Challenges in the management of new daily persistent headache at a tertiary headache center-A retrospective real-world evidence study.

OBJECTIVE: In this retrospective cross-sectional real-world evidence study from the Danish Headache Center (DHC), a national tertiary headache center in Denmark, we sought to identify potential pharmacological agents for the treatment of new daily persistent headache (NDPH). BACKGROUND: NDPH is an enigmatic headache disorder with abrupt onset and chronic duration for which evidence-based treatments are lacking. NDPH is a diagnosis of exclusion, for which secondary headaches must be ruled out and the etiology remains idiopathic. The sparse investigations of this disorder have not yielded a pathophysiological basis and no effective treatment for NDPH has been found. METHODS: All patients with an NDPH diagnosis at the DHC were enrolled (n = 64). First, we reviewed the records of all patients with an NDPH diagnosis to evaluate whether they fulfilled the diagnostic criteria. Next, we extracted all the trialled acute and prophylactic pharmacological interventions for the included patients. Then, pharmacological interventions that had been tried in ≥ 20 patients were analyzed post hoc with efficacy as the outcome, which was stratified in five effect categories ("no effect," "partial effect," "full effect," "partial effect and cessation due to adverse events," and "full effect and cessation due to adverse events"). Descriptive statistical analysis was performed, and the results were schematically presented (see Table 2). RESULTS: Fifty-one patients out of 64 were found to fulfill NDPH criteria and were included in the study. The drugs tried by ≥ 20 patients were amitriptyline (n = 34), candesartan (n = 27), and mirtazapine (n = 20). No patients experienced a complete effect with these drugs while 9% (3/34), 26% (7/27), and 15% (3/20) experienced a partial effect with no adverse events that led to treatment discontinuation, respectively. The remaining patients experienced either no effect or a partial effect with adverse events leading to treatment discontinuation. CONCLUSION: In this study we add real-world evidence to suggest that prophylactic drugs conventionally used for treating chronic migraine and chronic tension-type headache have limited utility for treating NDPH; however, a partial response in 26% of patients using candesartan and 15% of patients using mirtazapine warrants further investigation in randomized double-blinded placebo-controlled trials.

Comparison of the blink reflex in classical and idiopathic trigeminal neuralgia.

BACKGROUND: Previous findings indicate that the blink reflex is useful to distinguish between primary (classical/idiopathic) and secondary trigeminal neuralgia. No prior studies have investigated whether the blink reflex could identify differences in electrophysiological responses between classical and idiopathic trigeminal neuralgia. With this in mind, we investigated the blink reflex in a cohort of classical and idiopathic trigeminal neuralgia patients. METHODS: Participants were consecutively enrolled in the study. According to magnetic resonance imaging findings, the patients were subgrouped into either classical or idiopathic trigeminal neuralgia. Assessors were blinded to the subgroup and pain side, and the blink reflex was examined to assess R1 and R2 latencies, as well as the area under the curve. RESULTS: The study group constituted of 55 patients with primary trigeminal neuralgia: 25 patients with classical trigeminal neuralgia and 30 patients with idiopathic trigeminal neuralgia. None of the blink reflex latencies (R1 and R2) or the area under the curve significantly differed between the two subgroups when adjusted for age and sex (p > 0.05). CONCLUSIONS: Our findings suggest that the blink reflex cannot be used to differentiate classical and idiopathic trigeminal neuralgia patients, and that both subgroups may share common pathophysiological mechanisms.Trial Registration: ClinicalTrials.gov Identifier: NCT05328661.

Fundus imaging and perimetry in patients with idiopathic intracranial hypertension-an intermethod and interrater validity study.

BACKGROUND AND PURPOSE: There is a need to improve the diagnostic process of patients suspected of papilledema. In patients with known or suspected idiopathic intracranial hypertension a fundus imaging and perimetric visual field assessment system (COMPASS) performed at a headache center was validated in comparison to an assessment (Topcon plus OCTOPUS) at a neuroophthalmological clinic. METHODS: For intermethod assessment, blinded fundus images and perimetry from COMPASS versus Topcon plus OCTOPUS were assessed by a neuroophthalmologist. For interrater assessment, fundus images and perimetry obtained by the COMPASS system were assessed by an untrained medical doctor, a trained neurologist and a trained medical student and compared to the neuroophthalmologist's assessments. RESULTS: For the intermethod variation of the presence of papilledema on fundus images, a kappa value of 0.60, sensitivity of 87% and specificity of 73% were found. The interrater variation of the presence of papilledema on fundus images showed kappa values ranging from 0.43 to 0.74, sensitivity values ranging from 70% to 96% and specificity values ranging from 46% to 93% when comparing the assessments made by the headache center staff with neuroophthalmologist's assessments. The COMPASS showed a 59% sensitivity and moderate agreement in detecting visual field defects compared with OCTOPUS. The visual field assessment showed only slight to fair agreement from 0.19 to 0.31 between assessments made by the headache center staff and the neuroophthalmologist. CONCLUSION: The COMPASS system can be used with reasonable sensitivity in the assessment of papilledema in patients suspected of idiopathic intracranial hypertension at a tertiary headache center.

