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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. [ABSTRACT FROM AUTHOR]

Small subsets of patients who fail to respond to pharmacological treatment may benefit from alternative treatment methods. In the last decade, neurostimulation is being explored as a potential treatment option for the patients with chronic, severely disabling refractory primary headaches. To alleviate pain, specific nerves and brain areas have been stimulated, and various methods have been explored: deep brain stimulation, occipital nerve stimulation, and sphenopalatine ganglion stimulation are among the more invasive ones, whereas transcranial magnetic stimulation and supraorbital nerve stimulation are noninvasive. Vagal nerve stimulation can be invasive or noninvasive, though this review included only data for noninvasive VNS. Most of these methods have been tested in small open‐label patient series; recently, more data from randomized, controlled, and blinded studies are available. Although neurostimulation treatments have demonstrated good efficacy in many studies, it still has not been established as a standard treatment in refractory patients. This review analyzes the available evidence regarding efficacy and safety of different neurostimulation modalities for the treatment of chronic migraine and cluster headache. [ABSTRACT FROM AUTHOR]

The article discusses a study which aims to enhance the diagnosis of idiopathic intracranial hypertension (IIH) by determining the nosography of headaches observed as a major, chronic and disabling complication of IIH. It is also mentioned that the International Classification of Headache Disorders (ICHD) specifically the diagnostic criteria for headaches attributed to IIC must be reviewed and field-tested to improve clinical applicability, sensitivity and specificity.

Background Medication overuse headache ( MOH) affects between 1% and 2% of the general population but is present in up to 50% of patients seen in headache centers. There are currently no internationally accepted guidelines for treatment of MOH. Methods A review of the current literature on MOH treatment and pathophysiology. Results We conclude that headache frequency can be reduced to episodic headache in more than 50% of the patients by simple detoxification and information. Approximately half the patients will not have need for prophylactic medication after withdrawal. Pain perception is altered in patients with MOH but can be restored to a baseline pattern, indicating a reversible mechanism in the central sensitization leading to chronic pain. The great comorbidity with depression and anxiety could be a consequence of the altered serotonin metabolism indicating a reversible and potentially treatable condition. Conclusion Increased focus on MOH is extremely important, as MOH both can and should be treated and prevented. MOH is thus a diagnosis that should be considered in all chronic headache patients as the very first step in their management strategy. In the general population, prevention campaigns against MOH are essential to minimize chronic pain disability. [ABSTRACT FROM AUTHOR]

The medical treatment of patients with chronic primary headache syndromes (chronic migraine, chronic tension-type headache, chronic cluster headache, hemicrania continua) is challenging as serious side effects frequently complicate the course of medical treatment and some patients may be even medically intractable. When a definitive lack of responsiveness to conservative treatments is ascertained and medication overuse headache is excluded, neuromodulation options can be considered in selected cases. Here, the various invasive and non-invasive approaches, such as hypothalamic deep brain stimulation, occipital nerve stimulation, stimulation of sphenopalatine ganglion, cervical spinal cord stimulation, vagus nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and transcutaneous electrical nerve stimulation are extensively published although proper RCT-based evidence is limited. The European Headache Federation herewith provides a consensus statement on the clinical use of neuromodulation in headache, based on theoretical background, clinical data, and side effect of each method. This international consensus further gives recommendations for future studies on these new approaches. In spite of a growing field of stimulation devices in headaches treatment, further controlled studies to validate, strengthen and disseminate the use of neurostimulation are clearly warranted. Consequently, until these data are available any neurostimulation device should only be used in patients with medically intractable syndromes from tertiary headache centers either as part of a valid study or have shown to be effective in such controlled studies with an acceptable side effect profile. [ABSTRACT FROM AUTHOR]

The Global Campaign against Headache, as a collaborative activity with the World Health Organization (WHO), was formally launched in Copenhagen in March 2004. In the month it turns 18, we review its activities and achievements, from initial determination of its strategic objectives, through partnerships and project management, knowledge acquisition and awareness generation, to evidence-based proposals for change justified by cost-effectiveness analysis. [ABSTRACT FROM AUTHOR]

The prevalence of cluster headache is 0.1% and cluster headache is often not diagnosed or misdiagnosed as migraine or sinusitis. In cluster headache there is often a considerable diagnostic delay - an average of 7 years in a population-based survey. Cluster headache is characterized by very severe or severe orbital or periorbital pain with a duration of 15-180 minutes. The cluster headache attacks are accompanied by characteristic associated uni-lateral symptoms such as tearing, nasal congestion and/or rhinorrhoea, eyelid oedema, miosis and/or ptosis. In addition, there is a sense of restlessness and agitation. Patients may have up to eight attacks per day. Episodic cluster headache (ECH) occurs in clusters of weeks to months duration, whereas chronic cluster headache (CCH) attacks occur for more than 1 year without remissions. Management of cluster headache is divided into acute attack treatment and prophylactic treatment. In ECH and CCH the attacks can be treated with oxygen (12 L/min) or subcutaneous sumatriptan 6 mg. For both oxygen and Sumatriptan ther e are two randomized, placebo-controlled trials demon-strating efficacy. In both ECH and CCH, verapamil is the prophylactic drug of choice. Verapamil 360 mg/day was found to be superior to placebo in one clinical trial. In clinical practice, daily doses of480-720mg are mostly used. Thus, the dose of verapamil used in cluster headache treatment may be double the dose used in cardiology, and with the higher doses the PR interval should be checked with an ECG. At the start of a cluster, transitional preventive treatment such as corticosteroids or greater occipital nerve blockade can be given. In CCH and in long-standing clusters of ECH, lithium, methysergide, topiramate, valproic acid and ergotamine tartrate can be used as add-on prophylactic treatment. In drug-resistant CCH, neuromodulation with either occipital nerve stim-ulation or deep brain stimulation of the hypothalamus is an alternative treatment strategy. For most cluster headache patients there are fairly good treatment options both for acute attacks and for prophylaxis. The big problem is the diagnosis of cluster headache as demonstrated by the diagnostic delay of 7 years. How-ever, the relatively short-lasting attack of pain in one eye with typical asso-ciated symptoms should lead the family doctor to suspect cluster headache resulting in a referral to a neurologist or a headache centre with experience in the treatment of cluster headache. [ABSTRACT FROM AUTHOR]

The article presents a study of adverse drug reactions (ADRs), particularly neurosensory disturbance (NSD), associated with the use of local anesthetics in dentistry. Data sets of 1995-2007 annual sales of local anesthetics, of adverse local anesthetic reactions, and clinical sample of 115 NSD patients were reviewed. Results showed a highly substantial overrepresentation of NSDs linked with articaine 4% with mandibular blocks.

