Hypersensitivity to CGRP as a predictive biomarker of migraine prevention with erenumab.

BACKGROUND: The present study aimed to investigate the predictive value of calcitonin gene-related peptide (CGRP)-induced migraine attacks for effectiveness to erenumab treatment in people with migraine. METHODS: In total, 139 participants with migraine underwent a single experimental day involving a 20-min infusion with CGRP. Following this, the participants entered a 24-week treatment period with erenumab. The primary endpoints were the predictive value of CGRP-induced migraine attacks on the effectiveness of erenumab, defined as ≥50% reduction in monthly migraine days, or ≥ 50% reduction in either monthly migraine or monthly headache days of moderate to severe intensity. RESULTS: Among participants with CGRP-induced migraine attacks, 60 of 99 (61%) achieved ≥50% reduction in monthly migraine days during weeks 13-24 with erenumab. Conversely, 13 of 25 (52%) where CGRP infusion did not induce a migraine achieved the same endpoint (p = 0.498). There were no significant differences between the ≥50% reduction in either monthly migraine or monthly headache days of moderate to severe intensity between CGRP-sensitive and non-sensitive participants (p = 0.625). CONCLUSIONS: Our findings suggest that the CGRP-provocation model cannot be used to predict erenumab's effectiveness. It remains uncertain whether this finding extends to other monoclonal antibodies targeting the CGRP ligand or to gepants.Trial Registration: The study was registered at ClinicalTrials.gov (NCT04592952).

Discontinuing the recommendation of hip precautions does not increase the risk of early dislocation after primary total hip arthroplasty using 36-mm heads: a population-based study from the Danish Hip Arthroplasty Register.

BACKGROUND AND PURPOSE: Dislocation is a severe complication following total hip arthroplasty (THA). Hip precautions have been recommended in the initial postoperative period but evidence supporting this practice is limited. We therefore conducted a population-based study to evaluate the association between discontinuing recommending postoperative hip precautions and the risk of early dislocation. METHODS: This is a cohort study with data from the Danish Hip Arthroplasty Register and the Danish National Patient Register. We included patients who underwent primary THA for osteoarthritis in 2004-2019 in public hospitals in the Capital Region of Denmark. The cohort was divided into the hip precautions group, comprising patients operated on between 2004 and 2009, and the no-precautions group operated on between 2014 and 2019. The primary outcome was the difference in the absolute risk of dislocation within 3 months post-surgery. The secondary outcome assessed the same risk within 2 years. We evaluated the difference in absolute risk using absolute risk regression (ARR). RESULTS: The cumulative incidence of dislocation within 3 months was 2.9% (confidence interval [CI] 2.5-3.3) in the hip precautions group and 3.5% (CI 3.1-3.9) in the no-precautions group. The risk of dislocation was higher in the no-precautions group but failed to reach statistical significance in the crude (ARR 1.2, CI 0.9-1.6) and multivariate model (ARR 1.4, CI 0.9-2.2). CONCLUSION: We found a higher but statistically insignificant increase in the risk of early dislocation in the no-precautions group. The lack of significance in the association may be explained by the increased use of 36-mm femoral heads after the guideline revision.

An exploratory analysis of clinical and sociodemographic factors in CGRP-induced migraine attacks: A REFORM study.

