Cephalalgia Reports

Published by SAGE Publications
Online ISSN: 2515-8163
Publications
Tolosa-Hunt syndrome (THS) is a rare, idiopathic, non-specific inflammation within the cavernous sinus and/or superior orbital fissure leading to painful ophthalmoplegia. The authors describe the first case of a 12-year-old otherwise healthy girl who presented with painful ophthalmoplegia after a documented COVID-19 infection. Neuroimaging revealed inflammation within the ipsilateral cavernous sinus, Meckel’s cave, and orbital apex. After a comprehensive work-up was negative, the patient experienced prompt clinical and radiographic improvement with high-dose corticosteroids, and a diagnosis of THS was made.
 
T2w MRI-imaging (T2w) of the brain showing prominent subarachnoid space (arrow) and tortuosity of the optical nerve as well as slight flattening of both eyeballs.
Date and volume of CSF drainage.
Increased intracranial pressure in cerebral venous sinus thrombosis or metabolic disease has been reported. We present a case of new-onset chronic headache and bilateral papilledema in the setting of elevated intracranial pressure in strong temporal association to vaccination against COVID-19 with AstraZeneca. After repeated drainage of cerebrospinal fluid and conservative drug therapy, pathological findings were regredient. Even in absence of typical risk factors, increased intracranial pressure should be considered in case of clinical suspicion after COVID-19 vaccination.
 
The aim was to evaluate whether headache experts rarely, if ever, investigate spontaneous or provoked migraine/headache attacks. All the 494 Original Articles in five volumes of Cephalalgia (from 2014 to 2018) were screened and classified as dealing with spontaneous or provoked migraine/headache attacks, or other aspects of migraine/headache. Only 4.9% (24/494) of papers reported on studies of spontaneous and provoked migraine/headache attacks. Investigations of the pathophysiology of spontaneous or provoked migraine/headache attacks in humans could result in the development of better drugs for migraine, and to the identifications of biomarkers for use in personalized medicine.
 
Background Twitter is a leading microblogging platform, with over 126 million daily active users as of 2019, which allows for large-scale analysis of tweets related to migraine. June 2020 encompassed the National Migraine and Headache Awareness Month in the United States and the American Headache Society’s virtual annual conference, which offer opportunities for us to study online migraine advocacy. Objective We aim to study the content of individual tweets about migraine, as well as study patterns of other topics that were discussed in those tweets. In addition, we aim to study the sources of information that people reference within their tweets. Thirdly, we want to study how online awareness and advocacy movements shape these conversations about migraine. Methods We designed a Twitter robot that records all unique public tweets containing the word “migraine” from May 8th, 2020 to June 23rd, 2020, within a 400 km radius of New Brunswick, New Jersey, United States. We built two network analysis models, one for the months of May 2020 and June 2020. The model for the month of May served as a control group for the model for the month of June, the Migraine Awareness Month. Our network model was developed with the following rule: if two hashtag topics co-exist in a single tweet, they are considered nodes connected by an edge in our network model. We then determine the top 30 most important hashtags in the month of May and June through applications of degree, between-ness, and closeness centrality. We also generated highly connected subgraphs (HCS) to categorize clusters of conversations within each of our models. Finally, we tally the websites referenced by these tweets during each month and categorized these websites according to the HCS subgroups. Results Migraine advocacy related tweets are more popular in June when compared to May as judged by degree and closeness centrality measurements. They remained unchanged when judged by between-ness centralities. The HCS algorithm categorizes the hashtags into a large single dominant conversation in both months. In each of the months, advocacy related hashtags are apart of each of the dominant conversation. There are more hashtag topics as well as more unique websites referenced in the dominant conversation in June than in May. In addition, there are many smaller subgroups of migraine-related hashtags, and in each of these subgroups, there are a maximum of two websites referenced. Conclusion We find a network analysis approach to be fruitful in the area of migraine social media research. Migraine advocacy tweets on Twitter not only rise in popularity during migraine awareness month but also may potentially bring in more diverse sources of online references into the Twitter migraine conversation. The smaller subgroups we identified suggest that there are marginalized conversations referencing a limited number of websites, creating a possibility of an “echo chamber” phenomenon. These subgroups provide an opportunity for targeted migraine advocacy. Our study therefore highlights the success as well as potential opportunities for social media advocacy on Twitter.
 