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. [ABSTRACT FROM AUTHOR]

Activation of adenosine triphosphate-sensitive potassium (KATP) 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 KATP 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, vsjust 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 KATP 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 KATP channel inhibitors as therapeutic agents for cluster headaches. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Background: Idiopathic intracranial hypertension is characterized by increased intracranial pressure without any pathological findings on neuroimaging, except for signs of high intracranial pressure. Before diagnosing idiopathic intracranial hypertension secondary causes of increased intracranial pressure should be excluded.Objective: to characterize the phenotype of patients with secondary intracranial hypertension and to identify possible risk factors for secondary intracranial hypertension.Methods: We have systematically searched the PubMed database. The publications were analyzed according to the patient phenotype, age, gender, comorbidities, body mass index/weight status, and additional medication. The results are summarized in four categories: medication, infection, hormonal induced intracranial hypertension and miscellaneous groups of diseases related to sIH.Results: We identified 105 eligible papers which included 272 cases. There were 49.6% pediatric cases. Among the adult group,70.9% were women. A total of 40.4% of all cases were obese or overweight, 27% among adults and 13.4% among pediatric cases. Increased BMI and recent weight gain, anemia, renal diseases and hypertension were the most frequent comorbidities related to sIH.Conclusion: Among sIH patients, 40.4% were obese or overweight; two thirds were women. We recommend that even patients with a typical IIH phenotype should be screened for secondary causes. [ABSTRACT FROM AUTHOR]

The Global Campaign against Headache, as a collaborative activity with the World Health Organization (WHO), was formally launched in Copenhagen in March 2004. In the month it turns 18, we review its activities and achievements, from initial determination of its strategic objectives, through partnerships and project management, knowledge acquisition and awareness generation, to evidence-based proposals for change justified by cost-effectiveness analysis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Headache and facial pain are among the most common, disabling and costly diseases in Europe, which demands for high quality health care on all levels within the health system. The role of the Danish Headache Society is to educate and advocate for the needs of patients with headache and facial pain. Therefore, the Danish Headache Society has launched a third version of the guideline for the diagnosis, organization and treatment of the most common types of headaches and facial pain in Denmark. The second edition was published in Danish in 2010 and has been a great success, but as new knowledge and treatments have emerged it was timely to revise the guideline. The recommendations for the primary headaches and facial pain are largely in accordance with the European guidelines produced by the European Academy of Neurology. The guideline should be used a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organized in Denmark. This description is followed by sections on the characteristics, diagnosis and treatment of each of the most common primary and secondary headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular challenges regarding migraine and female hormones as well as headache in children are addressed. [ABSTRACT FROM AUTHOR]

The outcome of spontaneous intracranial hypotension (SIH) years after onset is largely unknown. The objective of our study was to describe our clinical experience and long-term outcomes in a case series of patients with SIH. From March 2007 to March 2022, demographic variables, clinical symptoms, neuroimaging findings, and response to treatment were retrospectively analyzed in patients with confirmed SIH and in a subgroup of patients with clinical symptoms but not confirmed by MR or LP, probable SIH (pSIH). We have included 37 SIH and 13 pSIH patients. The average age at onset was 44 years, and 59% (pSIH 46%) were women. All patients presented with a new-onset orthostatic headache. In the SIH group, brain MRI showed signs of intracranial hypotension in all patients, spinal MR was performed in 70%, and pathological findings were identified in 73%. The range of EBP was 1-8 (average 2.2). Good outcome after single or 2 EBPs had 42% (pSIH 46%) of patients. At follow-up, 81% (pSIH 54%) of patients had a favorable outcome. Relapse occurred in 16% of patients in the SIH group and none in the pSIH group. The mean follow-up time was 60 months. EBP is an effective and minimally invasive treatment, and efficacy seems independent of disease duration. The long-term prognosis is favorable in 80% of SIH patients and in half of pSIH patients. Despite the lack of MRI signs of low intracranial pressure on neuroimaging, pSIH patients should also be offered EBP, and more awareness of SIH is needed. [ABSTRACT FROM AUTHOR]

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 (pFWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic–diencephalic FC correlated negatively with a percent change in attack frequency (pFWER = 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Medication Overuse Headache: Inaccurate and Overdiagnosed," by L. Robbins in the 2014 issue.

Objectives: Medication‐overuse headache (MOH) is recognized as a biobehavioural disorder, warranting that both biological and psychological factors are targeted throughout treatment. A psychological factor of importance may be personality that could be used to tailor treatment if differences are found across headache diagnoses. The objectives were as follows: (a) To investigate if migraine patients and patients with MOH differed on personality traits, (b) To investigate if the two headache groups differed from a Danish normative sample, with respect to personality traits. Materials and Methods: The NEO‐Five‐Factor Inventory was completed, and an age‐matched cohort of episodic migraine patients (n = 94) and MOH patients (n = 94) was included. Multivariate regression models and sex‐stratified comparisons were made on patients' raw scores from five personality traits; neuroticism, extraversion, openness, agreeableness, and conscientiousness. The headache groups were also compared to personality traits from a Danish normative sample (n = 1032). Results: MOH females obtained significantly lower scores on extraversion (24.4 ± 4.3 vs 27.1 ± 7.2, P < 0.01), openness (23.7 ± 3.9 vs 26.2 ± 6.4, P < 0.01), and conscientiousness (28.9 ± 3.7 vs 34.6 ± 5.8, P > 0.01) as compared to female migraineurs. Males showed no differences. Compared to the normative sample, both headache groups showed a lower score on extraversion (P < 0.01). Furthermore, MOH patients had statistically significant lower scores on conscientiousness while the migraine patients had a higher score. Conclusion: Results suggests some personality trait differences between migraine and MOH patients. Especially, females showed different personality traits, where the MOH females appeared more introvert and less socially orientated. If confirmed in larger studies, this information could be used in personalized treatment in clinical practice. [ABSTRACT FROM AUTHOR]