OBJECTIVE: To investigate whether clinical and sociodemographic factors are associated with calcitonin gene-related peptide (CGRP) induced migraine attacks. METHODS: A total of 139 participants with migraine received a 20-minute intravenous infusion of CGRP (1.5 µg/min) on a single experiment day. The incidence of CGRP-induced migraine attacks was recorded using a headache diary during the 12-hour observational period post-infusion. Univariable and multivariable regression analyses were conducted to examine potential predictors' relationship with CGRP-induced migraine attacks. RESULTS: CGRP-induced migraine attacks were reported in 110 (79%) of 139 participants. Univariable analysis revealed that participants with cutaneous allodynia had higher odds of developing CGRP-induced migraine attacks, compared with those without allodynia (OR, 2.97, 95% CI, 1.28 to 7.43). The subsequent multivariable analysis confirmed this association (OR, 3.26, 95% CI, 1.32 to 8.69) and also found that participants with migraine with aura had lower odds of developing CGRP-induced migraine attacks (OR, 0.32, 95% CI, 0.12 to 0.84). CONCLUSION: Our results suggest that cutaneous allodynia and aura play a role in CGRP-induced migraine attacks, while other clinical and sociodemographic factors do not seem to have any noticeable impact. This indicates that the CGRP provocation model is robust, as the CGRP hypersensitivity remained unaffected despite differences among a heterogeneous migraine population.Trial Registration: ClinicalTrials.gov Identifier: NCT04592952.

Prevalence and clinical features of hemicrania continua in clinic-based studies: A systematic review and meta-analysis.

OBJECTIVE: To estimate the relative frequencies of hemicrania continua and its clinical features in adult patients who were evaluated for headache in a clinic-based setting. METHODS: PubMed and Embase were searched for observational, clinic-based studies published between 1 January 2004 and 1 February 2022, that reported on the relative frequencies of hemicrania continua and its clinical features. Two independent investigators (HMA and SA-K) screened titles, abstracts, and full text-articles. A random-effects meta-analysis was conducted to estimate pooled relative frequencies of hemicrania continua and its clinical features across clinic-based studies. RESULTS: Eleven clinic-based studies were deemed eligible for inclusion. Of these, eight studies reported on the relative frequency of hemicrania continua among adult patients (n = 9854) who were evaluated for headache in a tertiary care unit. The pooled relative frequency of hemicrania continua was found to be 1.8% (95% CI; 1.0-3.3). Considerable heterogeneity was noted across studies (I2 = 89.8%). The three most common symptoms associated with hemicrania continua were lacrimation (72.3%), conjunctival injection (69.8%), and restlessness/agitation (60.2%). CONCLUSION: The findings of this meta-analysis suggest that there is limited epidemiologic data on the relative frequencies of hemicrania continua and its clinical features. Standardized data acquisition and reporting are needed to estimate prevalence rates more accurately and to better understand epidemiologic patterns. This, in turn, should increase awareness of the impact that hemicrania continua has in clinical practice.

Dislocation rate after hip arthroplasty due to metastatic bone disease: a retrospective cohort study evaluating the postoperative dislocation risk across different articulating solutions.

BACKGROUND AND PURPOSE: Joint stability after hip replacement (HR) in patients with metastatic bone disease (MBD) is of special importance. Dislocation is the second leading cause of implant revision in HR, while survival after MBD surgery is poor with an expected 1-year survival of around 40%. As few studies have investigated the dislocation risk across different articulation solutions in MBD, we conducted a retrospective study on primary HR for patients with MBD treated in our department. PATIENTS AND METHODS: The primary outcome is the 1-year cumulative incidence of dislocation. We included patients with MBD who received HR at our department in 2003-2019. We excluded patients with partial pelvic reconstruction, total femoral replacement, and revision surgery. We assessed the incidence of dislocation with competing risk analysis with death and implant removal as competing risks. RESULTS: We included 471 patients. Median follow-up was 6.5 months. The patients received 248 regular total hip arthroplasties (THAs), 117 hemiarthroplasties, 70 constrained liners, and 36 dual mobility liners. Major bone resection (MBR), defined as resection below the lesser trochanter, was performed in 63%. The overall 1-year cumulative incidence of dislocation was 6.2% (95% CI 4.0-8.3). Dislocation stratified by articulating surface was 6.9% (CI 3.7-10) for regular THA, 6.8% (CI 2.3-11) for hemiarthroplasty, 2.9% (CI 0.0-6.8) for constrained liner, and 5.6% (CI 0.0-13) for dual mobility liners. There was no significant difference between patients with and without MBR (p = 0.5). CONCLUSION: The 1-year cumulative incidence of dislocation is 6.2% in patients with MBD. Further studies are needed to determine any real benefits of specific articulations on the risk of postoperative dislocation in patients with MBD.

