Publications by authors named "Rigmor H Jensen"

66 Publications

Experimental evidence of a functional relationship within the brainstem trigeminocervical complex in humans.

Pain 2021 Jul 28. Epub 2021 Jul 28.

Department of Systems Neuroscience, University Medical Center Eppendorf, Hamburg, Germany Department of Neurology, Rigshospitalet-Glostrup, Danish Headache Center, University of Copenhagen, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1097/j.pain.0000000000002417DOI Listing
July 2021

Treatment of medication overuse headache: Effect and predictors after 1 year-A randomized controlled trial.

Headache 2021 Jul 29;61(7):1112-1122. Epub 2021 Jul 29.

Danish Headache Center, Rigshospitalet-Glostrup, Valdemar Hansens Vej 5, Glostrup, 2600, Denmark.

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.
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http://dx.doi.org/10.1111/head.14177DOI Listing
July 2021

Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache.

Ann Neurol 2021 Aug 14;90(2):203-216. Epub 2021 Jul 14.

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

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 (r  < 0.1) with genomewide significance (p < 5 × 10 ), 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 (r  = 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.
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http://dx.doi.org/10.1002/ana.26146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362054PMC
August 2021

Guidelines of the International Headache Society for clinical trials with neuromodulation devices for the treatment of migraine.

Cephalalgia 2021 May 14:3331024211010413. Epub 2021 May 14.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

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.
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http://dx.doi.org/10.1177/03331024211010413DOI Listing
May 2021

Reference programme: diagnosis and treatment of headache disorders and facial pain. Danish Headache Society, 3rd edition, 2020.

J Headache Pain 2021 Apr 8;22(1):22. Epub 2021 Apr 8.

Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Valdemar Hansen Vej 5, 2600, Glostrup, Denmark.

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.
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http://dx.doi.org/10.1186/s10194-021-01228-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034101PMC
April 2021

Tension-type headache.

Nat Rev Dis Primers 2021 03 25;7(1):24. Epub 2021 Mar 25.

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.

Tension-type headache (TTH) is the most prevalent neurological disorder worldwide and is characterized by recurrent headaches of mild to moderate intensity, bilateral location, pressing or tightening quality, and no aggravation by routine physical activity. Diagnosis is based on headache history and the exclusion of alternative diagnoses, with clinical criteria provided by the International Classification of Headache Disorders, third edition. Although the biological underpinnings remain unresolved, it seems likely that peripheral mechanisms are responsible for the genesis of pain in TTH, whereas central sensitization may be involved in transformation from episodic to chronic TTH. Pharmacological therapy is the mainstay of clinical management and can be divided into acute and preventive treatments. Simple analgesics have evidence-based effectiveness and are widely regarded as first-line medications for the acute treatment of TTH. Preventive treatment should be considered in individuals with frequent episodic and chronic TTH, and if simple analgesics are ineffective, poorly tolerated or contraindicated. Recommended preventive treatments include amitriptyline, venlafaxine and mirtazapine, as well as some selected non-pharmacological therapies. Despite the widespread prevalence and associated disability of TTH, little progress has been made since the early 2000s owing to a lack of attention and resource allocation by scientists, funding bodies and the pharmaceutical industry.
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http://dx.doi.org/10.1038/s41572-021-00257-2DOI Listing
March 2021

Health-related quality of life in tension-type headache: a population-based study.

Scand J Pain 2021 Jan 22. Epub 2021 Jan 22.

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.

Objectives: 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.

Methods: 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).

Results: 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).

Conclusions: In a population sample, TTH, and to higher degree CTTH, are associated with decreased HRQoL.
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http://dx.doi.org/10.1515/sjpain-2020-0166DOI Listing
January 2021

Dependence-like behaviour in patients treated for medication overuse headache: A prospective open-label randomized controlled trial.

Eur J Pain 2021 04 7;25(4):852-861. Epub 2021 Jan 7.

Danish Headache Centre, Rigshospitalet, Glostrup, Denmark.

Background: Dependence-like behaviour may complicate withdrawal and increase risk of relapse of medication overuse headache (MOH). The most effective treatment for reducing dependence-like behaviour is unknown.

Objectives: To compare patient-reported outcomes among three treatment strategies for MOH. The primary outcome was change in Severity of Dependence Scale (SDS) score from baseline to 6 months.