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

Objective: 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 AR1 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 cross‑sectional 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. [ABSTRACT FROM AUTHOR]

Background: It is well recognized that underrepresented and minoritized groups do not have the same career opportunities. However, there are limited data on the range and specifics of potential barriers that withhold people in headache medicine and science from reaching their full potential. Moreover, people from different geographical regions often perceive different challenges. We aimed to identify world-wide perceived career barriers and possibilities for promoting equality amongst professionals in the headache fields.Methods: A cross-sectional online survey was conducted among professionals in the field of headache globally. The questions of the survey were aimed at assessing perceived career barriers in four domains: professional recognition, opportunities in scientific societies, clinical practice, and salary and compensation. Perceived mentorship was also assessed.Results: In total 580 responders completed the survey (55.3% women). Gender was the most important perceived barrier in almost all domains. Additionally, country of birth emerged as an important barrier to participation in international scientific societies. Career barriers varied across world regions.Conclusion: It is essential that longstanding and ongoing disparities by gender and country of origin for professionals in the headache field are globally acknowledged and addressed in areas of recruitment, retention, opportunities, mentor- and sponsorships, and advancement. [ABSTRACT FROM AUTHOR]

Background: Our objective was to assess optic nerve sheath diameter (a marker of elevated intracranial pressure) and optic disc elevation (a marker of papilledema) in pseudotumor cerebri syndrome using transorbital sonography. Methods: The study was a prospective case-control study. We included patients with new-onset pseudotumor cerebri syndrome and matched healthy controls. All had fundoscopy, lumbar puncture with opening pressure and transorbital sonography. Sonography was assessed by a blinded observer. Results: We evaluated 45 patients and included 23 cases. We recruited 35 controls. Optic nerve sheath diameter was larger in pseudotumor cerebri syndrome compared to controls (6.3 ± 0.9 mm versus 5.0 ± 0.5 mm, p < 0.001) and so was optic disc elevation (0.9 ± 0.4 mm versus 0.4 ± 0.1 mm, p < 0.001). The optimal cut-off point for optic nerve sheath diameter was 6 mm with a sensitivity of 74% for prediction of pseudotumor cerebri syndrome and 68% for prediction of elevated opening pressure. Specificity was 94%. The optimal cut-off point for optic disc elevation was 0.6 mm. Sensitivity was 100% and specificity 83% for prediction of pseudotumor cerebri syndrome. Conclusion: Optic disc elevation and optic nerve sheath diameter are increased in new-onset pseudotumor cerebri syndrome. Optic disc elevation achieved high specificity and excellent sensitivity for diagnosis of pseudotumor cerebri syndrome. Transorbital sonography (TOS) is a potential, non-invasive screening tool for pseudotumor cerebri syndrome in headache clinics. [ABSTRACT FROM AUTHOR]

Introduction: Idiopathic intracranial hypertension (IIH) is a disorder of increased intracranial fluid pressure (ICP) of unknown etiology. This study aims to investigate osmolality of cerebrospinal fluid (CSF) from patients with IIH. Methods: We prospectively collected CSF from individuals referred on suspicion of IIH from 2011–2013. Subjects included as patients fulfilled Friedman and Jacobson’s diagnostic criteria for IIH. Individuals in whom intracranial hypertension was refuted were included as controls. Lumbar puncture with ICP measurement was performed at inclusion and repeated for patients after three months of treatment. Osmolality was measured with a Vapor Pressure Osmometer. Results: We collected 90 CSF samples from 38 newly diagnosed patients and 28 controls. At baseline 27 IIH-samples and at 3 months follow-up 35 IIH-samples were collected from patients. We found no significant differences in osmolality between 1) patients at baseline and controls (p = 0. 86), 2) patients at baseline and after 3 months treatment (p = 0.97), and 3) patients with normalized pressure after 3 months and their baseline values (p = 0.79). Osmolality in individuals with normal ICP from 6–25 cmH2O (n = 41) did not differ significantly from patients with moderately elevated ICP from 26–45 cmH2O (n = 21) (p = 0.86) and patients with high ICP from 46–70 cmH2O (n = 4) (p = 0.32), respectively. There was no correlation between osmolality and ICP, BMI, age and body height, respectively. Mean CSF osmolality was 270 mmol/kg (± 1 SE, 95% confidence interval 267–272) for both patients and controls. Conclusions: CSF osmolality was normal in patients with IIH, and there was no relation to treatment, ICP, BMI, age and body height. Mean CSF osmolality was 270 mmol/kg and constitutes a reference for future studies. Changes in CSF osmolality are not responsible for development of IIH. Other underlying pathophysiological mechanisms must be searched. [ABSTRACT FROM AUTHOR]

Idiopathic intracranial hypertension is a disorder characterised by raised intracranial pressure that predominantly affects young, obese women. Pathogenesis has not been fully elucidated, but several causal factors have been proposed. Symptoms can include headaches, visual loss, pulsatile tinnitus, and back and neck pain, but the clinical presentation is highly variable. Although few studies have been done to support evidence-based management, several recent advances have the potential to enhance understanding of the causes of the disease and to guide treatment decisions. Investigators of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) reported beneficial effects of acetazolamide in patients with mild visual loss. Studies have also established weight loss as an effective disease-modifying treatment, and further clinical trials to investigate new treatments are underway. The incidence of idiopathic intracranial hypertension is expected to increase as rates of obesity increase; efforts to reduce diagnostic delays and identify new, effective approaches to treatment will be key to meeting the needs of a growing number of patients. [ABSTRACT FROM AUTHOR]