Calcitonin gene-related peptide causes migraine aura.

BACKGROUND: Although the involvement of calcitonin gene-related peptide (CGRP) in migraines is well-established, its specific role in investigating the aura phase, which often precedes the headache, remains largely unexplored. This study aims to instigate CGRP's potential in triggering aura, thus establishing its role in the early stages of migraine. METHODS: In this open-label, non-randomized, single-arm trial, 34 participants with migraine with aura received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min on a single experimental day. Participants were required to be free of headache and report no use of acute medications 24 h before infusion start. The primary endpoint was the incidence of migraine aura during the 12-hour observational period after the start of infusion. RESULTS: Thirteen (38%) of 34 participants developed migraine aura after CGRP infusion. In addition, 24 (71%) of 34 participants developed migraine headache following CGRP infusion. CONCLUSIONS: Our findings suggest that CGRP could play an important role in the early phases of a migraine attack, including during the aura phase. These insights offer a new perspective on the pathogenesis of migraines with aura. They underscore the need for additional research to further explore the role of CGRP in these initial stages of a migraine attack, and potentially inform future development of therapeutic interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04592952.

White matter hyperintensities and cerebral microbleeds in persistent post-traumatic headache attributed to mild traumatic brain injury: a magnetic resonance imaging study.

OBJECTIVE: To examine whether white matter hyperintensities (WMHs) and cerebral microbleeds (CMBs) are more prevalent in people with persistent post-traumatic headache attributed to mild traumatic brain injury (TBI), compared with healthy controls. METHODS: A magnetic resonance imaging (MRI) study of adults with persistent post-traumatic headache attributed to mild TBI and age- and gender-matched healthy controls. A semi-structured interview and validated self-report instruments were used to record data on demographics, clinical characteristics, and comorbidities. Imaging data were obtained on a 3T MRI Scanner using a 32-channel head coil. Participants and controls underwent a single MRI session, in which fluid-attenuated inversion recovery was used to visualize WMHs, and susceptibility-weighted imaging was used to detect CMBs. The primary outcomes were (I) the difference in the mean number of WMHs between participants with persistent post-traumatic headache and healthy controls and (II) the difference in the mean number of CMBs between participants with persistent post-traumatic headache and healthy controls. All images were examined by a certified neuroradiologist who was blinded to the group status of the participants and controls. RESULTS: A total of 97 participants with persistent post-traumatic headache and 96 age- and gender-matched healthy controls provided imaging data eligible for analyses. Among 97 participants with persistent post-traumatic headache, 43 (44.3%) participants presented with ≥ 1 WMH, and 3 (3.1%) participants presented with ≥ 1 CMB. Compared with controls, no differences were found in the mean number of WMHs (2.7 vs. 2.1, P = 0.58) and the mean number of CMBs (0.03 vs. 0.04, P = 0.98). CONCLUSIONS: WMHs and CMBs were not more prevalent in people with persistent post-traumatic headache than observed in healthy controls. Future studies should focus on other MRI techniques to identify radiologic biomarkers of post-traumatic headache.

Total tenderness score and pressure pain thresholds in persistent post-traumatic headache attributed to mild traumatic brain injury.

