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Background Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide can provoke cluster headache attacks in up to half of cluster headache patients in their active phase. At present, it is unknown whether provoked attacks are mediated via calcitonin gene-related peptide or mast cell activation. Methods All enrolled patients with cluster headache were randomly allocated to receive a continuous infusion of either PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We collected clinical data and measured plasma levels of calcitonin gene-related peptide and markers of mast cell activation (tryptase and histamine) at fixed time points: at baseline (T0), at the end of the infusion (T20), 10 min after the infusion (T30), and 70 min after the infusion (T90). Results Blood was collected from episodic cluster headache patients in active phase (n = 14), episodic cluster headache patients in remission (n = 15), and chronic cluster headache patients (n = 15). At baseline, plasma levels of calcitonin gene-related peptide, tryptase, and histamine were not different among the three study groups. Plasma levels of calcitonin gene-related peptide ( p = 0.7074), tryptase ( p = 0.6673), or histamine ( p = 0.4792) remained unchanged during provoked attacks compared to attack-free patients. Conclusion Cluster headache attacks provoked by either PACAP38 or vasoactive intestinal polypeptide were not accompanied by alterations of plasma calcitonin gene-related peptide, tryptase or histamine. The provoked attacks may not be mediated by calcitonin gene-related peptide or mast cell activation. Trial Registration: The study is registered at ClinicalTrials.gov (NCT03814226).

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.

ObjectiveTo explore the prevalence of poor social support and loneliness among people with chronic headache, and how these might be effect modifiers in the relationships between chronic headache and stress, medication overuse, and self-rated health.BackgroundPoor social support and loneliness are consistently linked to worse health outcomes. There are few epidemiologic studies on their effect on headache.MethodsThe Danish Capital Region Health Survey, a cross-sectional survey, was conducted in 2017. Participants were asked about headache, pain medication use, social support, loneliness, perceived stress, and self-rated health. Data were accessed from sociodemographic registers. Logistic regression analyses were performed to test for effect modification.ResultsThe response rate was 52.6% (55,185 respondents) and was representative of the target population. People with chronic headache were more likely to report poor social support and loneliness compared to those without chronic headache ( p ConclusionPoor social support and loneliness were prevalent among people with chronic headache. The combination of chronic headache and poor social support or loneliness showed higher odds ratios for stress, medication overuse, and poor self-rated health compared to those with good social support and low loneliness scores. The effect of loneliness in the relationship between chronic headache and medication overuse warrants further study.

Background Early symptoms prior to a cluster headache bout have been reported to occur days or weeks before the actual beginning of the cluster headache bouts. This study aimed to describe the prevalence of pre-cluster (premonitory) symptoms and examine the predictability of an upcoming cluster headache bout. Methods 100 patients with episodic cluster headache were included in this retrospective cross-sectional study. All patients underwent a semi-structured interview including 25 questions concerning pre-cluster symptoms. Results Pre-cluster symptoms were reported by 86% of patients with a mean of 6.8 days (interquartile range 3–14) preceding the bout. An ability to predict an upcoming bout was reported by 57% with a mean 4.6 days (interquartile range 2–7) before the bout. Occurrence of shadow attacks was associated with increased predictability (odds ratio: 3.06, confidence interval: 1.19–7.88, p-value = 0.020). In remission periods, 58% of patients reported mild cluster headache symptoms and 53% reported occurrence of single shadow attacks. Conclusions The majority of episodic cluster headache patients experienced pre-cluster symptoms, and more than half could predict an upcoming bout, suggesting the significant potential of early intervention. Furthermore, the experience of mild cluster headache symptoms and infrequent shadow attacks in remission periods is common and suggest an underlying pathophysiology extending beyond the cluster headache bouts.

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).

Introduction Cephalic autonomic symptoms occur in 27‒73% of migraine patients during attacks. The role of parasympathetic activation in migraine attack initiation remains elusive. Low frequency stimulation of the sphenopalatine ganglion increases parasympathetic outflow. In this study, we hypothesized that low frequency stimulation of the sphenopalatine ganglion would provoke migraine-like attacks in migraine patients. Methods In a double-blind randomized sham-controlled crossover study, 12 migraine patients with a sphenopalatine ganglion neurostimulator received low frequency or sham stimulation for 30 min on two separate days. We recorded headache characteristics, cephalic autonomic symptoms, ipsilateral mechanical perception and pain thresholds, mean blood flow velocity in the middle cerebral artery (VMCA) and diameter of the superficial temporal artery during and after stimulation. Results Five patients (42%) reported a migraine-like attack after low frequency stimulation compared to six patients (50%) after sham ( p = 1.000). We found a significant increase in mechanical detection thresholds during low frequency stimulation compared to baseline ( p = 0.007). Occurrence of cephalic autonomic symptoms and changes in mechanical perception thresholds, VMCA and diameter of the superficial temporal artery showed no difference between low frequency stimulation compared to sham ( p = 0.533). Conclusion Low frequency stimulation of the sphenopalatine ganglion did not induce migraine-like attacks or autonomic symptoms in migraine patients. These data suggest that increased parasympathetic outflow by the sphenopalatine ganglion neurostimulator does not initiate migraine-like attacks. Study protocol: ClinicalTrials.gov registration number NCT02510742