Background: The kaolin induced obstructive hydrocephalus (OHC) model is well known for its ability to increase intracranial pressure (ICP) in experimental animals. Papilledema (PE) which is a predominant hallmark of elevated ICP in the clinic has not yet been studied in this model using high-resolution digital fundus microscopy. Further, the long-term effect on ICP and optic nerve head changes have not been fully demonstrated. In this study we aimed to monitor epidural ICP after induction of OHC and to examine changes in the optic disc. In addition, we validated epidural ICP to intraventricular ICP in this disease model.Method: Thirteen male Sprague-Dawley rats received an injection into the cisterna magna containing either kaolin-Ringer's lactate suspension (n = 8) or an equal amount of Ringer's lactate solution (n = 5). Epidural ICP was recorded post-operatively, and then continuously overnight and followed up after 1 week. The final epidural ICP value after 1 week was confirmed with simultaneous ventricular ICP measurement. Optic disc photos (ODP) were obtained preoperatively at baseline and after one week and were assessed for papilledema.Results: All animals injected with kaolin developed OHC and had significant higher epidural ICP (15.49 ± 2.47 mmHg) compared to control animals (5.81 ± 1.33 mmHg) on day 1 (p < 0.0001). After 1 week, the epidural ICP values were subsided to normal range in hydrocephalus animals and there was no significant difference in epidural ICP between the groups. Epidural ICP after 1 week correlated with the ventricular ICP with a Pearson's r = 0.89 (p < 0.0001). ODPs from both groups showed no signs of acute papilledema, but 5 out of 8 (62.5%) of the hydrocephalus animals were identified with peripapillary changes.Conclusions: We demonstrated that the raised ICP at day 1 in the hydrocephalus animals was completely normalized within 1 week and that epidural ICP measurements are valid method in this model. No acute papilledema was identified in the hydrocephalus animals, but the peripapillary changes indicate a potential gliosis formation or an early state of a growing papilledema in the context of lateral ventricle dilation and increased ICP. [ABSTRACT FROM AUTHOR]

Chronic cluster headache (CCH) often resists to prophylactic pharmaceutical treatments resulting in patients’ life damage. In this rare but pragmatic situation escalation to invasive management is needed but framing criteria are lacking. We aimed to reach a consensus for refractory CCH definition for clinical and research use. The preparation of the final consensus followed three stages. Internal between authors, a larger between all European Headache Federation members and finally an international one among all investigators that have published clinical studies on cluster headache the last five years. Eighty-five investigators reached by email. Proposed criteria were in the format of the International Classification of Headache Disorders III-beta (description, criteria, notes, comments and references). Following this evaluation eight drafts were prepared before the final. Twenty-four (28.2%) international investigators commented during two rounds. Refractory CCH is described in the present consensus as a situation that fulfills the criteria of ICHD-3 beta for CCH with at least three severe attacks per week despite at least three consecutive trials of adequate preventive treatments. The condition is rare, but difficult to manage and invasive treatments may be needed. The consensus addresses five specific clinical and paraclinical diagnostic criteria followed by three notes and specific comments. Although refractory CCH may be not a separate identity these specific diagnostic criteria should help clinicians and investigators to improve patient’s quality of life. [ABSTRACT FROM AUTHOR]

The article presents a review of existing literature to document oxygen's therapeutic effect on cluster headache (CH). A PubMed search was conducted which ended in 11 relevant studies, with six probing the efficacy of oxygen treatment and the other five focusing on hyperbaric oxygen treatment of two case studies. Topics discussed include the signs of CH, oxygen's mechanism of action and CH treatment alternatives, including normabaric oxygen treatment and hyperbaric oxygen (HBO) treatment.

Abstract: The existence of a trigeminocervical complex has been suggested based on animal data, but only indirect evidence exists in humans. We investigated the functional relationship between the trigeminal and the occipital region by stimulating one region and measuring electrical pain thresholds (EPTs) of the corresponding opposite region. This study consists of 2 single-blinded, randomised protocols. Forty healthy participants were recruited in the propaedeutic protocol I. Electrical pain thresholds were measured on the V1 and the greater occipital nerve (GON) dermatome bilaterally as well as on the left forearm longitudinally before and after application of topical capsaicin. Protocol II was then online preregistered, and, additionally, the ipsilateral trigeminal dermatomes V2 and V3 were tested. Greater occipital nerve stimulation increased the EPT ipsilateral at V1 after 20 minutes (P = 0.006) compared with baseline, whereas trigeminal stimulation increased the EPT at the ipsilateral (P = 0.023) as well as the contralateral GON (P = 0.001) after capsaicin application. Protocol II confirmed these results and additionally showed that GON stimulation with capsaicin increased EPTs ipsilateral at all 3 trigeminal dermatomes and that trigeminal stimulation on V1 led to an ipsilateral increase of EPTs at GON, V2, and V3. Our data suggest a strong functional interplay between the trigeminal and occipital system in humans. The fact that the stimulation of one of these dermatomes increases the EPT of the respective other nerve could be explained by segmental inhibition on the brainstem level. [ABSTRACT FROM AUTHOR]

The article discusses the rationale, methods, and development of neurostimulation as a treatment for intractable chronic cluster headache. It states that the rationale behind the therapies is according to the emerging evidence from hormonal, clinical, and neuroimaging studies. It says that the stated therapies require weeks to months of stimulation for the occurrence of a prophylactic effect suggesting brain plasticity as a potential mechanism.

Objective: To investigate the safety and efficacy of intranasal ketamine for the treatment of a single cluster headache (CH) attack. Background: Acute treatment options for patients with CH who have an insufficient response to oxygen and triptans are limited. Intranasal ketamine has anecdotally been successful in treating a CH attack. Methods: We conducted an open‐label pilot study enrolling 23 patients with chronic CH (International Classification of Headache Disorders, 3rd edition), and of these, 20 patients treated a single CH attack with intranasal ketamine. Under in‐hospital observation, patients received 15 mg of intranasal ketamine every 6 min a maximum of five times. The primary endpoint was a 50% reduction in pain intensity within 15 min after initiating treatment. Results: The primary endpoint was not met; 15 min after the first ketamine administration, the mean reduction in pain intensity was 1.1 (95% confidence interval [CI]: −0.6 to 2.7, p = 0.188) on the numeric rating scale (NRS), equivalent to a 15% reduction in pain intensity. However, 30 min after the first application, the pain intensity was reduced by 59% on an 11‐point NRS (mean difference: 4.3, 95% CI: 2.4–6.2, p < 0.001, N = 16) and 11 out of 16 (69%) scored 4 or below on the NRS. Four patients received rescue medication 15 min after the first ketamine application and were therefore excluded from the analysis at 30 min. Half of the patients preferred ketamine to oxygen and/or sumatriptan injection. No serious adverse events were identified during the trial. Conclusion: Intranasal ketamine may be an effective acute treatment for CH at 30 min but should be tested in a larger controlled design. Patients and physicians should be conscious of the abuse potential of ketamine. [ABSTRACT FROM AUTHOR]

Paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever. APAP is widely used by pregnant women as governmental agencies, including the FDA and EMA, have long considered APAP appropriate for use during pregnancy when used as directed. However, increasing experimental and epidemiological research suggests that prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders. Here we summarize this evidence and call for precautionary action through a focused research effort and by increasing awareness among health professionals and pregnant women. APAP is an important medication and alternatives for treatment of high fever and severe pain are limited. We recommend that pregnant women should be cautioned at the beginning of pregnancy to: forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time. We suggest specific actions to implement these recommendations. This Consensus Statement reflects our concerns and is currently supported by 91 scientists, clinicians and public health professionals from across the globe. [ABSTRACT FROM AUTHOR]

Background: Human and animal models suggest that central sensitisation plays a role in medication-overuse headache(MOH). We aimed to study pain perception in MOH patients before and a year after withdrawal.Methods: We examined pain perception in 35 MOH patients before and two, six and 12 months after detoxification. Forbaseline comparison, we tested 40 healthy controls. We measured cephalic and extra-cephalic pressure-pain thresholdsand supra-threshold pressure-pain scores and extra-cephalic pain thresholds, supra-threshold pain scores and temporalsummation for electrical stimulation.Results: Of the 35 patients, 21 patients completed the entire study and remained cured of MOH. Statistically significantdifferences between patients and healthy controls were found in cephalic pressure-pain thresholds (137.3 kPa vs. 170 kPa,p<0.05), extra-cephalic pressure pain thresholds (213.3 vs. 274.3 kPa, p<0.05), in cephalic supra-threshold pressurepainscores measured on a 100mm visual analogue scale (61 vs. 27 mm, p<0.05) and extra-cephalic supra-threshold painscores for electrical stimulation (19.0 vs. 10.0 mm, p<0.05). Cephalic supra-threshold pain scores decreased statisticallysignificantly from 50.3mm at baseline to 28.0mm at the 12-month follow-up. In contrast to controls, temporal summationwas not found in MOH patients before withdrawal, but after detoxification temporal summation normalised.Conclusion: The central nervous system is sensitised in patients with MOH. For the first time we demonstrate that thepain perception continues to normalise up to a year after detoxification. This emphasises the importance of detoxificationand follow-up to prevent relapse. [ABSTRACT FROM AUTHOR]

Background: Evidence for optimal medication-overuse headache treatment is lacking. Some experts suggest reduced symptomatic medication with prophylactics from the start of withdrawal, while others suggest a two-month drug-free period with multidisciplinary education.Aim: To examine the acceptability, feasibility and outcome of these two regimes in a non-randomised open-label study.Methods: Patients able to undergo outpatient detoxification, with medication-overuse headache that had previously been unsuccessfully treated by specialists and without significant co-morbidities were treated with (A) individual withdrawal with restricted symptomatic medication and prophylactics from Day 1 or (B) a two-month drug-free period and multidisciplinary education in groups. All patients received close one-year follow-up.Results: Eighty-six of 98 patients completed follow-up. Both treatments proved highly effective—80.0% of Group A and 85.4% of Group B were cured of medication-overuse headache. Headache-frequency reduction was 40.2% in Group A and 38.4% in group B. In 48.9% of group A and 48.8% of group B, headache-frequency reduction was >50%. Programme B required fewer resources from the staff and only 61.9% of these patients needed prophylactics after two months compared with 84.8% in programme A.Conclusions: Both structured detoxification programmes proved highly effective with one-year close follow-up in previously treatment-resistant patients with medication-overuse headache. We suggest multidisciplinary education for patients in groups and delaying initiation of prophylactics until after the detoxification. [ABSTRACT FROM PUBLISHER]

Objective.- To evaluate the long-term efficacy of a structured, multidisciplinary treatment program in patients who had been treated unsuccessfully for medication overuse headache by specialists in an open-label design. Background.- Medication overuse headache is a common and disabling disease. Management is complicated by substantial treatment failure and relapse, and those who relapse and nonresponders to treatment are often excluded from studies on medication overuse headache. Methods.- Patients with medication overuse headache who had previously been unsuccessfully treated by specialists and referred to a specialized, tertiary headache centre were recruited. They underwent a structured 2-month detoxification program and were subsequently closely followed up for 10 months by a multidisciplinary team of physicians, nurses, physiotherapists, and psychologists. Results.- Eighty-six of 98 patients completed the study. Primary Outcome.- At 12-month follow-up, headache frequency was reduced by 39.3% ( P < .001), 71 patients (82.6%) remained cured of medication overuse, reduction in headache frequency of more than 50% occurred in 42 patients (48.8%), and 52 (60.5%) reverted to episodic headache. Both of these figures had increased significantly from month 2 to month 12 ( P < .001). Medication use was reduced by 62.8% ( P < .001). Conclusion.- Patients with medication overuse headache previously regarded treatment-resistant benefit considerably from multidisciplinary treatment in a structured detoxification program with close follow-up. [ABSTRACT FROM AUTHOR]