Methods: Patients with MOH were randomized to (1) withdrawal combined with preventive medication from start (W+P), (2) preventive medication without withdrawal (P), or (3) withdrawal with optional preventive medication 2 months after withdrawal (W). At baseline, 2, and 6 months, patients filled out SDS (used for measurements of dependence-like behaviour and treatment feasibility), Headache Under-Response of Treatment (HURT) and WHO Quality of Life BREF questionnaires.

Results: Out of 120 patients with MOH, 100 completed the 6-month follow-up and filled out questionnaires. The W+P arm was the most effective in treating MOH. After 6 months, the SDS score was reduced by 3.69 (95% CI 3.23-4.49) in the W+P arm, by 3.19 (95% CI 2.43-3.96) in the W arm, and by 1.65 (95% CI 0.96-2.33) in the P arm (p = 0.04). At baseline and after 2 months, the P arm was considered the most feasible treatment, but at 6-month follow-up, there was no difference in feasibility score, change in HURT score, or quality of life.

Conclusions: Dependence-like behaviour was reduced most in the two withdrawal arms. Withdrawal combined with preventive medication is recommended for the treatment of MOH.

Significance: Withdrawal combined with preventive medication from start is the treatment strategy that reduces dependence-like behaviour the most in MOH patients. Patients initially considered preventive treatment without withdrawal as the most feasible treatment. However, no difference in feasibility between the three arms was found at 6-month follow-up. Withdrawal combined with preventive medication is recommended for treatment of MOH.
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http://dx.doi.org/10.1002/ejp.1715DOI Listing
April 2021

The effect of pituitary adenylate cyclase-activating peptide-38 and vasoactive intestinal peptide in cluster headache.

Cephalalgia 2020 11 22;40(13):1474-1488. Epub 2020 Sep 22.

Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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 ( = 1.000). In chronic cluster headache, PACAP38 and vasoactive intestinal peptide both induced cluster-like attacks in 7/15 patients ( = 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 PAC-receptor as being solely responsible for attack induction. clinicaltrials.gov (identifier NCT03814226).
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http://dx.doi.org/10.1177/0333102420940689DOI Listing
November 2020

Evidence of localized and widespread pressure pain hypersensitivity in patients with tension-type headache: A systematic review and meta-analysis.

Cephalalgia 2021 02 22;41(2):256-273. Epub 2020 Sep 22.

Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, Denmark.

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). https://doi.org/10.17605/OSF.IO/R29HY.
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http://dx.doi.org/10.1177/0333102420958384DOI Listing
February 2021

S100B and NSE in Cluster Headache - Evidence for Glial Cell Activation?

Headache 2020 Sep 16;60(8):1569-1580. Epub 2020 Jun 16.

Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1111/head.13864DOI Listing
September 2020

Long-term monitoring of intracranial pressure in freely-moving rats; impact of different physiological states.

Fluids Barriers CNS 2020 Jun 9;17(1):39. Epub 2020 Jun 9.

Danish Headache Center, Department of Neurology, Glostrup Research Institute, Rigshospitalet-Glostrup, University of Copenhagen, Nordstjernevej 42, 2600, Glostrup, Denmark.

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.
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http://dx.doi.org/10.1186/s12987-020-00199-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285467PMC
June 2020

Guide to preclinical models used to study the pathophysiology of idiopathic intracranial hypertension.

Eye (Lond) 2020 08 2;34(8):1321-1333. Epub 2020 Jan 2.

Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.

Idiopathic intracranial hypertension (IIH) is characterised by raised intracranial pressure (ICP) and papilloedema in the absence of an identifiable secondary cause typically occurring in young women with obesity. The impact is considerable with the potential for blindness, chronic disabling headaches, future risk of cardiovascular disease and marked healthcare utilisation. There have been marked advances in our understanding the pathophysiology of IIH including the role of androgen excess. Insight into pathophysiological underpinnings has arisen from astute clinical observations, studies, and an array of preclinical models. This article summarises the current literature pertaining to the pathophysiology of IIH. The current preclinical models relevant to gaining mechanistic insights into IIH are then discussed. In vitro and in vivo models which study CSF secretion and the effect of potentially pathogenic molecules have started to glean important mechanistic insights. These models are also useful to evaluate novel therapeutic targets to abrogate CSF secretion. Importantly, in vitro CSF secretion assays translate into relevant changes in ICP in vivo. Models of CSF absorption pertinent to IIH, are less well established but highly relevant and of future interest. There is no fully developed in vivo model of IIH but this remains an area of importance. Progress is being made to improve our understanding of the underlying aetiology in IIH including the characterisation of disease biomarkers and their mechanistic role in driving disease pathology. Preclinical models, used to evaluate IIH mechanisms are yielding important mechanistic insights. Further work to refine these techniques will provide translatable insights into disease aetiology.
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http://dx.doi.org/10.1038/s41433-019-0751-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376028PMC
August 2020

Episodic and Chronic Cluster Headache: Differences in Family History, Traumatic Head Injury, and Chronorisk.