Objective To investigate clinical characteristics and treatment patterns in persistent post-traumatic headache attributed to mild traumatic brain injury. Methods A total of 100 individuals with persistent post-traumatic headache attributed to mild traumatic brain injury were enrolled between July 2018 and June 2019. Deep phenotyping was performed using a semi-structured interview while allodynia was assessed using the 12-item Allodynia Symptom Checklist. Results In 100 subjects with persistent post-traumatic headache, the mean headache frequency was 25.4 ± 7.1 days per month. The most common headache phenotype was chronic migraine-like headache (n = 61) followed by combined episodic migraine-like and tension-type-like headache (n = 29) while nine subjects reported “pure” chronic tension-type-like headache. The most frequent trigger factors were stress, lack of sleep, and bright lights. A history of preventive medication use was reported by 63 subjects, of which 79% reported failure of at least one preventive drug, while 19% reported failure of at least four preventive drugs. Cutaneous allodynia was absent in 54% of the subjects, mild in 23%, moderate in 17%, and severe in 6%. Conclusions The headache profile of individuals with persistent post-traumatic headache most often resembled a chronic migraine-like phenotype or a combined episodic migraine-like and tension-type-like headache phenotype. Migraine-specific preventive medications were largely reported to be ineffective. Therefore, there is a pressing need for pathophysiological insights and disease-specific therapies.

Objective To report efficacy and safety of galcanezumab in adults with chronic cluster headache. Background Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide and inhibits its biological activity. Methods This study comprised a prospective baseline period, a 12-week double-blind, placebo-controlled treatment period, and a 52-week open-label period. Up to six protocol-specified concomitant preventive medications were allowed if patients were on a stable dose for 2 months prior to the prospective baseline period. Patients were randomized 1:1 to monthly subcutaneous galcanezumab (300 mg) or placebo. The primary endpoint was overall mean change from baseline in weekly attack frequency with galcanezumab compared to placebo. Key secondary endpoints were ≥50% response rate and percentage of patients meeting sustained response. Results from the double-blind treatment period are reported. Results A total of 237 patients were randomized and treated (120 placebo; 117 galcanezumab). At baseline, the mean age was 45 years and 63% were using ≥1 preventive drug. The primary endpoint was not met; mean change in weekly attack frequency was −4.6 placebo versus −5.4 galcanezumab ( p = 0.334). Key secondary endpoints also were not met. Injection site-related treatment-emergent adverse events were more common in the galcanezumab than the placebo group, with significantly more injection site erythema. Conclusion Treatment with galcanezumab 300 mg did not achieve its primary and key secondary endpoints. This study underscores the potential distinct biology of cCH as well as the significant unmet need for safe, effective, and well-tolerated preventive treatment. The safety profile of galcanezumab in cCH is consistent with that observed in trials of episodic CH and migraine. Trial registration NCT02438826; https://www.clinicaltrials.gov/ct2/show/NCT02438826 .

Background and aim Cluster headache attacks exhibit a nocturnal predilection, but little is known of long-term sleep and circadian rhythm. The aim was to compare actigraphy measures, firstly in episodic cluster headache patients in bout and in remission and, secondly, to compare each disease phase with controls. Methods Episodic cluster headache patients (ICHD III-beta), from the Danish Headache Center and healthy, age- and sex-matched controls participated. Sleep and activity were measured using actigraphy continuously for 2 weeks, along with sleep diaries and, for patients, also attack registration. Results Patients in bout (n = 17, 2.3 attacks/day) spent more time in bed (8.4 vs. 7.7 hours, p = 0.021) and slept more (7.2 vs. 6.6 hours, p = 0.036) than controls (n = 15). In remission (n = 11), there were no differences compared with controls. Neither were there differences between patients in the two disease phases. In five patients, attacks/awakenings occurred at the same hour several nights in a row. Conclusion Actigraphy offers the possibility of a continuous and long study period in a natural (non-hospital) environment. The study indicates that sleep does not differ between the bout and remission phase of episodic cluster headache. The repeated attacks/awakenings substantiate that circadian or homeostatic mechanisms are involved in the pathophysiology. The protocol was made available at ClinicalTrials.gov (NCT02853487).