OBJECTIVE: To investigate whether persistent post-traumatic headache attributed to mild traumatic brain injury (TBI) is associated with more pronounced pericranial tenderness and lower pressure pain thresholds (PPTs) in the head and neck region, compared with healthy controls. METHODS: Patients with persistent post-traumatic headache (n = 100) and age- and gender-matched healthy controls (n = 100) were included between July 2018 and June 2019. Total tenderness score (TTS) was used to assess pericranial tenderness by bilateral manual palpation in eight muscles or tendon insertions. Summation was then used to calculate a TTS from 0 to 48 based on individual right- and left-sided scores; higher TTS score indicated more pronounced pericranial tenderness. PPTs were examined in m. temporalis and m. trapezius (upper and middle part) using an electronic pressure algometer that applies increasing blunt pressure at a constant rate. RESULTS: The TTS score was higher in patients with persistent post-traumatic headache (median, 21; IQR, 12-31), compared with healthy controls (median, 10; IQR, 6-17; P < .001). PPTs were lower in patients with persistent post-traumatic headache than in controls in both the left-sided m. temporalis (mean ± SD, 157.5 ± 59.9 vs. 201.1 ± 65.2; P < .001) and right-sided m. temporalis (mean ± SD, 159.5 ± 63.8 vs. 212.3 ± 61.9; P < .001). Furthermore, patients with persistent post-traumatic headache also had lower left- and right-sided PPTs in the upper as well as middle part of m. trapezius, compared with healthy controls; all P values were .05 or less. CONCLUSIONS: Among patients with persistent post-traumatic headache, pericranial tenderness was more pronounced and PPTs in the head and neck region were lower than in healthy controls free of headache and mild TBI. Further research is needed to better understand the involvement of pericranial myofascial nociceptors in the disease mechanisms underlying post-traumatic headache.

Premonitory symptoms in migraine: a systematic review and meta-analysis of observational studies reporting prevalence or relative frequency.

BACKGROUND: Observational studies on the prevalence of premonitory symptoms in people with migraine, preceding the headache pain (or aura) phase, have shown conflicting results. We conducted a systematic review and meta-analysis to estimate the prevalence, and relative frequency among clinic populations, of premonitory symptoms in people with migraine, overall and of the multifarious individual symptoms, and to review the methodologies used to assess them. METHODS: We searched PubMed and Embase for studies published from database inception until 31st of May 2022. Two investigators independently screened titles, abstracts, and full texts. We retrieved observational studies that reported the prevalence/relative frequency of one or more premonitory symptoms in people with migraine. Two investigators independently extracted data and assessed risk of bias. Results were pooled using random-effects meta-analysis. Our main outcomes were the percentage of people with migraine who experienced at least one premonitory symptom and the percentages who experienced different individual premonitory symptoms. To describe our outcomes, we used the terms prevalence for data from population-based samples and relative frequency for data from clinic-based samples. We also descriptively and critically assessed the methodologies used to assess these symptoms. RESULTS: The pooled estimated prevalence in population-based studies of at least one premonitory symptom was 29% (95% CI: 8-63; I2 99%) and the corresponding pooled estimated relative frequency in clinic-based studies was 66% (95% CI: 45-82; I2 99%). The data from clinic-based studies only supported meta-analysis of 11 of 96 individual symptoms, with relative frequency estimates ranging from 11 to 49%. Risk of bias was determined as high in 20 studies, moderate in seven, and low in two. CONCLUSIONS: The substantial between-study heterogeneity demands cautious interpretation of our estimates. Studies showed wide methodological variations, and many lacked rigor. Overall, the evidence was insufficient to support reliable prevalence estimation or characterization of premonitory symptoms. More data are needed, of better quality, to confirm the existence of a distinctive premonitory phase of migraine, and its features. Methodological guidelines based on expert consensus are a prerequisite.

Real-world long-term efficacy and safety of erenumab in adults with chronic migraine: a 52-week, single-center, prospective, observational study.