Headache 2020 03 23;60(3):515-525. Epub 2019 Dec 23.

The Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, Glostrup, Denmark.

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.
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http://dx.doi.org/10.1111/head.13730DOI Listing
March 2020

Medication-overuse headache: The effect of a patient educational programme-A randomized controlled trial.

Eur J Pain 2020 02 21;24(2):435-447. Epub 2019 Nov 21.

Research Unit of Health Sciences, University Hospital of Southern Denmark, Esbjerg, Denmark.

Background: Little is known about the effects of non-pharmacological interventions among medication-overuse headache (MOH) patients, although non-pharmacological approaches combined with pharmacological treatment are recommended. The objective was to evaluate the effect of an educational programme as an add-on to standard treatment.

Methods: Medication-overuse headache patients were randomized (1:1) in a single-centre setting to standard treatment with 12 weeks of education (I-group) versus standard treatment (C-group). The primary outcome was measurement of reduction in headache days/last month at 9 months' follow-up. Secondary outcomes were headache intensity, acute medication intake, bothersomeness, disability, physical activity and patient satisfaction. The between-group differences were analysed using a mixed-effects model for repeated measurements with a between group factor (I-group vs. C-group) and a time factor (baseline, 4 and 9 months).

Results: Ninety-eight patients were randomized (I-group: n = 48, C-group: n = 50), with 40 and 39 patients completing the study, respectively. Intention-to-treat analyses showed that both groups experienced statistically significant reductions in headache days/last month (I-group: -4 ± 6 days (95% CI 2.47; 5.95), p < .001) versus C-group: -4 ± 9 days ([95% CI 1.53; 6.79], p = .003), but there were no significant differences between groups (mean ± SE):Δ: 0.7 days ([95% CI, -2.50; 3.93], p = .66). At follow-up, 85% from the I-group and 86% from C-group, no longer fulfilled the criteria for MOH.

Conclusion: The compliance rate was high, indicating that patients were motivated for receiving education, but we found no additional benefits of adding an educational programme to standard treatment. Future research focusing on the MOH complexity, group heterogeneity, duration and content of educational programmes is warranted.

Significance: Randomized controlled trials (RCTs) of non-pharmacological intervention such as patient educational programmes are of great importance, as this approach is common in the clinical practice. Medication-overuse headache (MOH) is a heterogenetic patient group, which must be taken into account when conducting RCTs of non-pharmacological interventions. An educational programme based on Motivational Interviewing is well-tolerated among MOH patients, however, no superior effects were found from adding the educational programme to standard treatment versus standard treatment alone.
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http://dx.doi.org/10.1002/ejp.1500DOI Listing
February 2020

Verapamil and Cluster Headache: Still a Mystery. A Narrative Review of Efficacy, Mechanisms and Perspectives.

Headache 2019 09 24;59(8):1198-1211. Epub 2019 Jul 24.

Department of Neurology, Danish Headache Center, Rigshospitalet-Glostrup, Glostrup, Denmark.

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.
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http://dx.doi.org/10.1111/head.13603DOI Listing
September 2019

Diagnostic delay of cluster headache: A cohort study from the Danish Cluster Headache Survey.

Cephalalgia 2020 01 10;40(1):49-56. Epub 2019 Jul 10.

Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, University of Copenhagen, Glostrup, Denmark.

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 ( < 0.001). Onset after 1990 was associated with shorter diagnostic delay (OR = 0.28,  < 0.001), whereas attack duration > 180 minutes (OR = 1.62,  < 0.034), migraine-like features (OR = 1.30,  < 0.043) and nocturnal attacks (OR = 1.39,  < 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,  < 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.
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http://dx.doi.org/10.1177/0333102419863030DOI Listing
January 2020

Personality traits in migraine and medication-overuse headache: A comparative study.

Acta Neurol Scand 2019 Aug 15;140(2):116-122. Epub 2019 May 15.