Background The mechanisms behind the severe pain of cluster headache remain enigmatic. A distinguishing feature of the attacks is the striking rhythms with which they occur. We investigated whether statistical modelling can be used to describe 24-hour attack distributions and identify differences between subgroups. Methods Common hours of attacks for 351 cluster headache patients were collected. Probability distributions of attacks throughout the day (chronorisk) was calculated. These 24-hour distributions were analysed with a multimodal Gaussian fit identifying periods of elevated attack risk and a spectral analysis identifying oscillations in risk. Results The Gaussian model fit for the chronorisk distribution for all patients reporting diurnal rhythmicity (n = 286) had a goodness of fit R2 value of 0.97 and identified three times of increased risk peaking at 21:41, 02:02 and 06:23 hours. In subgroups, three to five modes of increased risk were found and goodness of fit values ranged from 0.85–0.99. Spectral analysis revealed multiple distinct oscillation frequencies in chronorisk in subgroups including a dominant circadian oscillation in episodic patients and an ultradian in chronic. Conclusions Chronorisk in cluster headache can be characterised as a sum of individual, timed events of increased risk, each having a Gaussian distribution. In episodic cluster headache, attacks follow a circadian rhythmicity whereas, in the chronic variant, ultradian oscillations are dominant reflecting a loss of association with sleep and perhaps explaining observed differences in the effects of specific treatments. The results demonstrate the ability to accurately model chronobiological patterns in a primary headache.

Background Low frequency (LF) stimulation of the sphenopalatine ganglion (SPG) may increase parasympathetic outflow and provoke cluster headache (CH) attacks in CH patients implanted with an SPG neurostimulator. Methods In a double-blind randomized sham-controlled crossover study, 20 CH patients received LF or sham stimulation for 30 min on two separate days. We recorded headache characteristics, cephalic autonomic symptoms (CAS), plasma levels of parasympathetic markers such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal peptide (VIP), and mechanical detection and pain thresholds as a marker of sensory modulation. Results In the immediate phase (0–60 min), 16 (80%) patients experienced CAS after LF stimulation, while nine patients (45%) reported CAS after sham ( p = 0.046). We found no difference in induction of cluster-like attacks between LF stimulation (n = 7) and sham stimulation (n = 5) ( p = 0.724). There was no difference in mechanical detection and pain thresholds, and in PACAP and VIP plasma concentrations between LF and sham stimulation ( p ≥ 0.162). Conclusion LF stimulation of the SPG induced autonomic symptoms, but no CH attacks. These data suggest that increased parasympathetic outflow is not sufficient to induce CH attacks in patients. Study protocol ClinicalTrials.gov registration number NCT02510729

Aims To evaluate the impact of treatment success on depression and anxiety symptoms in medication-overuse headache (MOH) and whether depression and anxiety can be predictors of treatment outcome. Methods All consecutive patients entering the detoxification program were analysed in a prospective, non-randomised fashion over a six-month period. Depression and anxiety were assessed using the Hospital Anxiety and Depression Scale. Results A total of 663 MOH patients were evaluated, and 492 completed the entire protocol. Of these, 287 ceased overuse and reverted to an episodic pattern (responders) and 23 relapsed into overuse. At the final evaluation, the number of patients with depressive symptoms was reduced by 63.2% among responders ( p Conclusions Symptomatology referred to affective state and anxiety can be significantly reduced by the treatment of MOH. Baseline levels of depression and anxiety do not generally predict the outcome at six months. Their persistence may represent a trait of patients with a negative outcome, rather than the consequence of a treatment failure.

The aim of the current study was to compare lower urinary tract symptoms (LUTS), erectile dysfunction (ED), and quality of life (QoL) in poststroke and healthy men. Thirty poststroke men with stroke-related LUTS, and as controls, 96 healthy men participated in this controlled, cross-sectional study. Participants filled in the Danish Prostate Symptom Score (DAN-PSS-1) Questionnaire, the International Index of Erectile Function (IIEF-5), the 36-Item Short Form (SF-36), the Nocturia Quality-of-Life (N-QoL) Questionnaire. In the age group ≤55 years, comparing poststroke men with healthy controls both with LUTS, the results indicated DAN-PSS-1, total score median 13 (4-17) versus 3 (2-6), p = .05; IIEF-5 25 (14-25) versus 24 (23-25), p = .06; SF-12, total score 499 (360-679) versus 695 (644-734), p = .02; and N-QoL 98 (70-100) versus 96 (90-100), p = .65. In the age group >55 years, comparing poststroke men with healthy controls both with LUTS, the results indicated DAN-PSS-1, total score 13 (8-24) versus 5 (2-7), p < .01; IIEF-5 13 (5-20) versus 25 (24-25), p < .01; SF-36, total score 585 (456-718) versus 742 (687-772), p < .01; and N-QoL, total score 81 (66-95) versus 98 (80-100), p < .01. The results demonstrated that in age group above, but not below 55 years, poststroke men with LUTS had significantly higher frequency of severe and bothersome LUTS and ED than the healthy controls with LUTS, while QoL and N-QoL were significantly lower in comparison. It is recommended to identify and assess older poststroke men for LUTS, ED, and QoL.