BACKGROUND: Clinical trials have shown that erenumab is effective and well-tolerated for the preventive treatment of chronic migraine. To extend the results from clinical trials, we assessed the real-world efficacy and safety of erenumab in patients with chronic migraine from the outpatient clinic at the Danish Headache Center. METHODS: A 52-week, single-center, prospective, observation study of erenumab in adults with chronic migraine who are eligible for treatment with monoclonal antibodies against CGRP or its receptor in Denmark. The primary outcome was defined as proportion of patients who achieved ≥ 30% reduction in monthly migraine days (MMDs) from baseline to weeks 9-12. RESULTS: A total of 300 adult patients with chronic migraine were enrolled and received at least one dose of erenumab. At baseline, the mean (SD) number of monthly headache days was 23 ± 4.9 and mean number of MMDs was 16.8 ± 6.4. Of 300 enrolled patients, 273 (91.0%) patients completed 12 weeks of treatment, and 119 (39.7%) completed 52 weeks of treatment. The number of patients who achieved ≥ 30% reduction in MMDs from baseline to weeks 9-12 was 195 (71.4%) of 273 patients. Sustained ≥ 30% reduction in MMDs at all assessment periods throughout the 52-week treatment period was achieved by 102 (34%) of 300 patients. Adverse events occurred in 220 (73.3%) out of 300 patients. The most common adverse event was constipation. Treatment discontinuation due to lack of tolerability occurred in 41 (13.7%) patients. CONCLUSIONS: Among adult patients with chronic migraine and previous failure of medications for migraine prevention, erenumab was found to be effective and well-tolerated.

CGRP-induced migraine-like headache in persistent post-traumatic headache attributed to mild traumatic brain injury.

OBJECTIVE: To ascertain whether intravenous infusion of calcitonin gene-related peptide (CGRP) can induce migraine-like headache in people with persistent post-traumatic headache attributed to mild traumatic brain injury (TBI) and no pre-existing migraine. METHODS: A non-randomized, single-arm, open-label study at a single site in Denmark. Eligible participants were aged 18 to 65 years and had a known history of persistent post-traumatic headache attributed to mild TBI for ≥ 12 months. All participants received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min. A headache diary was used to collect outcome data until 12 h after the start of CGRP infusion. The primary end point was the incidence of migraine-like headache during 12-hour observational period. RESULTS: A total of 60 participants completed the study protocol and provided data for the analysis of the primary end point. The median age was 32.5 (IQR, 25.5-43.0) years; 43 participants (72%) were female. Following CGRP infusion, 43 (72%) of 60 participants developed migraine-like headache during the 12-hour observational period. The median time to peak headache intensity was 40 min (IQR, 20-60), and the median peak headache intensity was 6 (IQR, 5-8) on the 11-point numeric rating scale. CONCLUSION: Intravenous infusion of CGRP is a potent inducer of migraine-like headache in people with persistent post-traumatic headache attributed to mild TBI. This observation underscores the importance of CGRP in the genesis of migraine-like headache that is often experienced by individuals who are afflicted by persistent post-traumatic headache. Further research is warranted to ascertain whether other signaling molecules also contribute to the disease mechanisms underlying post-traumatic headache.

Hypersensitivity to Calcitonin Gene-Related Peptide in Post-Traumatic Headache.

OBJECTIVE: To demonstrate that calcitonin gene-related peptide (CGRP) induces headache exacerbation with migraine-like features in patients with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). METHODS: A randomized, double-blind, placebo-controlled, two-way crossover study was conducted. Analyses were intention-to-treat. Eligible patients were aged 18 to 65 years and had a history of persistent PTH after mild TBI for at least 12 months. Patients were randomized to receive an intravenous infusion of 1.5µg/min of CGRP or placebo (isotonic saline) over 20 minutes on two separate experimental days. A 12-hour observational period was used to evaluate the following outcomes: (1) difference in incidence of headache exacerbation with migraine-like features and (2) difference in area under the curve for headache intensity scores. RESULTS: Thirty patients (mean age = 37 years, 25 women [83%]) were randomized and completed the study. During the 12-hour observational period, 21 of 30 patients (70%) developed headache exacerbation with migraine-like features after CGRP, compared with 6 patients (20%) after placebo (p < 0.001). The baseline-corrected area under the curve for headache intensity scores was significantly larger after CGRP, compared with placebo (p < 0.001). INTERPRETATION: Patients with persistent PTH are hypersensitive to CGRP, which underscores its pathophysiological importance. Furthermore, CGRP-targeted therapies might provide a novel mechanism-based treatment option for patients with persistent PTH. ANN NEUROL 2020;88:1220-1228.