Patients' data and headache features.
Previous headaches.
HIT scores in patients treated with onabotulinumtoxinA.
Review of associated headaches. a
Nummular headache (NH) is an unusual disorder attributed to a dysfunction of the epicranial nerves. We report a new series of cases, highlighting some clinical features, the association with other headaches, and the therapeutic response. Data of patients with NH, fulfilling ICHD-3 criteria, observed in a Headache Outpatient clinic during 5 years, were retrieved from records. Response to onabotulinumtoxinA was recorded prospectively and evaluated with a Headache Impact Test (HIT). Twenty-four patients, aged 53.8 (±14.6) years at diagnosis, 13 women, had definitive (N = 21) or probable (N = 3) NH for an average of 2.4 years. Headache was consistently localized, more frequently extratrigeminal (N = 15) and parietal, and confined to the scalp. Pain was unremitting since onset in 58.3% of mild-to-moderate severity often with superimposed paroxysms (66.7%) and local allodynia (70.8%). In five cases, there was a possible precipitant. Thirteen patients reported other headaches, preceding NH by 8.2 years. In eight persistent cases, there was a significant improvement on HIT, after onabotulinumtoxinA. Despite its persistence, NH may go unrecognized for years. It often follows other headache types and has some tropism for hair-covered regions of the scalp. OnabotulinumtoxinA seems effective in persistent cases.
 
Epidemiological profiles and clinical features of 31 patients with hemicrania continua.
Details of exacerbations in HC (n: 31 Patients).
Clinical features noted during follow-up.
A comparative study between HC of <12 months to HC of >12 months duration.
Diagnostic and therapeutic features noted from previous medical case sheet or records.
Introduction Till date, there is no prospective study in patients with hemicrania continua (HC). Methods Patients fulfilling the international classification of headache disorders criteria for HC were evaluated prospectively. All patients were subjected to a detailed clinical interview, based on a structured questionnaire. Before starting indomethacin, all patients were instructed to fill a headache diary for at least 5 days. Gradual tapering of indomethacin was done at regular intervals. Results We enrolled 41 patients over 4.5 years, 31 of whom met the criteria after confirming the indomethacin response. The mean age was 41 years, and 55% were female. The mean duration of headache was 43.6 months. All patients had continuous strictly unilateral pain with episodic exacerbations. At least one cranial autonomic feature was noted in 81% of patients. Twenty-five patients (81%) felt a sense of restlessness during exacerbations. The mean follow-up was 2.5 years. Three-fourths of patients noted a reduction in indomethacin dose after an average 2.5 of years follow-up. The mean reduction of the dose in the follow-up was statistically significant (172 mg vs. 110 mg, p < 0.001). All patients missed the drug for various reasons over the observation period. The headache reappeared within 48 h in 97% of patients. Conclusion Misdiagnosis of HC is still very common. Patients may not volunteer about the background pain and will focus only on the exacerbations. HC rarely remits, but indomethacin requirements may decrease over time. Skipping of the effective drug leads to the immediate reappearance of pain.
 
Background Rimegepant, a small molecule oral calcitonin gene-related peptide (CGRP) receptor antagonist, is approved for the acute and preventive treatment of migraine. We hypothesized that intermittent CGRP receptor blockade with rimegepant 75 mg acute treatment as needed (PRN) might result in reductions in monthly migraine days (MMD) over time, and was evaluated as the study objective. Methods This was a post-hoc analysis of adults with ≥6 MMD at baseline who self-administered rimegepant 75 mg orally PRN for acute treatment of migraine up to 52-weeks in an open-label safety study (BHV3000-201; NCT03266588). Outcome measures (defined as median time to) and response rates (defined as proportion of patients reporting) were captured for ≥30% and ≥50% reduction of baseline MMD. Results 1044 participants with ≥6 MMD at baseline were analyzed. Median time to ≥30% reduction in MMD was 12 weeks (IQR; 4–40 weeks); median time to ≥50% reduction was 32 weeks (IQR; 12-NR weeks). Reduction in MMD was observed over time regardless of baseline migraine frequency, however higher baseline MMD were associated with a longer time to achieving ≥30% or ≥50% MMD reduction. Conclusion In participants presenting with ≥6 MMD, PRN acute treatment of migraine attacks over 52-weeks with oral rimegepant 75 mg was observed to confer reductions in migraine frequency. Trial registration NCT03266588
 