Background Short-lasting unilateral neuralgiform headache attacks (SUNA) is a primary headache characterized by frequent attacks of severe headaches in association with ipsilateral cranial autonomic features. SUNA is defined as a strictly unilateral pain and bilateral cases are very unusual, so secondary causes should be searched for vigorously if there are bilateral symptoms. Despite a number of therapeutic trials, effective management for the majority of SUNA patients is not available at present. Management of SUNA is often difficult. Case We report the case of a young boy with bilateral SUNA attacks, with no detected underlying cause, who is responsive to indomethacin. Conclusion Rarely, primary SUNA can present with bilateral symptoms. According to our experience in this case, indomethacin should always be offered to patients with suspected SUNA.

Purpose The purpose of this article is to investigate possible differences in effect between three types of masks in the acute treatment of cluster headache (CH). Patients and methods Fifty-seven CH patients according to ICHD-II-criteria participated in a single-blinded, semi-randomized, placebo-controlled, crossover inpatient study, and 102 CH attacks were treated with 100% oxygen delivered by demand valve oxygen (DVO), O2ptimask or simple mask (15 liters/min) or placebo delivered by DVO for 15 minutes. Primary endpoint: Two-point decrease of pain on a five-point rating scale within 15 minutes. Results Only 10 CH patients had multiple attacks and reached the point of placebo. There were no significant differences between masks in the primary endpoints ( p = 0.412). After 15 minutes 48% had a two-point decrease using the DVO compared to 45% with placebo ( p = 0.867). After 30 minutes 68% were pain free or had pain relief using DVO and 45% by placebo ( p = 0.061). The DVO was preferred by 62% compared to 5% and 33% for simple mask ( p 2ptimask ( p = 0.061). In the first attack the DVO was significantly better at achieving pain relief at 15 minutes ( p = 0.018). Treatment with DVO or O2ptimask reduced the need for rescue medication compared to the simple mask (23%, 19%, 50%, respectively). No treatment-related adverse events were observed. Conclusion The primary endpoint with pain relief at 15 minutes was non-significant; however, a post hoc analysis of the first attack significantly favored DVO. Further, therapy by O2ptimask and DVO resulted in a decreased need for rescue medication. We recommend that CH patients be offered DVO or O2ptimask before oxygen therapy is abandoned.

Objectives The sphenopalatine ganglion (SPG) plays a pivotal role in cluster headache (CH) pathophysiology as the major efferent parasympathetic relay. We evaluated the long-term effectiveness of SPG stimulation in medically refractory, chronic CH patients. Methods Thirty-three patients were enrolled in an open-label follow-up study of the original Pathway CH-1 study, and participated through 24 months post-insertion of a microstimulator. Response to therapy was defined as acute effectiveness in ≥ 50% of attacks or a ≥ 50% reduction in attack frequency versus baseline. Results In total, 5956 attacks (180.5 ± 344.8, range 2–1581 per patient) were evaluated. At 24 months, 45% ( n = 15) of patients were acute responders. Among acute responders, a total of 4340 attacks had been treated, and in 78% of these, effective therapy was achieved using only SPG stimulation (relief from moderate or greater pain or freedom from mild pain or greater). A frequency response was observed in 33% ( n = 11) of patients with a mean reduction of attack frequency of 83% versus baseline. In total, 61% (20/33) of all patients were either acute or frequency responders or both. The majority maintained their therapeutic response through the 24-month evaluation. Conclusions In the population of disabled, medically refractory chronic CH patients treated in this study, SPG stimulation is an effective acute therapy in 45% of patients, offering sustained effectiveness over 24 months of observation. In addition, a maintained, clinically relevant reduction of attack frequency was observed in a third of patients. These long-term data provide support for the use of SPG stimulation for disabled patients and should be considered after medical treatments fail, are not tolerated or are inconvenient for the patients.

Background Cluster headache (CH) is a disabling headache disorder with chronobiological features. The posterior hypothalamus is involved in CH pathophysiology and is a hub for autonomic control. We studied autonomic response to the head-up tilt table test (HUT) including heart rate variability (HRV) in CH patients and compared results to healthy controls. Methods and materials Twenty-seven episodic and chronic CH patients and an equal number of age-, sex- and BMI-matched controls were included. We analyzed responses to HUT in the time and frequency domain and by non-linear analysis. Results CH patients have normal cardiovascular responses compared to controls but increased blood pressure. In the frequency analysis CH patients had a smaller change in the normalized low- (LF) (2.89 vs. 13.38, p Conclusions CH patients show decreased autonomic response to HUT compared to healthy controls. This can be interpreted as dysregulation in the posterior hypothalamus and supports a theory of central autonomic mechanisms involvement in CH.