Tension-type headache (TTH) is the most prevalent primary headache disorder. We assessed the cross-sectional impact of TTH on health related quality of life (HRQoL) in a general population. We also examined the association of HRQoL scores with headache frequency, disability, medication overuse, poor self-rated health, psychiatric comorbidity, and pain sensitivity in individuals with TTH. A sample of 547 subjects completed a headache diagnostic interview, the SF-12 to calculate physical (PCS) and mental (MCS) health component scores, depression (major depression inventory [MDI]) and neuroticism (Eysenck Personality Questionnaire) measures. We defined the following headache diagnosis categories: pure TTH, pure migraine, and coexistent headache (TTH + migraine). Cases were further classified into chronic (≥15) or episodic (<15 headache days/month). Using generalized linear models (GLM) adjusted for age, sex and education, both PCS-12 and MCS-12 scores varied in groups distinguished by migraine and TTH status; scores were lower for individuals with coexistent headache (TTH + migraine; n=83), followed by pure TTH (n=97) and pure migraine (n=43) compared to the no headache group (n=324) (p≤0.001). In analyses considering chronicity, PCS-12 scores were lower in chronic coexistent headache followed by pure chronic TTH (CTTH), episodic migraine +/− episodic TTH (ETTH) and pure ETTH than in the no headache group (p≤0.001). MCS-12 scores were lower in pure CTTH, followed by chronic coexistent headache, episodic migraine +/− ETTH and pure ETTH compared to the no headache group (p≤0.001). Multiple regression models showed that in TTH, lower PCS-12 scores were associated with age (p=0.04), female sex (p=0.02), and poor self-rated health (p≤0.001). Lower MCS-12 scores in TTH were associated with depression (p≤0.001). In a population sample, TTH, and to higher degree CTTH, are associated with decreased HRQoL. [ABSTRACT FROM AUTHOR]

Background: Although the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical trials of neuromodulation devices. In recognition of the distinct needs and challenges associated with their assessment in controlled trials, the Committee provides these recommendations for optimizing the design and conduct of controlled trials of neuromodulation devices for the acute and/or preventive treatment of migraine.Methods: An international group of headache scientists and clinicians with expertise in neuromodulation evaluated clinical trials involving neuromodulation devices that have been published since 2000. The Clinical Trials Committee incorporated findings from this expert analysis into a new guideline for clinical trials of neuromodulation devices for the treatment of migraine.Results: Key terms were defined and recommendations provided relative to the assessment of neuromodulation devices for acute treatment in adults, preventive treatment in adults, and acute and preventive treatment in children and adolescents. Ethical and administrative responsibilities were outlined, and a bibliography of previous research involving neuromodulation devices was created.Conclusions: Adoption of these recommendations will improve the quality of evidence regarding this important area in migraine treatment. [ABSTRACT FROM AUTHOR]

Objective: Identifying common genetic variants that confer genetic risk for cluster headache.Methods: We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses.Results: An association was found with cluster headache for 4 independent loci (r2  < 0.1) with genomewide significance (p < 5 × 10-8 ), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33-1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37-1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26-1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r2  = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients.Interpretation: This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203-216. [ABSTRACT FROM AUTHOR]

Background: Combined withdrawal and early preventive medication was the most effective treatment for medication overuse headache (MOH) within the first 6 months in a previous study, but results from a longer follow‐up period are lacking. Objective: (1) To measure the efficacy at 1 year of three different treatment approaches to MOH; (2) to compare withdrawal and early preventives (W+P), preventives with potential withdrawal therapy after 6 months (P+pW), and withdrawal with delayed potential preventives (W+pP); and (3) to identify predictors of chronic headache after 1 year. Methods: Patients with MOH and migraine and/or tension‐type headache were randomly assigned to one of the three outpatient treatments. Headache calendar and questionnaires were filled out. Primary outcome was a reduction in headache days/month after 1 year. Results: Of 120 patients, 96 completed 1‐year follow‐up, and all were included in our analyses. Overall headache days/month were reduced from 24.6 (23.4–25.8) to 15.0 (13.0–17.0) (p < 0.0001), and only 11/96 patients (11%) relapsed. Reduction in monthly headache days was 10.3 days (95% CI: 6.7–13.9) in the W+P group, 10.8 days (95% CI: 7.6–14) in the P+pW group, and 7.9 days (95% CI: 5.1–10.7) in the W+pP group. No significant differences in treatment effect were seen between the three groups (p = 0.377). After 1 year, 39/96 (41%) had chronic headache. Predictors of chronic headache after 1 year were higher headache frequency (aOR 1.19; 1.09–1.31), more days with acute medication (aOR 1.11; 1.03–1.19), higher pain intensity (aOR 1.04; 1.01–1.08), and depression (aOR 4.7; 1.38–18.95), whereas higher self‐rated health (aOR 0.61; 0.36–0.97) and high caffeine consumption (aOR 0.40; 0.16–0.96) were predictors of a lower risk of chronic headache. No adverse events were reported. Conclusions: All treatment strategies proved effective in treating MOH with a low relapse rate. The W+P strategy leads to the fastest effect, confirming earlier treatment recommendations. Identification of predictors for chronic headache may help identify more complex patients. [ABSTRACT FROM AUTHOR]

Objective: This meta-analysis evaluates pressure pain sensitivity values in symptomatic and distant pain-free areas comparing individuals with tension-type headache to controls. Databases and data treatment: Electronic databases were searched for cross-sectional or prospective case-control studies comparing pressure pain thresholds in patients with tension-type headache to headache-free controls. Data were extracted by three reviewers. The methodological quality was assessed by the Newcastle-Ottawa Quality Assessment Scale. Meta-analyses of trigeminal, extra-trigeminal (neck) and distant pain-free areas in tension-type headache were compared to headache-free controls. Frequency of tension-type headache and gender were taken into account. Results: Twenty studies were included. Patients with tension-type headache exhibited lower pressure pain thresholds than headache-free controls: Trigeminal (MD −49.11 kPa, 95% CI −66.05 to −32.17), cervical spine (MD −88.17 kPa, 95% CI −108.43 to −67.92) and distant pain-free areas (MD −98.43 kPa, 95% CI −136.78 to −60.09). Differences were significant for chronic, episodic, and mixed episodic and chronic tension-type headache within the trigeminal and neck (symptomatic areas), but only significant for chronic tension-type headache (MD −102.86, 95% CI −139.47 to −66.25 kPa) for distant pain-free areas. In general, women had lower pressure pain thresholds than men. The methodological quality ranged from fair (45%) to good (40%). The results showed a high heterogeneity and publication bias. Conclusion: This first meta-analysis addressing pressure pain thresholds differences in symptomatic and distant pain-free areas between patients with tension-type headache and controls found low to moderate evidence supporting the presence of pressure pain hypersensitivity in the trigeminal and neck areas in tension-type headache in comparison with headache-free controls. Sensitivity to pressure pain was widespread only in chronic, not episodic, tension-type headache (moderate evidence). Registration number: https://doi.org/10.17605/OSF.IO/R29HY [ABSTRACT FROM AUTHOR]