Background Ubrogepant is a novel, oral calcitonin gene–related peptide receptor antagonist approved by the US Food and Drug Administration for acute treatment of migraine with or without aura in adults. Objectives To assess potential pharmacokinetic (PK) drug–drug interactions in healthy participants and inform the safety and tolerability of ubrogepant alone and in combination with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) in healthy participants and participants with migraine. Methods Two phase 1, three-way crossover studies randomized healthy adults to 100 mg ubrogepant alone, 1000 mg acetaminophen or 500 mg naproxen alone, and 100 mg ubrogepant plus 1000 mg acetaminophen or 500 mg naproxen. Geometric mean ratios (GMRs) and 90% confidence intervals were calculated based on statistical comparison of maximum plasma drug concentration ( C max ) and area under the plasma drug concentration–time curve (AUC) for treatment in combination versus alone. Two phase 3 randomized trials included adults with migraine. Treatment-emergent adverse events (TEAEs) were evaluated. Results Time to C max and terminal elimination half-life for all treatments were unchanged when coadministered. Ubrogepant C max and AUC increased by approximately 40% when coadministered with acetaminophen. Acetaminophen C max decreased by 24% (GMR = 0.76) when coadministered with ubrogepant. There were no significant PK interactions between ubrogepant and naproxen. TEAE rates in the acetaminophen and NSAID rescue medication groups were similar to ubrogepant alone. Conclusions Coadministration of ubrogepant and acetaminophen resulted in a statistically significant increase in ubrogepant exposure and a decrease in acetaminophen C max ; however, these changes were not clinically relevant. No statistically or clinically relevant changes in PK were associated with ubrogepant and naproxen coadministration. No safety concerns were identified for ubrogepant alone or in combination with acetaminophen or NSAIDs.
 
Sumatriptan activates a subpopulation of carvacrolsensitive rat TG neurons. Rat TG neurons in primary culture were stimulated with sumatriptan, carvacrol (Carv, 100 mM), capsaicin (Caps, 1 mM) and KCl (60 mM). The averaged responses of all 47 carvacrol-sensitive neurons are illustrated. Note the robust calcium transient evoked by sumatriptan in these neurons. Data are represented as mean + SEM, horizontal bars indicate the duration of application. SEM: standard error of the mean.
Venn diagram of sensitivity to capsaicin, carvacrol, and sumatriptan in rat TG neurons. All 27 sumatriptan-sensitive neurons were a subset of the 47 carvacrol-sensitive neurons. All carvacrol-sensitive neurons were a subset of the 161 capsaicinsensitive neurons.
Membrane currents evoked by sumatriptan in HEK293-hTRPA1 cells. Illustrative whole-cell patch clamp recording from a HEK293t cell transiently transfected with hTRPA1 voltageclamped at À60 mV, and subjected to 400-ms voltage ramps from À100 mV to þ100 mV every 4 s. Under the exposure to sumatriptan (100 mM), a slowly developing but in the end, large current developed. The current at þ80 mV (circles) and À80 mV (squares) are visualized in the upper panel. The current-voltage relationship before and at the end of the respective application bars showed a TRPA1-typical outward rectification in response to sumatriptan and carvacrol (lower panel). This current was almost completely inhibited by the TRPA1 antagonist HC030031 (10 mM), see blue trace Suma þ HC. All sumatriptan-sensitive cells (n ¼ 3) were also activated by the TRPA1 agonist carvacrol (100 mM). Horizontal bars indicate the duration of application.
Background Migraine therapy with sumatriptan may cause adverse side effects like pain at the injection site, muscle pain, and transient aggravation of headaches. In animal experiments, sumatriptan excited or sensitized slowly conducting meningeal afferents. We hypothesized that sumatriptan may activate transduction channels of the “irritant receptor,” the transient receptor potential ankyrin type (TRPA1) expressed in nociceptive neurons. Methods Calcium microfluorometry was performed in HEK293t cells transfected with human TRPA1 (hTRPA1) or a mutated channel (TRPA1-3C) and in dissociated trigeminal ganglion neurons. Membrane currents were recorded in the whole-cell patch clamp configuration. Results Sumatriptan (10 and 400 µM) evoked calcium transients in hTRPA1-expressing HEK293t cells also activated by the TRPA1 agonist carvacrol (100 µM). In TRPA1-3C-expressing HEK293t cells, sumatriptan had hardly any effect. In rat trigeminal ganglion neurons, sumatriptan, carvacrol, and the transient receptor potential vanillod type 1 agonist capsaicin (1 µM) generated robust calcium signals. All sumatriptan-sensitive neurons (8% of the sample) were also activated by carvacrol (14%) and capsaicin (48%). In HEK293-hTRPA1 cells, sumatriptan (100 µM) evoked outwardly rectifying currents, which were almost completely inhibited by the TRPA1 antagonist HC-030031 (10 µM). Conclusion Sumatriptan activates TRPA1 channels inducing calcium inflow and membrane currents. TRPA1-dependent activation of primary afferents may explain the painful side effects of sumatriptan.
 