Purpose Our aim was to review the existing literature to document oxygen’s therapeutic effect on cluster headache. Method A PubMed search resulted in 28 hits, and from these and their references we found in total 11 relevant studies. We included six studies that investigated the efficacy of oxygen treatment. One study is observational and the remaining five are RCTs. Another five studies were on hyperbaric oxygen treatment hereof two case studies. Conclusion Oxygen therapy can be administered at different flow rates. Three studies investigate the effect of low-flow oxygen, 6–7 l/min, and found a positive response in 56%, 75% and 82%, respectively, of the patients. One study investigates high-flow oxygen, 12 l/min, and found efficacy in 78% of attacks. The effect of hyperbaric oxygen therapy has been investigated in a few small studies and there is evidence only for an acute, but not a prophylactic effect. Despite the fact that only a few high-quality RCT studies are available, oxygen treatment is close to an ideal treatment because it is effective and safe. However, sufferers of cluster headache do not always have access to oxygen because of logistic and financial concerns.

Background The aetiology behind chronic post-traumatic headache (CPTH) after mild head injury is unclear and management is complicated. In order to optimize treatment strategies we aimed to characterize a CPTH population. Methods Ninety patients with CPTH and 45 patients with chronic primary headaches were enrolled from the Danish Headache Center. All patients were interviewed about demographic and headache data. They completed the Harvard Trauma Questionnaire (HTQ), Rivermead Post Concussion Symptoms Questionnaire, SF-36 and a headache diary. Results The CPTH group experienced more cognitive ( p < 0.001) and somatic symptoms ( p = 0.048) and rated their self-perceived health as more affected in terms of physical function ( p = 0.036), physical role function ( p = 0.012) and social function ( p = 0.012) than the control group. Surprisingly, 31% of the CPTH group had a score equal to or above the cut-off score for having post-traumatic stress disorder (PTSD) according to the HTQ. In terms of demographics and headache, the groups were comparable except the CPTH group were more often without affiliation to the labour market ( p < 0.001). Conclusions The loss of work capacity and high levels of disability for the CPTH patients suggests directions for further research into what important factors are embedded in the patients’ PTSD symptoms and might explain their prolonged illness.

Purpose of review Neurostimulation has emerged as a viable treatment for intractable chronic cluster headache. Several therapeutic strategies are being investigated including stimulation of the hypothalamus, occipital nerves and sphenopalatine ganglion. The aim of this review is to provide an overview of the rationale, methods and progress for each of these. Latest findings Results from a randomized, controlled trial investigating sphenopalatine ganglion stimulation have just been published. Reportedly the surgery is relatively simple and it is apparently the only therapy that provides relief acutely. Summary The rationale behind these therapies is based on growing evidence from clinical, hormonal and neuroimaging studies. The overall results are encouraging, but unfortunately not all patients have benefited. All the mentioned therapies require weeks to months of stimulation for a prophylactic effect to occur, suggesting brain plasticity as a possible mechanism, and only stimulation of the sphenopalatine ganglion has demonstrated an acute, abortive effect. Predictors of effect for all modes of neurostimulation still need to be identified and in the future, the least invasive and most effective strategy must be preferred as first-line therapy for intractable chronic cluster headache.

BackgroundHuman 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.MethodsWe examined pain perception in 35 MOH patients before and two, six and 12 months after detoxification. For baseline comparison, we tested 40 healthy controls. We measured cephalic and extra-cephalic pressure-pain thresholds and supra-threshold pressure-pain scores and extra-cephalic pain thresholds, supra-threshold pain scores and temporal summation for electrical stimulation.ResultsOf the 35 patients, 21 patients completed the entire study and remained cured of MOH. Statistically significant differences between patients and healthy controls were found in cephalic pressure-pain thresholds (137.3 kPa vs. 170 kPa, p ConclusionThe central nervous system is sensitised in patients with MOH. For the first time we demonstrate that the pain perception continues to normalise up to a year after detoxification. This emphasises the importance of detoxification and follow-up to prevent relapse.

Background High frequency (HF) stimulation of the sphenopalatine ganglion (SPG) is an emerging abortive treatment for cluster headache (CH) attacks. HF SPG stimulation is thought to exert its effect by physiologically blocking parasympathetic outflow. We hypothesized that low frequency (LF) SPG stimulation may activate the SPG, causing increased parasympathetic outflow and thereby provoking cluster attacks in CH patients. Methods In a double-blind randomized cross-over study, seven CH patients implanted with an SPG neurostimulator were randomly allocated to receive HF or LF stimulation for 3 min on 2 separate days. We recorded headache characteristics and autonomic symptoms during and after stimulation. Results Six patients completed the study. Three out of six patients (50%) reported ipsilateral cluster-like attacks during or within 30 min of LF SPG stimulation. These cluster-like attacks were all successfully treated with the therapeutic HF SPG stimulation. One out of six reported a cluster-like attack with 3 min HF SPG stimulation, which was also successfully treated with continued HF therapeutic SPG stimulation. Discussion LF SPG stimulation may induce cluster-like attacks with autonomic features, which can subsequently be treated by HF SPG stimulation. Efferent parasympathetic outflow from the SPG may initiate autonomic symptoms and activate trigeminovascular sensory afferents, which may initiate the onset of pain associated with CH.