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.

A history of International Headache Society grants and their impact on headache careers.

BACKGROUND: The International Headache Society has been offering multiple award opportunities for young researchers and clinicians for many years, with the aim of supporting the development of careers in headache science and medicine. METHODS: In order to assess the outcomes of the International Headache Society award grants, a questionnaire was sent to all previous recipients, investigating a series of aspects related to their work, both during and after award completion. RESULTS: Of 44 total questionnaires sent, 36 were returned. Eighty-one percent of the recipients reported to have remained in the headache field since the award, half of them held a current academic position and over three-quarters had stayed in contact with the host institution. The totality of questionnaire responders stated that the grant had had a significantly positive impact on their careers. CONCLUSIONS: The International Headache Society grants have assisted many young researchers in building an academic and clinical career in the field of headache, throughout the years.

Treatment experiences and clinical characteristics in migraine and tension-type headache patients before the first visit to a tertiary headache center.

OBJECTIVES: To investigate previous treatment and clinical characteristics in migraine and tension-type headache patients at their first visit to a tertiary headache center. METHODS: This was a cross-sectional study using data obtained from electronic questionnaires and medical charts. Migraine and tension-type headache patients were investigated at their first visit to the Danish Headache Center. RESULTS: Out of 382 patients the main diagnoses of primary headaches were: 36% with episodic migraine, 43% with chronic migraine, 3% with episodic tension-type headache and 17% with chronic tension-type headache. The majority had attempted non-pharmacological treatment options such as physiotherapy (episodic migraine: 53%, chronic migraine: 68%, episodic tension-type headache: 50%, chronic tension-type headache: 65%) and acupuncture: (episodic migraine: 45%, chronic migraine: 62%, episodic tension-type headache: 17%, chronic tension-type headache: 51%). The majority of migraine patients had tried no more than one triptan (episodic migraine: 71%, chronic migraine: 66%). In total, 35% of episodic migraine and 19% of chronic migraine patients as well as 50% of episodic tension-type headache and 41% of chronic tension-type headache patients had never tried preventive medication. The headache under-response to treatment (HURT) questionnaire score was higher in chronic migraine (score 15) and chronic tension-type headache (score 16) patients than the episodic forms (P < 0.004). CONCLUSIONS: Headache patients had attempted several non-pharmacological treatments prior to their first visit at a tertiary headache center in Denmark. The limited use of acute and preventive treatment before the first visit demonstrates a need for better treatment at the primary and secondary care level.

Telemedicine in headache care: A systematic review.

OBJECTIVE: Telemedicine is defined as video-based consultations with synchronous video and sound. This systematic review investigated the use of telemedicine for headache patients. The primary outcomes of interest were treatment efficacy, feasibility, safety, convenience, compliance, and patient satisfaction. METHODS: A systematic literature search was performed using PubMed and Embase. Thirteen articles met the eligibility criteria and were included in the review. A systematic review protocol was registered on the International Prospective Register of Systematic Reviews, registration number CRD42021265875. RESULTS: There were no significant differences in treatment efficacy, patient satisfaction, compliance or safety using telemedicine when compared to traditional consultations. Telemedicine was found to be convenient due to being less time-consuming and expensive, especially for patients with limited access to health care. Despite the frequent occurrence of technical errors, telemedicine was found to be feasible. CONCLUSION: Telemedicine consultations are similar in quality to traditional in-office headache consultations and can be a more convenient solution for eligible headache patients.

The role of cytokines in migraine: A systematic review.

