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

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

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

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

Objective: Caffeine, a non‐selective adenosine receptor (AR) antagonist, is the most consumed psychostimulant in the world. Caffeine has been suggested to regulate cerebrospinal fluid secretion and is known both to alleviate and to trigger headache; however, its effect on the regulation of intracranial pressure (ICP) is not known. Therefore, we aimed to investigate the effects of caffeine on ICP and nociceptive responses. Methods: Female Sprague–Dawley rats were implanted with a novel telemetric device for continuous ICP recordings, which allowed for continuous recordings in freely moving rats. A single dose of caffeine (30 or 120 mg/kg intraperitoneally) was given. In a second group (non‐implanted), the acute effects of 30 mg/kg caffeine on periorbital threshold using Von Frey testing and spontaneous behavior were utilized using an automated behavioral registration platform (Laboratory, Animal, Behavior, Observation, Registration and Analysis System) in a randomized cross‐over study. Quantitative polymerase chain reaction and immunofluorescence were used to localize ARs in the choroid plexus. Results: A single dose of 30 mg/kg caffeine lowered the ICP by 35% at 165 min after administration (saline: 0.16 ± 0.9 vs caffeine: −1.18 ± 0.9 ΔmmHg, p = 0.0098) and lasted up to 12 h. Administration of 120 mg/kg caffeine showed a faster onset of decrease in ICP within 15 min by 50% (p = 0.0018) and lasted up to 12 h. The periorbital pain thresholds were higher after 1 h (saline: 224.6 ± 15.1 vs caffeine: 289.5 ± 8.7 g, p = 0.005) and lasted up to 5 h. Caffeine‐treated rats had increased locomotor activity, speed, and changed grooming behavior. Expression of AR1 was found in the choroid plexus. Conclusions: This study demonstrates that caffeine has a lowering effect on ICP as an acute treatment. Interestingly, caffeine acutely caused an increased response in cephalic thresholds supporting hypoalgesic effects. Future studies investigating the beneficial effects of caffeine for elevated ICP are warranted. [ABSTRACT FROM AUTHOR]

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

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

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

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. [ABSTRACT FROM AUTHOR]

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

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

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. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

Summary: Introduction: Cluster headache is characterized by attacks of severe unilateral pain accompanied by cranial and systemic autonomic changes. Our knowledge of the latter is imperfect. This study aimed to investigate the effect of low‐frequency sphenopalatine ganglion stimulation on cardiac autonomic regulation. Materials and methods: In a double‐blind, randomized, sham‐controlled crossover design, patients received low‐frequency and sham stimulation. RR intervals were recorded, and heart rate variability was analysed (time‐domain, frequency‐domain, nonlinear parameters). Headache characteristics, including cranial autonomic symptoms, were recorded at baseline and every 10 min for 60 min. Results: Sixteen patients were included. Changes in heart rate variability from baseline in the analysed parameters differed significantly between low‐frequency and sham stimulation. Initially, during low‐frequency stimulation, there was a greater increase in heart rate compared to sham (P<0·05) and changes in the frequency, nonlinear and time domain (P<0·05) reflecting a higher sympathetic tone. These preceded the observed cranial autonomic symptoms. Ten episodes of cluster‐like attacks were reported (six following low‐frequency stimulation, four following sham). During these, parasympathetic tone (P<0·05) was higher compared to baseline. Conclusions: In cluster headache patients subjected to low‐frequency and sham stimulation of the sphenopalatine ganglion, we found changes indicating higher sympathetic tone during low‐frequency stimulation preceding cranial autonomic symptoms or cluster pain. During cluster pain, regardless of stimulation parameters, we saw increased parasympathetic activity, congruent with previous reports. The results indicate involvement of cardiac autonomic regulation before and during cluster headache attacks. [ABSTRACT FROM AUTHOR]