The HURT Questionnaire consists of eight questions which the patient answers as a measure of effectiveness of intervention against headache. This first assessment of clinical utility was conducted in headache specialist centres in three countries in order to demonstrate that HURT was responsive to change induced by effective management. We administered HURT on three occasions to 159 consecutive patients seeking non-urgent care from centres in Denmark and the United Kingdom: the first before the initial visit to the centres; the second at the initial visit; and the third when the specialist judged that the best possible outcome had been achieved in each patient. Questionnaires were also answered by 42 patients at initial and final visits to a centre in Italy. Internal consistency reliability was very good ( α = 0.85) while test-retest reliability was fair to low ( κ = 0.38–0.62 and rs = 0.49–0.76), possibly because headache was unstable prior to start of management. There were significant changes in responses post-intervention compared with baseline ( p

Medication-overuse headache (MOH) is a debilitating condition in which frequent and prolonged use of medication for the acute treatment of pain results in the worsening of the headache. The purpose of this paper is to review the most recent literature on MOH and discuss future avenues for research. MOH accounts for a substantial share of the global burden of disease. Prevalence is often reported as 1–2% but can be as high as 7% overall, with higher proportions among women and in those with a low socioeconomic position. Management consists of withdrawing pain medication, focusing on prophylactic and nonmedical treatments, and limiting acute symptomatic medication. Stress reduction and lifestyle interventions may support the change towards rational pain medication use. Support, follow up, and education are needed to help patients through the detoxification period. There is fertile ground for research in MOH epidemiology, pathophysiology, and neuroimaging. Randomized and long-term follow-up studies on MOH treatment protocols are needed. Further focused research could be of major importance for global health.

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.

Introduction: Despite the high prevalence of headaches, multidisciplinary headache clinics are few and their efficacy still needs validation. The objective was to characterise patients and treatment results in a tertiary headache centre. Subjects and methods: A systematic review of all referred patients in the Danish Headache Centre in a 2-year period. Outcome results were analysed with respect to diagnoses and sociodemographics. Results: A total of 1326 patients with a mean age of 43.7 years and male : female ratio of 3 : 7 were included. In total, frequency and absence rate from work were reduced from 20 to 11 days ( P Conclusions: The present analysis provided support for a multidisciplinary approach in a tertiary headache centre. Further evaluation of specific treatment strategies and outcome predictors are important for future planning.

This study, which is a part of the initiative 'Lifting The Burden: The Global Campaign to Reduce the Burden of Headache Worldwide', assesses and presents all existing evidence of the world prevalence and burden of headache disorders. Population-based studies applying International Headache Society criteria for migraine and tension-type headache, and also studies on headache in general and 'chronic daily headache', have been included. Globally, the percentages of the adult population with an active headache disorder are 46% for headache in general, 11% for migraine, 42% for tension-type headache and 3% for chronic daily headache. Our calculations indicate that the disability attributable to tension-type headache is larger worldwide than that due to migraine. On the World Health Organization's ranking of causes of disability, this would bring headache disorders into the 10 most disabling conditions for the two genders, and into the five most disabling for women.

The aim of the present study was to investigate the impact of static contraction of the shoulder and neck muscles on muscle tenderness and headache in patients with tension-type headache. Twenty patients with frequent episodic tension-type headache and 20 healthy age- and sex-matched controls were examined using a placebo-controlled cross-over design. The subjects performed static contraction of the trapezius muscles (active procedure) or the anterior tibial muscles (placebo procedure) with 10% of maximal force for 30 min. Total tenderness score, local tenderness score and headache intensity were evaluated before and after the static work. Changes in headache intensity were followed for 24 h. Pericranial tenderness increased significantly more in patients than in controls after the active procedure ( P = 0.04). The increase in pericranial tenderness tended to be higher after the active procedure than after the placebo procedure in patients ( P = 0.08) and in controls ( P = 0.07). Sixty per cent of the patients and 20% of the healthy controls developed headache after the active procedure. Fifty per cent of the patients and none of the controls developed headache after the placebo procedure. There was no significant difference in headache development between the active and the placebo procedure in patients or controls. These findings demonstrate that tension-type headache patients are more liable to develop shoulder and neck pain in response to static exercise than healthy controls.

The clinical presentation of chronic post-traumatic headache in 53 patients from a highly specialized headache clinic was analysed and classified according to the diagnostic criteria of the primary headaches in The International Headache Classification 2nd Edition, and compared with the 1st Edition. All patients fulfilled the criteria for both editions indicating that the restrictions in the 2nd Edition have no major influence on the prevalence in specialized clinics. We found the phenomenology to be very heterogeneous, but the vast majority (77%) of patients presented with headache resembling chronic tension-type headache, either as the only manifestation or in combination with migraine symptoms. For the first time episodic tension-type headache is described as occurring after head trauma. The prevalence of coexisting analgesic overuse was 42% and the treatment outcome for these patients was just as favourable as in primary headaches, whereas the time-consuming multidisciplinary treatment demonstrated only very modest results.