BACKGROUND: Cytokines are important endogenous substances that are involved in immune and inflammatory responses. Neurogenic inflammation has been proposed to play a role in migraine involving altered cytokine levels. Therefore, we aimed to provide a systematic review on the current knowledge on cytokine levels in migraine patients during and outside attacks. METHODS: Databases of PubMed and Embase were systematically searched for studies investigating cytokine levels in migraine patients during and outside attacks. RESULTS: Screening yielded identification of 45 articles investigating 18 cytokines in total. We found that the interictal level of the anti-inflammatory cytokine, interleukin 10, was decreased, while the level of transforming growth factor beta 1 was increased in migraine patients compared to controls. Levels of pro-inflammatory cytokines, tumor necrosis factor α and interleukin 6, were increased outside attacks compared to controls. Ictal levels of cytokines were unchanged or varying compared to the interictal state in migraine patients. Three studies reported dynamic cytokines levels during the course of an attack. CONCLUSION: The findings of the current review underline a possible involvement of cytokines in the proposed inflammatory mechanisms of migraine. However, future studies are needed to expand our knowledge of the exact role of cytokines in the migraine pathophysiology with focus on cytokines TNF-α, IL-1ß, IL-6 and IL-10 while applying refined methodology.

Sensitivity of the SNNOOP10 list in the high-risk secondary headache detection.

AIM: To evaluate the diagnostic accuracy of the SNNOOP10 list in the detection of high-risk headaches. METHODS: Patients that visited the Hospital Clínico San Carlos (Madrid) emergency department due to headache that were allocated to a Manchester Triage System level between critical and urgent were prospectively included but retrospectively analysed. A researcher blind to the patients' diagnosis administered a standardised questionnaire and afterwards a neurologist blind to the questionnaire results diagnosed the patient according to the International Classification of Headache Disorders. The primary endpoint was to assess the sensitivity of the SNNOOP10 list in the detection of high-risk headaches. Secondary endpoints included the evaluation of the sensitivity, specificity, positive predictive value, negative predictive value and area under the curve of each SNNOOP10 item. RESULTS: Between April 2015 and October 2021, 100 patients were included. Patients were 44 years old (inter-quartile range: 33.6-64.7) and 57% were female. We identified 37 different diagnoses. Final diagnosis was a primary headache in 33%, secondary headache in 65% and cranial neuralgia in 2%. There were 46 patients that were considered as having high-risk headache. Patients from the primary headache group were younger and more frequently female. Sensitivity of SNNOOP10 list was 100% (95% confidence interval: 90.2%-100%). The items with higher sensitivity were neurologic deficit or disfunction (75.5%), pattern change or recent onset of the headache (64.4%), onset after 50 years (64.4%). The most specific items were posttraumatic onset of headache (94.5%), neoplasm in history (89.1%) and systemic symptoms (89%). The area under the curve of the SNNOOP10 list was 0.66 (95% CI: 0.55-0.76). CONCLUSION: The red flags from the SNNOOP10 list showed a 100% sensitivity in the detection of high-risk headache disorders.

Telephone follow-up on treatment and patient satisfaction at a Danish tertiary headache center: A prospective study.