The objectives of the study are to investigate the incidence of new or worsening headache after cochlear implant (CI) surgery and activation and to determine whether there are predictors of associated headache. We performed a cross-sectional survey of patients who had CI surgery. The frequency and severity of headache, onset of headache relative to surgery and device activation, medication use, family history, headache triggers, and accompanying cranial autonomic symptoms were recorded and analyzed. Thirty-seven subjects were enrolled. In the time period after CI surgery but before CI activation, none reported a new headache and four (11%) reported a worsening headache. After CI activation, six (16%) developed new headache and five (14%) developed worsening headache. These 11 subjects also experienced a significantly higher mean of 6.3 headache days/month following CI activation ( p < 0.009). Providers should be aware that new or worsening headache can be reported following CI activation, although not immediately following CI surgery.
 
Common TEAEs (occurring in 2% of patients) in either treatment group by percentage of patients and percentage of attacks (safety population).
GLADIATOR was a prospective, randomized, open-label, phase 3 study of lasmiditan 100 mg or 200 mg dosed intermittently for up to 1 year in patients with episodic migraine. Most patients had completed one of two single-attack studies before participation. A total of 2030 patients received ≥1 lasmiditan dose and 19,879 migraine attacks were treated. Safety results were similar to the previously reported interim analysis. The most frequently reported treatment-emergent adverse events (TEAEs) included dizziness (18.5%), somnolence (8.5%), and paresthesia (6.8%), with frequency of adverse events appearing to decrease with subsequently treated attacks. At 2 h post-dose, 26.7% and 32.2% of all attacks treated with lasmiditan 100 mg and 200 mg, respectively, were pain free. This pattern was generally consistent across study quarters and treated attacks. In conclusion, during a 1-year treatment period, intermittent lasmiditan for episodic migraine treatment was associated with generally decreasing TEAEs and consistent efficacy.
 
Consolidated Standards of Reporting Trials (CONSORT) diagram.
Examples of strategies to enhance feasibility in pediatric ED migraine trials. ED: emergency department.
Objective To assess the feasibility of a randomized controlled trial protocol that aims to determine the efficacy and safety of oral dexamethasone compared to placebo for the prevention of migraine recurrence in children and adolescents visiting the pediatric emergency department (ED) with migraine. Methods This study was a two-arm, parallel-group, randomized, placebo-controlled, double-blind pilot trial of patients presenting to the pediatric ED with migraine. Eligible participants were randomized at 1:1 ratio to receive either oral dexamethasone 0.6 mg/kg (maximum 15 mg) or matched placebo as a single dose. Efficacy and safety outcomes were assessed at discharge, 48 h and 7 days after discharge. The primary outcome of the trial was feasibility and was assessed through participant recruitment rate, follow-up completion rates, participant satisfaction ratings and comparison of enrolled versus non-enrolled participants. Efficacy and safety outcomes were not analyzed given that this was a pilot study. Results Twelve participants were enrolled over the 6-month recruitment period. This represents 60% of the planned sample size and a 10.5% recruitment rate. No other feasibility issues were identified and patients expressed high satisfaction rates with their treatment: 90.9% were satisfied with their treatment at discharge and at 48-h follow-up and 81.8% were satisfied with their treatment at 7-day follow-up (81.8%). There were no significant differences observed when comparing enrolled participants to those not enrolled. Conclusion This pilot randomized controlled trial is the first to assess dexamethasone in the pediatric ED for the prevention of migraine recurrence. The protocol is feasible but recruitment in a single center was lower than expected. Future pediatric ED migraine studies may use innovative or pragmatic trial designs to maximize feasibility from a recruitment standpoint.
 