Research Unit of Health Science, Hospital of South West Jutland, Esbjerg, Denmark.

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.
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http://dx.doi.org/10.1111/ane.13111DOI Listing
August 2019

Calcitonin-gene related peptide and disease activity in cluster headache.

Cephalalgia 2019 04 9;39(5):575-584. Epub 2019 Mar 9.

1 Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1177/0333102419837154DOI Listing
April 2019

The influence of lifestyle and gender on cluster headache.

Curr Opin Neurol 2019 06;32(3):443-448

Department of Neurology, Danish Headache Center, University of Copenhagen, Copenhagen, Denmark.

Purpose Of Review: Cluster headache is by many regarded as a males' disorder that is often accompanied by an unhealthy lifestyle. We aimed to study the influence of sex and lifestyle factors on clinical presentation, the diagnostic process and management.

Recent Findings: Overall, the clinical presentation of cluster headache in both sexes was similar; however, chronic cluster headache may occur more frequently in women than in men. Misdiagnosis was most prevalent in women and more women than men were not correctly diagnosed until seen in a highly specialized center. In relation to lifestyle, smoking prevalence remains very high and some studies suggest that obesity and use of illegal drugs may be pronounced as well. In contrast to previous beliefs, recent findings on alcohol consumption report a lower use in patients than in controls. Overall, men and to some extent chronic patients were more prone to some unhealthy lifestyle factors than women and episodic patients.

Summary: Despite an overall similar clinical presentation in men and women, the diagnostic process was more problematic for women in the form of more frequent misdiagnosis and failure to diagnose women in the primary and secondary sectors. Unhealthy lifestyle factors are prevalent in cluster headache and may ultimately have consequences for the management of the disease.
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http://dx.doi.org/10.1097/WCO.0000000000000680DOI Listing
June 2019

Circulating nociceptin and CGRP in medication-overuse headache.

Acta Neurol Scand 2019 Mar 11;139(3):269-275. Epub 2018 Dec 11.

Department of Neurology, Rigshospitalet-Glostrup, Danish Headache Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Previous studies found low serum levels of nociceptin in migraine patients but high serum levels of calcitonin gene-related peptide (CGRP). CGRP can elicit migraine-like headache. Medication-Overuse Headache (MOH) often has migraine features and can mimic chronic migraine. We therefore hypothesized that as in migraine, serum levels of nociceptin would be lower and CGRP serum levels higher in MOH patients compared with those in healthy volunteers. We hypothesized that the serum levels would normalize after detoxification.

Methods: Seventeen MOH patients, hereof 70.6% with chronic migraine and MOH, and 30 sex and age matched headache-free controls were included. MOH patients underwent a 2-month outpatient detoxification program and after 6 months, 10 patients and 19 controls were retested. Blood samples were analyzed blinded.

Results: We found no differences in the levels of nociceptin and CGRP between MOH patients and controls (P = 0.65 and P = 0.59). The mean headache frequency reduction was 43% and 70% of patients reverted to episodic headache after 6 months, but the levels of nociceptin and CGRP were unchanged (P = 0.71 and P = 0.82).

Conclusion: In contrast to previous findings in migraine patients, we found normal serum levels of nociceptin and CGRP in MOH patients. Thus, we find no evidence that the increased headache frequency of MOH patients could be caused by altered nociceptin and CGRP levels. This underlines the importance of identifying medication overuse in chronic headache and treating the MOH.
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http://dx.doi.org/10.1111/ane.13053DOI Listing
March 2019

European headache federation guideline on idiopathic intracranial hypertension.

J Headache Pain 2018 Oct 8;19(1):93. Epub 2018 Oct 8.

Metabolic Neurology, Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, UK.

Background: Idiopathic Intracranial Hypertension (IIH) is characterized by an elevation of intracranial pressure (ICP no identifiable cause. The aetiology remains largely unknown, however observations made in a number of recent clinical studies are increasing the understanding of the disease and now provide the basis for evidence-based treatment strategies.

Methods: The Embase, CDSR, CENTRAL, DARE and MEDLINE databases were searched up to 1st June 2018. We analyzed randomized controlled trials and systematic reviews that investigate IIH.

Results: Diagnostic uncertainty, headache morbidity and visual loss are among the highest concerns of clinicians and patients in this disease area. Research in this field is infrequent due to the rarity of the disease and the lack of understanding of the underlying pathology.