OBJECTIVE: We investigated whether telephone follow-up consultations could lead to appropriate adjustment of treatments and a higher degree of patient satisfaction among patients with migraine and tension-type headache (TTH). BACKGROUND: Migraine and TTH are disabling headache forms requiring optimized treatment. METHODS: In a prospective, non-randomized, quality control study with controls comparing telephone-interview intervention (TeII) with business-as-usual (BAU) treatment, we included newly referred patients with migraine and/or TTH. The TeII group was contacted by telephone by healthcare professionals at 8 and 16 weeks after the first visit addressing headache treatment. Electronic questionnaires were sent to all participants before the first visit and after 6 months. Predefined outcomes were number of patients with change in preventive and acute medication; change in headache frequency; migraine frequency; scores from the eight-item Headache Under-Response to Treatment (HURT-8) questionnaire, Insomnia Severity Index (ISI), and Hospital Anxiety and Depression Scale (HADS); and patient satisfaction after 6 months. RESULTS: From May 2020 to April 2021, there were 230 patients enrolled in the TeII program, whereof 96 patients were included in the analysis. For the BAU group, 91 patients with similar sex and age distribution were identified via medical-record reviews in the same period. More patients in the TeII group than in the BAU group had a change in acute medication (27/96 [28%] vs. five of 91 [6%], p < 0.001) and preventive medication (28/96 [29%] vs. 12/91 [13%], p = 0.006). Headache days per month decreased in the TeII group (-4.6, 95% confidence interval [CI] -6.5 to -2.7; p = 0.001) and the BAU group (-2.5, 95% CI -4.6 to -0.4; p = 0.018), without significant difference between the groups (p = 0.080). There was no difference in migraine frequency between the groups (TeII: 1.0 day, 95% CI, -1.3 to 1.0; BAU: 1.0 day, 95% CI, -2.5 to 0.5; p = 0.718) or HURT-8 score (TeII: 10.5, 95% CI 9.5-11.5; BAU: 13.0, 95% CI 11.7-14.2; p = 0.053). There were no changes in the ISI score (TeII: 1.0, interquartile range [IQR] 6; p = 0.152; BAU: 0.5, IQR 4.5; p = 0.824), HADS-Anxiety score (TeII: -5, IQR 5.3; p = 0.186; BAU: 1.0, IQR 4.0; p = 0.445), or HADS-Depression score (TeII: 0.0, IQR 3.0; p = 0.163; BAU: 0.0, IQR 2.0; p = 0.303) in any of the groups. There was a higher degree of patient satisfaction in the TeII group compared with the BAU group in treatment (median [IQR] score 4 [3-5] vs. 3 [3-4], p < 0.001), headache improvement (median [IQR] 3 [2-4] vs. 2 [1-3], p = 0.002), the headache program (median [IQR] 4 [3-5] vs. 3 [3-4], p < 0.001), and information (median [IQR] 4 [3-5] vs. 3 [3-4], p = 0.005). CONCLUSION: Patients with migraine and/or TTH benefit from a telephone follow-up approach within the first 6 months of their treatment course in terms of more efficient treatment and higher patient satisfaction.

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.

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.

Green Flags and headache: A concept study using the Delphi method.

OBJECTIVE: The aim of this study was to collect and rate Green Flags, that is, symptoms or pieces of information indicating that a patient is more likely to suffer from a primary than from a secondary headache. BACKGROUND: When assessing headaches, a central question to be answered is whether the pain is primary or secondary to another disorder. To maximize the likelihood of a correct diagnosis, relevant signs and symptoms must be sought, identified, and weighed against each other. METHODS: The project was designed as a Delphi study. In the first round, an expert panel proposed green flags that were rated anonymously in two subsequent rounds. Proposals with an average rating of 4.0 and higher on a scale from 0 to 5 reached consensus. RESULTS: Five Green Flags reached consensus: (i) "The current headache has already been present during childhood"; (ii) "The headache occurs in temporal relationship with the menstrual cycle"; (iii) "The patient has headache-free days"; (iv) "Close family members have the same headache phenotype"; and (v) "Headache occurred or stopped more than one week ago." CONCLUSIONS: We propose five Green Flags for primary headache disorders. None being a pathognomonic sign, we recommend searching for both Green Flags and Red Flags. If both are present, a secondary headache should be suspected. Overall, the application of the Green Flag concept in clinical practice is likely to increase diagnostic accuracy and improve diagnostic resource allocation. Prospective studies in clinical populations should be conducted to validate these Green Flags.

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.

Pain sensitivity in men who have never experienced a headache: an observer blinded case control study.

BACKGROUND: Headache affects 90-99% of the population. Based on the question "Do you think that you never ever in your whole life have had a headache?" 4% of the population say that they have never experienced a headache. The rarity of never having had a headache suggests that distinct biological and environmental factors may be at play. We hypothesized that people who have never experienced a headache had a lower general pain sensitivity than controls. METHODS: We included 99 male participants, 47 headache free participants and 52 controls, in an observer blinded nested case-control study. We investigated cold pain threshold and heat pain threshold using a standardized quantitative sensory testing protocol, pericranial tenderness with total tenderness score and pain tolerance with the cold pressor test. Differences between the two groups were assessed with the unpaired Student's t-test or Mann-Whitney U test as appropriate. RESULTS: There was no difference in age, weight or mean arterial pressure between headache free participants and controls. We found no difference in pain detection threshold, pericranial tenderness or pain tolerance between headache free participants and controls. CONCLUSION: Our study clearly shows that freedom from headache is not caused by a lower general pain sensitivity. The results support the hypothesis that headache is caused by specific mechanisms, which are present in the primary headache disorders, rather than by a decreased general sensitivity to painful stimuli. TRIAL REGISTRATION: Registered at ClinicalTrials.gov ( NCT04217616 ), 3rd January 2020, retrospectively registered.