Hypersensitivity to calcitonin gene-related peptide in chronic migraine.

OBJECTIVE: To investigate if calcitonin gene-related peptide infusion induces migraine-like attacks in chronic migraine patients. METHODS: Fifty-eight patients with chronic migraine, either with or without headache on the experimental day, were assessed for the incidence of migraine-like attacks after an intravenous infusion with calcitonin gene-related peptide 1.5 µg/min over 20 min. The primary endpoint was the incidence of migraine-like attacks after calcitonin gene-related peptide. Exploratory endpoints were the association between the incidence of migraine-like attacks and presence of headache on the experimental day, and headache frequency in the past month. Migraine-like attack data was compared to a historic cohort of 91 episodic migraine patients without headache on the experimental day. Total tenderness score, pressure-pain threshold and supra-threshold pressure pain at baseline were investigated in relation to incidence of migraine-like attacks and presence of headache on the experimental day. RESULTS: In total, 83% of the 58 chronic migraine patients developed migraine-like attacks after calcitonin gene-related peptide infusion. Migraine-like attacks were found in 92% of chronic migraine patients with headache on the experimental day compared to 65% of chronic migraine patients without headache on the experimental day (p = 0.035). No differences were observed in total tenderness score and pressure-pain threshold between chronic migraine patients with and without headache on the experimental day. The incidence of migraine-like attacks following calcitonin gene-related peptide in chronic migraine patients without headache (65%) was equal to the historic cohort of 91 episodic migraine patients without headache (67%) on the experimental day. CONCLUSIONS: Chronic migraine patients are hypersensitive to calcitonin gene-related peptide. The potency of calcitonin gene-related peptide as a migraine inductor is increased in chronic migraine patients with ongoing headache. We suggest that calcitonin gene-related peptide, besides being a migraine trigger also acts as a modulator of nociceptive transmission in the trigeminal system.

Nocebo response in human models of migraine: A systematic review and meta-analysis of randomized, double-blind, placebo-controlled, two-way crossover trials in migraine without aura and healthy volunteers.

BACKGROUND: Human models of migraine have been used for the past 30 years to test putative 'trigger' molecules and ascertain whether they induce migraine attacks in humans. However, nocebo effects using this model have never been systematically explored. OBJECTIVE: To assess the nocebo response rate in randomised clinical trials conducted at the Danish Headache Center, and in which human models of migraine were used. METHODS: In this systematic review and meta-analysis, we searched PubMed for studies of human models of migraine with a randomised, double-blind, placebo-controlled, two-way crossover design that included data on the incidence of migraine attacks or headache after infusion of placebo. A total of 943 articles were screened by title and abstract. Of these, 27 studies met the inclusion criteria (published between 1994 and 2020) and were included in the qualitative and quantitative analysis. We performed a random effects meta-analysis for the incidence of migraine attacks or delayed headache after placebo infusion. RESULTS: Twenty-seven studies were eligible for inclusion: 12 studies reported data for adults with migraine (n = 182), whereas 16 studies reported data on healthy volunteers (n = 210). For adults with migraine, the incidence of migraine attacks after placebo was 8.1% (95% CI = 2.5-15.5%, I2 = 50.8%). The incidence of delayed headache was 25.9% (95% CI = 18.5-34.1%, I2 = 18.9%). For healthy volunteers, the incidence of migraine attacks after placebo was 0.5% (95% CI = 0.0-3.6%, I2 = 0.0%) while the incidence of delayed headache was 10.5% (95% CI = 4.8-17.6%, I2 = 45.2%). CONCLUSION: The nocebo response in randomised, placebo-controlled two-way crossover trials with intravenous infusions of placebo in migraine is negligible. Future studies using human models of migraine can be conducted by assuming a nocebo response rate of 15.5%.

Psychiatric and cognitive comorbidities of persistent post-traumatic headache attributed to mild traumatic brain injury.