Conclusions: This European Headache Federation consensus paper provides evidence-based recommendations and practical advice on the investigation and management of IIH.
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http://dx.doi.org/10.1186/s10194-018-0919-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755569PMC
October 2018

Neurostimulation for the treatment of chronic migraine and cluster headache.

Acta Neurol Scand 2019 Jan 29;139(1):4-17. Epub 2018 Oct 29.

Danish Headache Center, Rigshospital-Glostrup, Glostrup, Denmark.

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.
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http://dx.doi.org/10.1111/ane.13034DOI Listing
January 2019

Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial.

JAMA Neurol 2018 10;75(10):1187-1197

Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Importance: Signaling molecule calcitonin gene-related peptide (CGRP) induces migraine attacks and anti-CGRP medications abort and prevent migraine attacks. Whether CGRP provokes cluster headache attacks is unknown.

Objective: To determine whether CGRP induces cluster headache attacks in episodic cluster headache in active phase, episodic cluster headache in remission phase, and chronic cluster headache.

Design, Setting, And Participants: A randomized, double-blind, placebo-controlled, 2-way crossover study set at the Danish Headache Center, Rigshospitalet Glostrup, in Denmark. Analyses were intent to treat. Inclusion took place from December 2015 to April 2017. Inclusion criteria were diagnosis of episodic/chronic cluster headache, patients aged 18 to 65 years, and safe contraception in women. Exclusion criteria were a history of other primary headache (except episodic tension-type headache <5 days/mo), individuals who were pregnant or nursing; cardiovascular, cerebrovascular, or psychiatric disease; and drug misuse.

Interventions: Thirty-seven patients with cluster headaches received intravenous infusion of 1.5 μg/min of CGRP or placebo over 20 minutes on 2 study days.

Main Outcomes And Measures: Difference in incidence of cluster headache-like attacks, difference in area under the curve (AUC) for headache intensity scores (0 to 90 minutes), and difference in time to peak headache between CGRP and placebo in the 3 groups.

Results: Of 91 patients assessed for eligibility, 32 patients (35.2%) were included in the analysis. The mean (SD) age was 36 (10.7) years (range, 19-60 years), and the mean weight was 78 kg (range, 53-100 kg). Twenty-seven men (84.4%) completed the study. Calcitonin gene-related peptide induced cluster headache attacks in 8 of 9 patients in the active phase (mean, 89%; 95% CI, 63-100) compared with 1 of 9 in the placebo group (mean, 11%; 95% CI, 0-37) (P = .05). In the remission phase, no patients with episodic cluster headaches reported attacks after CGRP or placebo. Calcitonin gene-related peptide-induced attacks occurred in 7 of 14 patients with chronic cluster headaches (mean, 50%; 95% CI, 20-80) compared with none after placebo (P = .02). In patients with episodic active phase, the mean AUC from 0 to 90 minutes for CGRP was 1.903 (95% CI, 0.842-2.965), and the mean AUC from 0 to 90 minutes for the placebo group was 0.343 (95% CI, 0-0.867) (P = .04). In patients with chronic cluster headache, the mean AUC from 0 to 90 minutes for CGRP was 1.214 (95% CI, 0.395-2.033), and the mean AUC from 0 to 90 minutes for the placebo group was 0.036 (95% CI, 0-0.114) (P = .01). In the remission phase, the mean AUC from 0 to 90 minutes for CGRP was 0.187 (95% CI, 0-0.571), and the mean AUC from 0 to 90 minutes for placebo was 0.019 (95% CI, 0-0.062) (P > .99).

Conclusions And Relevance: Calcitonin gene-related peptide provokes cluster headache attacks in active-phase episodic cluster headache and chronic cluster headache but not in remission-phase episodic cluster headache. These results suggest anti-CGRP drugs may be effective in cluster headache management.

Trial Registration: ClinicalTrials.gov (NCT02466334).
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http://dx.doi.org/10.1001/jamaneurol.2018.1675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233850PMC
October 2018

Cluster headache is associated with unhealthy lifestyle and lifestyle-related comorbid diseases: Results from the Danish Cluster Headache Survey.

Cephalalgia 2019 02 22;39(2):254-263. Epub 2018 Jun 22.

2 Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet-Glostrup, University of Copenhagen, Glostrup, Denmark.

Aim: To compare the prevalence of unhealthy lifestyle factors and comorbid disorders in cluster headache patients with headache-free controls, in order to discuss pathophysiology and possible consequences.