Objective and Background Important elements of cluster headache ( CH) pathophysiology may be seated in the posterior hypothalamus. Cranial autonomic features are inherent, but involvement of systemic autonomic control is still debated. We aimed to characterize autonomic function as investigated by baroreflex sensitivity ( BRS) in CH patients. Methods Twenty-six active CH patients and an equal number of age-, sex-, and BMI-matched controls underwent head-up tilt table test and BRS was determined by the sequence method. Results Compared with controls, patients exhibited a blunted reactivity of RR intervals in response to falls and increases in systolic blood pressure ( SBP) (15.3 vs 20.0 ms/mmHg, P = .0041) in the supine position. Also, compared with controls, BRS was lower in patients having suffered an attack within the past 12 hours (n = 13, 12.5 vs 22.3 ms/mmHg, P = .0091), opposed to those patients who had not (n = 13, 16.0 ms/mmHg, P = .1523). In the tilted position, the drop in SBP at the carotid sinuses was higher in patients who had recently suffered an attack. Despite this, they exhibited a less marked shortening of RR intervals when compared with patients who had been attack free for longer. Conclusions CH patients exhibit a subclinical blunting of BRS that may be affected by the attacks themselves. The fast RR interval fluctuations used in this method reflects cardiovagal responses, thus the blunted responses are suggestive of dysfunction in the parasympathetic division of the autonomic nervous system or in the central relay of impulses from the baroreceptors. [ABSTRACT FROM AUTHOR]

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

Objective To examine whether detoxifying patients with medication-overuse headache can reduce long-term medication costs. Background Direct costs of medications in medication-overuse headache have been reported to be very high but have never been calculated on the basis of exact register data. Long-term economic savings obtained by detoxification have never been investigated. Methods We conducted a registry-based observational retrospective follow-up study on 336 medication-overuse headache patients treated and discharged from the Danish Headache Center over a 2-year period. By means of the Danish Register of Medicinal Product Statistics, we collected information on the costs and use of prescription-only medication 1 year before admission and 1 year after discharge from Danish Headache Center. Results The average medication costs per patient per year decreased with 24%, from US$971 before treatment to US$737 after ( P = .001), and the average medication use decreased with 14.4% ( P = .02). Savings were most pronounced for patients overusing triptans. In this group, the average medication costs per patient per year decreased with 43% ( P < .001), while the average triptan use decreased with 38% ( P < .001). Conclusions The study demonstrates that detoxification of medication-overuse headache at a tertiary headache center has a long-lasting effect on the medication costs and use, in particular among patients overusing triptans. The results may not be generalizable to all countries and may be sensitive to the costs of triptans. [ABSTRACT FROM AUTHOR]

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

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

Objectives: Medication-overuse headache (MOH) is recognized as a biobehavioural disorder, warranting that both biological and psychological factors are targeted throughout treatment. A psychological factor of importance may be personality that could be used to tailor treatment if differences are found across headache diagnoses. The objectives were as follows: (a) To investigate if migraine patients and patients with MOH differed on personality traits, (b) To investigate if the two headache groups differed from a Danish normative sample, with respect to personality traits., Materials and Methods: The NEO-Five-Factor Inventory was completed, and an age-matched cohort of episodic migraine patients (n = 94) and MOH patients (n = 94) was included. Multivariate regression models and sex-stratified comparisons were made on patients' raw scores from five personality traits; neuroticism, extraversion, openness, agreeableness, and conscientiousness. The headache groups were also compared to personality traits from a Danish normative sample (n = 1032)., Results: MOH females obtained significantly lower scores on extraversion (24.4 ± 4.3 vs 27.1 ± 7.2, P < 0.01), openness (23.7 ± 3.9 vs 26.2 ± 6.4, P < 0.01), and conscientiousness (28.9 ± 3.7 vs 34.6 ± 5.8, P > 0.01) as compared to female migraineurs. Males showed no differences. Compared to the normative sample, both headache groups showed a lower score on extraversion (P < 0.01). Furthermore, MOH patients had statistically significant lower scores on conscientiousness while the migraine patients had a higher score., Conclusion: Results suggests some personality trait differences between migraine and MOH patients. Especially, females showed different personality traits, where the MOH females appeared more introvert and less socially orientated. If confirmed in larger studies, this information could be used in personalized treatment in clinical practice., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)