OBJECTIVE: To investigate the association of psychiatric and cognitive comorbidities with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). METHODS: A total of 100 patients with persistent PTH attributed to mild TBI and 100 age- and gender-matched healthy controls free of mild TBI were enrolled between July 2018 and June 2019. Quality of sleep was evaluated using the Pittsburgh Sleep Quality Index, while symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Cognitive impairment was evaluated using the Montreal Cognitive Assessment questionnaire, while post-traumatic stress disorder (PTSD) was assessed using the Harvard Trauma Questionnaire. RESULTS: In 100 patients with persistent PTH, 85% reported poor quality sleep, compared with 42% of healthy controls (P < 0.01). The relative frequency of probable to high risk of anxiety was 52% in the persistent PTH group vs. 8% in healthy controls (P < 0.01), while the relative frequency of probable to high risk of depression was 42% in the persistent PTH group vs. 2% in healthy controls (P < 0.01). Furthermore, 27% of the patients with persistent PTH had mild cognitive impairment while 10% had probable PTSD. CONCLUSIONS: Poor quality of sleep as well as symptoms suggestive of anxiety and depression were more common in patients with persistent PTH than healthy controls. Clinicians should screen patients with persistent PTH for these comorbidities and develop treatment plans that account for their presence.

Persistent post-traumatic headache attributed to mild traumatic brain injury: Deep phenotyping and treatment patterns.

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.

Unrecognized challenges of treating status migrainosus: An observational study.

BACKGROUND: Status migrainosus is a condition with limited epidemiological knowledge, and no evidence-based treatment guideline or rational-driven assessment of successful treatment outcome. To fill this gap, we performed a prospective observational study in which we documented effectiveness of treatment approaches commonly used in a tertiary headache clinic. MATERIAL AND METHODS: Patients with episodic and chronic migraine who experienced continuous and prolonged attacks for more than 72 hours were treated with dexamethasone (4 mg orally twice daily for 3 days), ketorolac (60 mg intramuscularly), bilateral nerve blocks (1-2% lidocaine, 0.1-0.2 ml for both supraorbital and supratrochlear nerves, 1 ml for both auriculotemporal nerves, and 1 ml for both greater occipital nerves), or naratriptan (2.5 mg twice daily for 5 days). Hourly (for the first 24 hours) and daily (for first 30 days) change in headache intensity was documented using appropriate headache diaries. RESULTS: Fifty-four patients provided eligible data for 60 treatment attempts. The success rate of rendering patients pain free within 24 hours and maintaining the pain-free status for 48 hours was 4/13 (31%) for dexamethasone, 7/29 (24%) for nerve blocks, 1/9 (11%) for ketorolac and 1/9 (11%) for naratriptan. These success rates depended on time to remission, as the longer we allowed the treatments to begin to work and patients to become pain free (i.e. 2, 12, 24, 48, 72, or 96 hours), the more likely patients were to achieve and maintain a pain-free status for at least 48 hours. DISCUSSION: These findings suggest that current treatment approaches to terminating status migrainosus are not satisfactory and call attention to the need to develop a more scientific approach to define a treatment response for status migrainosus.

Low plasma levels of calcitonin gene-related peptide in persistent post-traumatic headache attributed to mild traumatic brain injury.

OBJECTIVE: To investigate the role of calcitonin gene-related peptide (CGRP) in persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). METHODS: A total of 100 individuals with persistent PTH attributed to mild TBI and 100 age- and gender-matched healthy controls were enrolled between July 2018 and June 2019. Blood was drawn from the antecubital vein and subsequently analyzed using a validated radioimmunoassay for human CGRP. Measurements were performed on coded samples by a board-certified laboratory technician who was blind to clinical information. RESULTS: CGRP plasma levels were lower in subjects with persistent PTH (mean, 75.8 pmol/L; SD, 26.4 pmol/L), compared with age- and gender-matched healthy controls (mean, 88.0 pmol/L; SD, 34.1 pmol/L) (p = 0.04). No correlation was found of CGRP plasma levels with monthly headache days (r = -0.11; p = 0.27), monthly migraine-like days (r = 0.15; p = 0.13), headache quality (r = -0.14; p = 0.15), or a chronic migraine-like headache phenotype (r = -0.02; p = 0.85). CONCLUSIONS: CGRP plasma measurements are unlikely a feasible blood-based biomarker of persistent PTH. Future studies should assess whether CGRP plasma measurements can be used to predict development of persistent PTH.