Methods: Cluster headache patients from the Danish cluster headache survey aged 18-65 years, diagnosed according to ICHD-II, were compared to sex- and age-matched headache-free controls. Participants completed questionnaires and structured interviews.

Results: A total of 400 cluster headache patients and 200 controls participated. Patients had a more unhealthy lifestyle compared with controls in the form of current and current/former smoking (48.3% vs. 9.0%, p < 0.001 and 74.5% vs. 30.0%, p < 0.001, respectively), higher average alcohol intake per week (98.2 grams vs. 77.9 grams, p = 0.033) and BMI (26.1 vs. 24.2 kg/m, p < 0.001), whereas coffee and energy drink consumption was equally distributed. Further, lifestyle-related, psychiatric and pain-related diseases were much more prevalent in patients compared with controls, except for diabetes. Sub-group analyses revealed that current/former smokers had a worse clinical presentation than never smokers.

Conclusion: Unhealthy lifestyle factors and lifestyle-related diseases were more prevalent in cluster headache patients compared to controls. As lifestyle-related diseases might have serious consequences in the management of cluster headache, it is key to inform patients at an early time point about the possible risks of their lifestyle choices.
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http://dx.doi.org/10.1177/0333102418784751DOI Listing
February 2019

Topiramate is more effective than acetazolamide at lowering intracranial pressure.

Cephalalgia 2019 02 13;39(2):209-218. Epub 2018 Jun 13.

1 Metabolic Neurology, Metabolic Neurology, Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, UK.

Background: The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats.

Methods: We measured intracranial pressure in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate.

Results: At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% ( p = 0.0009) and 21% ( p = 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% ( p = 0.018), compared to 5% reduction with acetazolamide ( p = >0.999).

Conclusion: Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intracranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest.
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http://dx.doi.org/10.1177/0333102418776455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376637PMC
February 2019

The role of personality, disability and physical activity in the development of medication-overuse headache: a prospective observational study.

J Headache Pain 2018 May 25;19(1):39. Epub 2018 May 25.

The Research Unit of Health Science, Hospital of Southwest Jutland, Esbjerg and Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.

Background: Factors associated with development of medication-overuse headache (MOH) in migraine patients are not fully understood, but with respect to prevention, the ability to predict the onset of MOH is clinically important. The aims were to examine if personality characteristics, disability and physical activity level are associated with the onset of MOH in a group of migraine patients and explore to which extend these factors combined can predict the onset of MOH.

Methods: The study was a single-center prospective observational study of migraine patients. At inclusion, all patients completed questionnaires evaluating 1) personality (NEO Five-Factor Inventory), 2) disability (Migraine Disability Assessment), and 3) physical activity level (Physical Activity Scale 2.1). Diagnostic codes from patients' electronic health records confirmed if they had developed MOH during the study period of 20 months. Analyses of associations were performed and to identify which of the variables predict onset MOH, a multivariable least absolute shrinkage and selection operator (LASSO) logistic regression model was fitted to predict presence or absence of MOH.

Results: Out of 131 participants, 12 % (n=16) developed MOH. Migraine disability score (OR=1.02, 95 % CI: 1.00 to 1.04), intensity of headache (OR=1.49, 95 % CI: 1.03 to 2.15) and headache frequency (OR=1.02, 95 % CI: 1.00 to 1.04) were associated with the onset of MOH adjusting for age and gender. To identify which of the variables predict onset MOH, we used a LASSO regression model, and evaluating the predictive performance of the LASSO-mode (containing the predictors MIDAS score, MIDAS-intensity and -frequency, neuroticism score, time with moderate physical activity, educational level, hours of sleep daily and number of contacts to the headache clinic) in terms of area under the curve (AUC) was weak (apparent AUC=0.62, 95% CI: 0.41-0.82).

Conclusion: Disability, headache intensity and frequency were associated with the onset of MOH whereas personality and the level of physical activity were not. The multivariable LASSO model based on personality, disability and physical activity is applicable despite moderate study size, however it can be considered as a weak classifier for discriminating between absence and presence of MOH.
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http://dx.doi.org/10.1186/s10194-018-0863-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970129PMC
May 2018

Therapeutic Approaches for the Management of Trigeminal Autonomic Cephalalgias.

Neurotherapeutics 2018 04;15(2):346-360

Danish Headache Centre, Department of Neurology, Rigshospitalet-Glostrup, University of Copenhagen, Copenhagen, Denmark.