Experimental studies in humans have shown that nitric oxide (NO) may play an important role in initiation of primary headaches. It has been proposed that activation of L-arginine-NO pathway and increased endogenous production of NO may be responsible for NO induced headache. NO is synthesized from L-arginine and that reaction also yields citrulline. In the present study we aimed to investigate plasma levels of citrulline and arginine as markers of NO production after infusion of the NO donor, glyceryl trinitrate (GTN). We recruited 16 patients with chronic tension-type headache and 16 healthy controls. The subjects were randomly allocated to receive 0.5 μg/kg/min GTN or placebo over 20 min. Patients were examined on headache free days. Blood samples were collected at baseline and 60 min after start of infusion. Both patients and controls developed stronger immediate headache on the GTN day than on the placebo day ( P = 0.008). The headache was more pronounced in patients than in controls ( P = 0.02). Plasma levels of citrulline increased significantly 60 min after start of GTN infusion compared to placebo infusion in patients ( P = 0.01) but not in controls ( P = 0.50). Plasma levels of arginine were unchanged in both patients ( P = 0.12) and controls ( P =0.18). We suggest that GTN administration may trigger endogenous production of NO in patients with chronic tension-type headache resulting in activation of perivascular sensory afferents.

A new experimental human model of myofascial pain using intramuscular infusion of a combination of bradykinin, serotonin (5-hydroxytryptamine), histamine, and prostaglandin E2 was applied to patients with episodic tension-type headache (ETTH) in order to examine pain perception. Fifteen patients with ETTH and 15 healthy controls completed the randomized, balanced, double-blinded, placebo-controlled study. Pain intensity, punctate hyperalgesia and allodynia, and pain quality were recorded. The combination induced a moderate and prolonged pain in both patients (median 51 min) ( P = 0.001) and controls (median 22 min) ( P = 0.001). Patients reported more pain than controls both after the combination ( P = 0.045) and after placebo ( P < 0.001). The McGill pain score [PRI(R)] was significantly higher in patients ( P = 0.002) and in controls ( P = 0.001), whereas pain quality and hyperalgesia were similar after the combination compared with placebo in the two groups. Due to side-effects nine subjects did not complete the study. The increased pain response, but similar qualitative pain perception, in ETTH patients may be explained by sensitization of peripheral nociceptors even though central mechanisms may also be involved.

The role of non-pharmacological therapies in the preventive treatment of tension-type headache (TTH) is still an object of debate. The primary aim of this study was therefore to investigate the therapeutic effect of physiotherapy in properly classified patients with TTH in a controlled trial. Fifty patients with TTH, 26 with episodic, frequent (ETTH) and 24 with chronic TTH (CTTH) fulfilling the International Headache Society classification criteria were included in the study. After a 4-week run-in period, they were randomized to either an 8-week period of standardized physiotherapy (group 1) or to an 8-week observation period followed by an identical course of physiotherapy (group 2); after the physiotherapy all patients were followed for a 12-week follow-up period. We then evaluated the number of days with headache, severity and duration of the headache attacks, and drug consumption for symptomatic treatment before and after the course of physiotherapy. Forty-eight patients completed the study. The average number of days with headache per 4-week period was reduced from 16.3 days at baseline to 12.3 days in the last 4 weeks of treatment [from 14.5 days to 10.5 days ( P < 0.001) in group 1 and from 18.1 days to 14.1 days ( P < 0.001) in group 2]. Severity and duration of headache as well as drug consumption were unchanged throughout the study. Analysing the response to treatment separately in the various subgroups, we found that the number of responders was significantly higher among patients with CTTH vs. patients with ETTH ( P < 0.002) and in females vs. males ( P < 0.02). No differences were found between patients with and without disorder of pericranial muscles. We conclude that a standardized physiotherapy programme has a good therapeutic effect, albeit on a restricted group of patients.

Despite tension-type headache represents one of the most frequent and costly diseases in modern society only very little research on this disease has actually been carried out. In contrast to former belief tension-type headache is a separate entity that can and should be separated from migraine. No specific biochemical abnormalities have yet been identified but a reliable human model of tension-type headache has been developed by means of infusion of a NO-donor, glyceryl trinitrate. Myofascial factors and peripheral sensitization of nociceptors play an important role in the episodic form, and central sensitization has been demonstrated in the chronic form. As chronic tension-type headache usually evolves from the episodic form, prevention and reversal of this central sensitization may be an important target for future pathophysiological studies and drug development.