Dizziness and vertigo during the prodromal phase and headache phase of migraine: A systematic review and meta-analysis.

OBJECTIVE: To assess the proportion of individuals who report dizziness and/or vertigo during the prodromal phase or headache phase of migraine. METHODS: The databases of MEDLINE and EMBASE were searched for studies on dizziness and/or vertigo during the prodromal phase or headache phase of migraine. Pooled relative frequencies were estimated using a random-effects meta-analysis. RESULTS: We identified nine articles eligible for inclusion. Of these, one study reported results for the prodromal phase, seven studies for the headache phase and one study for both the prodromal and headache phase. In the prodromal phase, 9.0% of individuals with migraine reported dizziness, while 3.3% reported vertigo. During the headache phase, relative frequency of dizziness ranged from 6.7% to 59.6%, while vertigo ranged from 6.4% to 44.7%. The meta-analysis showed a relative frequency of 35.7% for dizziness (95% CI = 13.7-61.5%, I2 = 99%) and 33.9% for vertigo (95% CI = 26.7-41.5%, I2 = 87%). Study quality was rated 5/9 or below for seven studies and 6/9 or above for two studies. CONCLUSION: We found that there is a scarcity of literature on dizziness and vertigo as prodromal- and headache-associated symptoms in individuals with migraine. Methodological variations confound comparisons of epidemiological patterns, although it appears that dizziness and vertigo are more frequent during the headache phase of migraine, compared with the prodromal phase. Future studies should ensure use of standardized definitions and rigorous methodology to enable accurate measurements of dizziness and vertigo in migraine.

Intravenous Endothelin-1 Infusion Does Not Induce Aura or Headache in Migraine Patients With Aura.

OBJECTIVE: To investigate whether intravenously infused provokes migraine aura and migraine headache in migraine patients with aura. BACKGROUND: Migraine with aura has been associated with endothelial dysfunction and increased stroke risk. The initiating mechanism of migraine aura symptoms is not known. Experimental provocation of migraine headache using vasoactive peptides has provided tremendous advances in the understanding of migraine pathophysiology but substances that can induce migraine aura have not been identified. Endothelin-1 (ET-1), an endogenous, potent vasoconstrictor peptide released from the vascular endothelium, has been proposed to trigger migraine aura. This hypothesis is based on reports of increased plasma ET-1 levels early during the migraine attacks and the observation that ET-1 applied to the cortical surface potently induces the cortical spreading depolarization, the underlying electrophysiological phenomenon of migraine aura, in animals. Further, endothelial damage due to, for example, carotid puncture and vascular pathology is known to trigger aura episodes. METHODS: We investigated whether intravascular ET-1 would provoke migraine aura in patients. Using a two-way crossover, randomized, placebo-controlled, double-blind design, we infused high-dose (8 ng/kg/minutes for 20 minutes) intravenous ET-1 in patients with migraine with typical aura. The primary end-point was the difference in incidence of migraine aura between ET-1 and placebo. Experiments were carried out at a public tertiary headache center (Danish Headache Center, Rigshospitalet Glostrup, Denmark). RESULTS: Fourteen patients received intravenous ET-1. No patients reported migraine aura symptoms or migraine headache during or up to 24 hours following the ET-1 infusion. Four patients reported mild to moderate headache only on the ET-1 day, 3 patients reported moderate headache on the placebo day, and 1 patient reported mild headache on both days. No serious adverse events occurred during or after infusion. CONCLUSIONS: Provocation of migraine aura by procedures or conditions involving vascular irritation is unlikely to be mediated by ET-1.