Trigeminal autonomic cephalalgia (TAC) encompasses 4 unique primary headache types: cluster headache, paroxysmal hemicrania, hemicrania continua, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms. They are grouped on the basis of their shared clinical features of unilateral headache of varying durations and ipsilateral cranial autonomic symptoms. The shared clinical features reflect the underlying activation of the trigeminal-autonomic reflex. The treatment for TACs has been limited and not specific to the underlying pathogenesis. There is a proportion of patients who are refractory or intolerant to the current standard medical treatment. From instrumental bench work research and neuroimaging studies, there are new therapeutic targets identified in TACs. Treatment has become more targeted and aimed towards the pathogenesis of the conditions. The therapeutic targets range from the macroscopic and structural level down to the molecular and receptor level. The structural targets for surgical and noninvasive neuromodulation include central neuromodulation targets: posterior hypothalamus and, high cervical nerves, and peripheral neuromodulation targets: occipital nerves, sphenopalatine ganglion, and vagus nerve. In this review, we will also discuss the neuropeptide and molecular targets, in particular, calcitonin gene-related peptide, somatostatin, transient receptor potential vanilloid-1 receptor, nitric oxide, melatonin, orexin, pituitary adenylate cyclase-activating polypeptide, and glutamate.
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http://dx.doi.org/10.1007/s13311-018-0618-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935647PMC
April 2018

Neck/shoulder function in tension-type headache patients and the effect of strength training.

J Pain Res 2018 23;11:445-454. Epub 2018 Feb 23.

Danish Headache Center, Department of Neurology, University of Copenhagen, Rigshospitalet-Glostrup, Glostrup.

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 (=0.047). A significantly lower RFD (25%) was noted in the TTH group than in the healthy controls (=0.031). A significant (<0.01) and moderate correlation to muscle tenderness was found. In the intervention, 23 patients completed ST and 21 patients completed EP. No significant between-group effect was observed, but at 22 weeks follow-up, both groups had a significant within-group effect of improved extension force steadiness (ST: =0.011 and EP: <0.01).

Conclusion: TTH patients showed a deteriorated muscle function, indicated by a lower force steadiness and RFD, compared to the healthy controls. The effect of ST was not larger than EP as both groups of TTH patients showed some improvement in neck and shoulder functions during the 10 weeks intervention and at follow-up. Future interventions are needed to elucidate if normalization of muscle function can lead to a reduction in headache.
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http://dx.doi.org/10.2147/JPR.S146050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827678PMC
February 2018

Long-term visual outcome in a Danish population of patients with idiopathic intracranial hypertension.

Acta Ophthalmol 2018 Nov 6;96(7):719-723. Epub 2018 Feb 6.

Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Purpose: Idiopathic intracranial hypertension (IIH) is characterized by raised intracranial pressure (ICP), normal cerebrospinal composition and exclusion of alternative causes to increased ICP. The aim of this study was to evaluate long-term visual outcome in a Danish population of IIH patients.

Methods: Retrospective chart review of 41 women diagnosed with IIH between June 2007 and March 2013. Best-corrected visual acuity (BCVA), colour vision, grade and type of visual field (VF) defects and grade of papilloedema according to the Modified Frisén Score were recorded at baseline visit (V0), 2-6 months (V1) and 13 months follow-up visit (V2) from time of diagnosis.

Results: Best-corrected visual acuity (BCVA) was reduced in 25% of eyes at V0, in 10% at V1 and in 15% at V2. Colour vision was barely affected. Visual field (VF) was affected (>grade 0) in 87% of eyes at V0 and VF defect grade significantly improved by 0.58 at V1 (p-value <0.0001) and by 0.55 at V2 (p-value <0.001). The most common type of VF defect at V0 was a nerve fibre layer defect (56.4%), and the second most common type was an enlarged blind spot (20.5%). There was no correlation between BCVA and VF defect type. Mean grade of papilloedema decreased from 2.2 at V0 to 0.5 at V2. The grade of papilloedema at V2 was not significantly related to the severity of papilloedema at V0 (p-values 0.65 and 0.48).

Conclusion: Idiopathic intracranial hypertension (IIH) is associated with long-term loss of visual function, and relevant treatment strategies need to be improved.
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http://dx.doi.org/10.1111/aos.13664DOI Listing
November 2018
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