Background: Previously reported increases in serum levels of vasodilating neuropeptides pituitary adenylate cyclase-activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) during attacks of cluster headache could indicate their involvement in cluster headache attack initiation. We investigated the attack-inducing effects of PACAP38 and vasoactive intestinal peptide in cluster headache, hypothesising that PACAP38, but not vasoactive intestinal peptide, would induce cluster-like attacks in episodic active phase and chronic cluster headache patients. Methods: In a double-blind crossover study, 14 episodic cluster headache patients in active phase, 15 episodic cluster headache patients in remission phase and 15 chronic cluster headache patients were randomly allocated to receive intravenous infusion of PACAP38 (10 pmol/kg/min) or vasoactive intestinal peptide (8 pmol/kg/min) over 20 min on two study days separated by at least 7 days. We recorded headache intensity, incidence of cluster-like attacks, cranial autonomic symptoms and vital signs using a questionnaire (0–90 min). Results: In episodic cluster headache active phase, PACAP38 induced cluster-like attacks in 6/14 patients and vasoactive intestinal peptide induced cluster-like attacks in 5/14 patients (p = 1.000). In chronic cluster headache, PACAP38 and vasoactive intestinal peptide both induced cluster-like attacks in 7/15 patients (p = 0.765). In episodic cluster headache remission phase, neither PACAP38 nor vasoactive intestinal peptide induced cluster-like attacks. Conclusions: Contrary to our hypothesis, attack induction was lower than expected and roughly equal by PACAP38 and vasoactive intestinal peptide in episodic active phase and chronic cluster headache patients, which contradicts the PAC1-receptor as being solely responsible for attack induction. Trial registration: clinicaltrials.gov (identifier NCT03814226). [ABSTRACT FROM AUTHOR]

Objective: Neuronal‐specific enolase (NSE) and protein S100B have gained considerable interest as the markers of CNS injury, glial cell activation, and/or blood‐brain barrier (BBB) disruption. No studies have investigated NSE and S100B in cluster headache (CH), but these biomarkers could contribute to the understanding of CH. Methods: Patients with episodic CH in bout (eCHa), in remission (eCHr), and chronic CH (cCH) were included in this randomized, double‐blind, placebo‐controlled, 2‐way cross‐over provocation study carried out at the Danish Headache Center. The primary endpoints included (1) differences of NSE and S100B in between groups (eCHa, eCHr, and cCH) at baseline; (2) differences over time in plasma concentrations of NSE and S100B between patient developing an attack and those who did not; (3) differences in plasma concentrations over time of NSE and S100B between active day and placebo day. Baseline findings were compared to the historical data on migraine patients and healthy controls and presented with means ± SD. Results: Nine eCHa, 9 eCHr, and 13 cCH patients completed the study and blood samples from 11 CGRP‐induced CH attacks were obtained. There were no differences in NSE levels between CH groups at baseline, but CH patients in active disease phase had higher levels compared with 32 migraine patients (9.1 ± 2.2 µg/L vs 6.0 ± 2.2 µg/L, P <.0001) and 6 healthy controls (9.1 ± 2.2 µg/L vs 7.3 ± 2.0 µg/L, P =.007). CGRP‐infusion caused no NSE changes and, but a slight, non‐significant, increase in NSE was seen in patients who reported a CGRP‐induced CH attack (2.39 µg/L, 95% Cl [−0.26, 3.85], P =.061). At baseline S100B levels in eCHa patients were higher compared to cCH patients (0.06 ± 0.02 µg/L vs 0.04 ± 0.02 µg/L, P =.018). Infusion of CGRP and CGRP‐induced attacks did not change S100B levels. Apart from induced CH‐attacks no other adverse events were noted. Conclusions: At baseline eCHa patients had higher S100B plasma levels than cCH patients and there was a slight, however not significant, NSE increase in response to CGRP‐induced CH attack. Our findings suggest a possible role of an ictal activation of glial cells in CH pathophysiology, but further studies are warranted. [ABSTRACT FROM AUTHOR]

Background: Elevated intracranial pressure (ICP) is observed in association with a range of brain disorders. There is limited insight into the regulatory mechanisms of ICP under physiological conditions, and consequently also under pathological conditions. Thereby, to understand the mechanisms underlying ICP dynamics, precise, valid and long-term ICP recordings are of importance in the preclinical setting. Herein, we used a novel telemetric system for ICP recordings which allowed for long-term recordings in freely-moving rats. The aim was to investigate ICP dynamics under different physiological states and investigate how factors such as surgery/recovery, body position, light–dark, co-housing, weight and anesthesia may influence ICP and its waveforms. Methods: A telemetric device was implanted epidurally in rats and signals were recorded continuously for up to 50 days (n = 14). Recording was divided into three experimental periods: a surgical recovery period (RP), a physiological period (PP) and an experimental period (EP). Histology was performed to study the morphology of implanted rats and non-implanted rats (n = 17). Results: For the first time, we can demonstrate continuous ICP recordings in freely-moving and co-housed rats for up to 50 days with a high degree of stability. The mean ICP in the recording periods were; RP: 3.2 ± 0.6 mmHg, PP: 5.0 ± 0.6 mmHg and EP: 4.7 ± 0.6 mmHg. In the RP, the ICP was significantly lower compared to the PP (P = 0.0034). Significant light–dark difference in ICP with 21% increase in respiratory slow-wave amplitude was observed in the co-housed animals but not in single-housed animals. The ICP signal was raised during the dark period relative to the light (Δ0.3 ± 0.07 mmHg, P = 0.0043). Administration of anesthesia gave a short-term increase in ICP followed by a significant decrease in ICP. No signs of tissue damage or inflammation were found in the implanted brains. Conclusions: ICP dynamics were influenced by several factors such as, use of anesthesia, light–dark difference and housing conditions. Our study demonstrates the importance of performing ICP physiological measurements in freely-moving animals. This has significant implications for moving the preclinical research field forward in order to properly study ICP physiology during disease development and to explore drug targets for alleviating increased ICP. [ABSTRACT FROM AUTHOR]

