgesic effects. Future studies investigating the beneficial effects of caffeine for elevated ICP are warranted., (© 2023 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Objective: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights., Methods: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses., Results: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine., Interpretation: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Aim: Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treatment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors collaborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tolerable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist., Findings: The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist's perspective use of verapamil and triptans may be worrisome and regular follow-up is essential when using verapamil and lithium., Conclusion: We find that there is a great and unmet need to pursue novel and targeted preventive modalities to suppress the horrific pain attacks for people with cluster headache., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Objectives and Background: Chronic cluster headache (CCH) is a rare but severely debilitating primary headache condition. A growing amount of evidence suggests that occipital nerve stimulation (ONS) can offer effective treatment in patients with severe CCH for whom conventional medical therapy does not have a sufficient effect. The paresthesia evoked by conventional (tonic) stimulation can be bothersome and may thus limit therapy. Burst ONS produces paresthesia-free stimulation, but the amount of evidence on the efficacy of burst ONS as a treatment for intractable CCH is scarce., Methods: In this case series, we report 15 patients with CCH treated with ONS at Aarhus University Hospital, Denmark, from 2013 to 2020. Nine of these received burst stimulation either as primary treatment or as a supplement to tonic stimulation. The results were assessed in terms of the frequency of headache attacks per week and their intensity on the Numeric Rating Scale, as well as the Patient Global Impression of Change (PGIC) with ONS treatment., Results: At a median (range) follow-up of 38 (16-96) months, 12 of the 15 patients (80%) reported a reduction in attack frequency of ≥50% (a reduction from a median of 35 to 1 attack/week, p < 0.001). Seven of these patients were treated with burst ONS. A significant reduction was also seen in maximum pain intensity. Overall, 10 patients stated a clinically important improvement in their headache condition following ONS treatment, rated on the PGIC scale. A total of 16 adverse events (nine of which were in the same patient) were registered., Conclusion: Occipital nerve stimulation significantly reduced the number of weekly headache attacks and their intensity. Burst ONS seems to function well alone or as a supplement to conventional tonic ONS as a preventive treatment for CCH; however, larger prospective studies are needed to determine whether the effect can be confirmed and whether the efficacy of the two stimulation paradigms is even., (© 2023 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)