Nitric oxide (NO) plays an important role in the pathophysiology of primary headaches including chronic tension-type headache (CTTH). Thus, a NO synthase inhibitor reduces headache and muscle hardness while the NO donor glyceryl trinitrate (GTN) causes more headache in patients than in healthy controls. Sensitization of myofascial pain pathways is important in CTTH, and the aim of the present study was to investigate if such mechanisms may also explain GTN-induced immediate headache in patients with CTTH. In a randomized, double-blind, crossover study 16 patients with CTTH and 16 healthy subjects received intravenous infusion of GTN (0.5 μg/kg per min for 20 min) or placebo on two headache-free days separated by at least 1 week. Muscle hardness, myofascial tenderness, mechanical and heat pain thresholds were measured at baseline and at 60 min and 120 min after start of infusion. In patients, GTN infusion resulted in a biphasic response with immediate headache and more pronounced delayed headache. A similar but less pronounced response was seen in controls. There was no difference between GTN and placebo regarding muscle hardness, myofascial tenderness or pressure and heat pain thresholds in either patients or controls ( P > 0.05). The unchanged sensitivity of pericranial myofascial pain pathways indicates that peripheral and central sensitization is not involved in the mechanisms of GTN-induced immediate headache.

The aim of the present study was to determine the intra- and interobserver variation during measurement of muscle hardness with a new instrument, a so-called hardness meter. In addition, we investigated the factors which may influence the recording of muscle hardness and whether the hardness differs within the same muscle. Hardness was measured at a standardized point on the trapezius muscle in 20 volunteers by 2 observers in random order and again by 1 of the observers after 30 min. Muscle hardness was then measured at 3 different locations on the trapezius muscle. In addition, the muscle hardness at the standard point was measured in 10 volunteers by both observers at 3 different speeds of the applied pressure. The intraobserver variation was 10% and the interobserver variation was 12% for recording of muscle hardness. There was no significant difference in hardness values from time to time within the same observer ( p=0.12), while there was a significant difference in hardness measurements between observers ( p=0.007). Muscle hardness differed significantly among the 3 anatomical locations ( p=0.03). For both observers, there was a significant difference among hardness recordings obtained at 3 different speeds ( p=0.01 and p=0.0001). In conclusion, we have shown that the hardness meter can measure muscle hardness reliably if the same observer is used throughout a study. The speed factor was a major source of variability. In addition, we have demonstrated that muscle hardness differs within the same muscle. We suggest that the muscle hardness meter will be an important tool in future research of the mechanisms leading to myofascial pain.

Serotonergic neurons play a major role in the regulation of pain and may therefore also be involved in the pathophysiology of tension-type headache. Platelets are important in the regulation of the free serotonin level in plasma and may be a model of serotonergic neurons. The aim of the present study was to investigate the peripheral serotonin (5HT) metabolism in patients with chronic tension-type headache. The 5HT levels in platelets and in plasma, the beta-thromboglobulin (ß-TG) levels in plasma, and the urinary excretion of 5-hydroxyindoleacetic acid (5HIAA) were measured in 40 patients with chronic tension-type headache and in 40 healthy controls. The platelet uptake index was calculated as the ratio between platelet 5HT and plasma 5HT levels. There were, no significant differences in platelet 5HT, plasma 5HT ß-TG, or 5HIAA between patients and controls. The platelet uptake index was significantly lower in patients 243 (136-367) than in controls 352 (202-508), p=0.03. Our results indicate that the peripheral 5HT metabolism is largely normal in patients with chronic tension-type headache.

A new instrument, the Diagnostic Headache Diary, based on the operational diagnostic criteria of the International Headache Society (IHS), was tested in 61 migraine patients from a headache research clinic using the clinical diagnosis (IHS criteria) for comparison. All patients kept the diary for one to eight months. The clinical and diary diagnosis of migraine with and without aura was the same in, respectively, 72 and 87% of the patients. Nausea, photophobia and phonophobia tended to be more pronounced at the clinical interview. The diary identified 20 more cases of episodic tension-type headache and 15 fewer cases of chronic tension-type headache than the clinical interview. Two blinded observers always made the same IHS diagnoses when interpreting the diagnostic headache diary. A combination of a clinical interview and the diagnostic headache diary gives a qualitatively and quantitatively more precise diagnosis than a clinical interview alone.

In 740 representative normal subjects a diagnostic headache interview and a neurological examination provided the necessary information to classify headache disorders according to the operational diagnostic criteria of the International Headache Society (IHS). Sixteen per cent (n = 119) had migraine, 78% (n = 578) tension-type headache. In migraineurs, pain was of a pulsating quality in 78%, severe in 85%, unilateral in 62%, and aggravated by routine physical activity in 96%. Tension-type headache was of a pressing quality in 78%, mild or moderate in 99%, bilateral in 90%, and 72% had no aggravation by physical activity. The accompanying symptoms of nausea, photo- and phonophobia occurred frequently and were usually moderate or severe in migraine subjects, and if present in subjects with tension-type headache, they were usually mild. Only two subjects had unclassifiable headache. The IHS Classification is thus exhaustive. The criteria may be improved by mandatory demands to the criterion of pain intensity leaving other features of pain as supportive for the diagnosis and by including graded severity of accompanying symptoms. A specific proposal is given.