Objective and Background: The diagnostic criteria of episodic and chronic cluster headache (cCH) were recently modified, yet pathophysiological differences between the two are still unclear. The aim of this cross‐sectional study is to identify and characterize other differences between episodic and cCH. Methods: Data from a retrospective, questionnaire‐ and interview‐based study were analyzed with a focus on associated factors including traumatic head injury (THI), familial history, and change of phenotype. Attack patterns were analyzed using Gaussian and spectral modeling. Results: 400 patients and 200 controls participated. A positive family history was more prevalent in chronic than episodic cluster headache (eCH) (34/146 (23%) vs 33/253 (13%), respectively, P =.008). A history of THI was more common in patients than controls (173/400 (43%) vs 51/200 (26%), respectively, P <.0001) and in chronic compared to eCH (77/146 (53%) vs 96/253 (37%), respectively, P =.004). Patients with a positive family history had a unique diurnal attack pattern with twice the risk of nocturnal attacks as patients who did not report family history. Patients reporting phenotype change had a chronobiological fingerprint similar to the phenotype they had experienced a transition into. A higher attack frequency in chronic patients was the only difference in symptom manifestation across all analyzed subgroups of patients. Conclusions: cCH is associated with a positive family history and THI. In familial CH, a peak in nocturnal chronorisk may implicate genes involved in diurnal‐, sleep‐ and homeostatic regulation. The stereotypical nature of the CH attacks themselves is confirmed and differences between subgroups should be sought in other characteristics. [ABSTRACT FROM AUTHOR]

Aim: To investigate the influence of clinical and demographic features on diagnostic delay in cluster headache patients, in order to discuss diagnostic pitfalls and raise disease awareness.Methods: A large, well-characterized cohort of 400 validated cluster headache patients from the Danish Cluster Headache Survey, diagnosed according to ICHD-II, were investigated. ANOVA was applied to investigate differences in diagnostic delay between groups. Selected independent variables were assessed in relation to diagnostic delay using a gamma regression model.Results: Diagnostic delay was significantly reduced for each decade of cluster headache onset from 1950-2010 (p < 0.001). Onset after 1990 was associated with shorter diagnostic delay (OR = 0.28, p < 0.001), whereas attack duration > 180 minutes (OR = 1.62, p < 0.034), migraine-like features (OR = 1.30, p < 0.043) and nocturnal attacks (OR = 1.39, p < 0.021) were associated with prolonged diagnostic delay. Further, diagnostic delay decreased with age of onset (age < 20: 13.8 years, age 20-40: 5.4 years and age > 40: 2.1 years, p < 0.001).Conclusion: Diagnostic delay was reduced for every decade investigated, whereas some atypical cluster headache features were associated with prolonged diagnostic delay. Better medical education and more disease awareness are needed to prevent misdiagnosis and prolonged diagnostic delay. [ABSTRACT FROM AUTHOR]

Objective: A evaluation of the effect of verapamil and other calcium channel blockers in cluster headache (CH) treatment and an investigation of possible effect mechanisms. Background: Verapamil has been used in the prevention of CH for almost 3 decades, however, the mode of action and therapeutic target is still unknown. Methods: A Pubmed search was conducted: "Verapamil"[Mesh] and "Cluster Headache"[Mesh]. We identified 5 relevant studies for CH. Publications were included if they made a substantial contribution within 3 prespecified areas: Efficacy (randomized controlled‐trials or open labels studies), safety, and mechanism of effect. Results: Clinical effect: Clinical preventive treatment of CH with verapamil is based on 2 randomized controlled studies and 3 open‐label studies. In total, 183 CH patients participated. Verapamil 360 mg/day was used in both controlled studies. Half of the chronic patients experienced benefit from verapamil treatment and the attack burden of episodic patients was, on average, reduced by 1 attack/day. Open‐label studies support a dose‐dependent level of efficacy. Mechanism of effect: Human and animal studies indicate that verapamil may exert its effect by modulating circadian rhythms, perhaps in central pacemakers, and/or by affecting release of calcitonin gene‐related peptide. Conclusion: Verapamil appears to be an effective prophylactic drug in the treatment of CH and despite the scarcity of controlled trials, it is still the drug of choice. A chronotherapeutic approach might increase the effect. More basic and pharmacokinetic research is needed before the mechanism can be fully understood. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide in cluster headache, we measured these vasoactive peptides interictally and during experimentally induced cluster headache attacks.Methods: We included patients with episodic cluster headache in an active phase (n = 9), episodic cluster headache patients in remission (n = 9) and patients with chronic cluster headache (n = 13). Cluster headache attacks were induced by infusion of calcitonin gene-related peptide (1.5 µg/min) in a randomized, double-blind, placebo controlled, two-way cross-over study. At baseline, we collected interictal blood samples from all patients and during 11 calcitonin gene-related peptide-induced cluster headache attacks.Results: At baseline, episodic cluster headache patients in remission had higher plasma levels of calcitonin gene-related peptide, 100.6 ± 36.3 pmol/l, compared to chronic cluster headache patients, 65.9 ± 30.5 pmol/l, ( p = 0.011). Episodic cluster headache patients in active phase had higher PACAP38 levels, 4.0 ± 0.8 pmol/l, compared to chronic cluster headache patients, 3.3 ± 0.7 pmol/l, ( p = 0.033). Baseline levels of vasoactive intestinal polypeptide did not differ between cluster headache groups. We found no attack-related increase in calcitonin gene-related peptide, PACAP38 or vasoactive intestinal polypeptide levels during calcitonin gene-related peptide-induced cluster headache attacks.Conclusions: This study suggests that cluster headache disease activity is associated with alterations of calcitonin gene-related peptide expression. Future studies should investigate the potential of using calcitonin gene-related peptide measurements in monitoring of disease state and predicting response to preventive treatments, including response to anti-calcitonin gene-related peptide monoclonal antibodies. [ABSTRACT FROM AUTHOR]