Delayed headache after COVID-19 vaccination: a red flag for vaccine induced cerebral venous thrombosis.

BACKGROUND: Headache is a frequent symptom following COVID-19 immunization with a typical onset within days post-vaccination. Cases of cerebral venous thrombosis (CVT) have been reported in adenovirus vector-based COVID-19 vaccine recipients. FINDINGS: We reviewed all vaccine related CVT published cases by April 30, 2021. We assessed demographic, clinical variables and the interval between the vaccination and onset of headache. We assessed whether the presence of headache was associated with higher probability of death or intracranial hemorrhage. We identified 77 cases of CVT after COVID-19 vaccination. Patients' age was below 60 years in 74/77 (95.8%) cases and 61/68 (89.7%) were women. Headache was described in 38/77 (49.4%) cases, and in 35/38 (92.1%) was associated with other symptoms. Multiple organ thrombosis was reported in 19/77 (24.7%) cases, intracranial hemorrhage in 33/77 (42.9%) cases and 19/77 (24.7%) patients died. The median time between vaccination and CVT-related headache onset was 8 (interquartile range 7.0-9.7) days. The presence of headache was associated with a higher odd of intracranial hemorrhage (OR 7.4; 95% CI: 2.7-20.8, p < 0.001), but not with death (OR: 0.51, 95% CI: 0.18-1.47, p = 0.213). CONCLUSION: Delayed onset of headache following an adenovirus vector-based COVID-19 vaccine is associated with development of CVT. Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vaccine, should receive a thorough clinical evaluation and CVT must be ruled out.

Increased neck muscle stiffness in migraine patients with ictal neck pain: A shear wave elastography study.

BACKGROUND: Ictal neck pain is a frequent symptom reported by half of migraine patients. It is unknown if neck pain is caused by peripheral or central mechanisms. Neck muscle stiffness can be investigated with ultrasound shear wave elastography. OBJECTIVES: To determine if migraine patients with ictal neck pain have stiffer neck muscles interictally compared with patients without ictal neck pain and controls. METHODS: This was a cross-sectional study investigating neck muscle stiffness, pressure pain thresholds and neck pain symptoms in 100 migraine patients recruited from a tertiary headache center and 46 controls. RESULTS: Patients with ictal neck pain had increased mean neck muscle stiffness interictally compared to both migraine patients without ictal neck pain (p = 0.018) and controls (p = 0.036). Muscle stiffness was negatively correlated with pressure pain thresholds in the neck in migraine patients with ictal neck pain (r = -0.292, p = 0.042). There were no differences in mean pressure pain thresholds between migraine subgroups. CONCLUSIONS: Migraine patients with ictal neck pain have stiffer neck muscles interictally compared with migraine patients without ictal neck pain and controls measured with ultrasound shear wave elastography. The increased stiffness could be due to local alterations in the neck muscles. Trial registration: clinical-trials.gov, identifier: NCT03626805.

Ictal neck pain investigated in the interictal state - a search for the origin of pain.

BACKGROUND: Neck pain is reported in more than 50% of migraine patients during migraine attacks and may be an important source to migraine pain. OBJECTIVES: To investigate phenotypical differences between migraine patients with and without ictal neck pain in the interictal phase. Additionally, to prospectively examine the association between pericranial muscle tenderness and the impending migraine attack. METHODS: Migraine patients (n = 100) and controls (n = 46) underwent a semi-structured interview and sensory testing interictally. Pericranial muscle tenderness was determined using total tenderness score and local tenderness score. The occurrence of migraine attacks was then prospectively recorded for the following seven days. RESULTS: Patients with ictal neck pain had increased tenderness of pericranial neck muscles compared to migraine patients without (p = 0.023). Ictal neck pain was not associated with migraine localization, tension-type headache, or markers of central sensitization. Prospective data of 84 patients showed that tenderness of trigeminal sensory innervated muscles increased the migraine attack rate (p = 0.035). CONCLUSION: The distinction of migraine patients based on the occurrence of ictal neck pain could indicate migraine subtypes and possible involvement of peripheral tissue in the pathophysiology. Whether treatment responses differ among these groups would be fascinating. Additionally, we found that cephalic muscle tenderness is a risk factor for an impending migraine attack.

Low frequency activation of the sphenopalatine ganglion does not induce migraine-like attacks in migraine patients.

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.

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.