Prevalence of headache and other predefined symptoms on migraine-free days in 271 patients with migraine. a
Presence and absence of moderate or severe headache, neck discomfort, and sensitivity to lights, noises, or odors on migraine-free days.
Use of acute medication on migraine-free days in 271 patients with migraine. a
Risk for developing migraine on the subsequent day in the presence of moderate or severe headache, neck discomfort, and sensitivity to lights, noises, or odors on migraine-free days. a
Background Treating migraine attacks early may improve outcome. The aim of this analysis was to investigate whether certain premonitory symptoms could be indicators for taking acute medication. Methods We analyzed 3-month diary data recorded by 271 patients with episodic migraine and looked at all migraine-free intervals. For investigating the interaction between acute medication and neck discomfort associated with sensitivity to lights, noises, or odors, we used a marginal structural model and a Cox regression analysis adjusted for moderate or severe headache. Results The patients (mean age 43 ± 15.4 years, 88% women) recorded a total of 20,219 diary days without migraine. In the marginal structural model analysis, the risk for occurrence of a migraine attack on the subsequent day was reduced when acute medication was used in the presence of neck discomfort associated with sensitivity to lights (hazard ratio 0.4; 95% confidence interval 0.2–0.7), noises (0.4; 0.3–0.7), or odors (0.2; 0.1–0.4). The marginal structural model showed lower risk of migraine attacks than the Cox regression analysis adjusted for moderate or severe headache in the majority of the cases. Conclusion Migraine attacks may be prevented when acute medication is used in the presence of neck discomfort associated with sensitivity to lights, noises, or odors. The results of this study may stimulate further prospective trials.
 
Vestibular function test profile in a patient with vestibular migraine (case 7). (a) Normal v-HITs; (b) ictal v-HITs shows reduced VOR gain with covert and overt refixation-saccades in the left HC; (c) v-HIT at 1 month follow-up shows recovery of VOR gain of the left HC; (d) ictal cervical and ocular vestibular-evoked myogenic potentials (cVEMP/oVEMP) are preserved bilaterally with normal amplitude asymmetry ratios; (e) normal ictal audiogram; (f) ictal right beating spontaneous horizontal nystagmus (black trace) with slow-phase velocity 7.3 s À1 and up-beating component (red trace) with slow-phase velocity 2.4 s À1 . v-HITs: video-head impulse tests; VOR: vestibulo-ocular reflex; AC: anterior canal; AC-cVEMP: air-conducted cervical vestibular-evoked myogenic potential; AR: asymmetry ratio; BC-oVEMP: bone-conducted ocular vestibular-evoked myogenic potential; HC: horizontal canal; PC: posterior canal; *: reduced VOR gain.
To describe clinical, oculographic and vestibular test profiles in patients with vestibular migraine (VM) who presented with acute peripheral vestibulopathy. VM was diagnosed according to Bárány Society or Neuhauser criteria. Neuro-otological examination, video-head impulse tests (v-HIT), cervical and ocular vestibular-evoked myogenic potentials (cVEMP/oVEMP), subjective visual horizontal (SVH) and audiometry were undertaken. Ten patients presented with prolonged vertigo. All had primary position unidirectional horizontal spontaneous nystagmus (mean slow-phase velocity 9.6 ± 7.0°). Horizontal canal vestibulo-ocular reflex was reduced in all (mean gain 0.54 ± 0.2) with refixation saccades (cumulative amplitude 6.4 ± 3.2°). Abnormality rates for cVEMP, oVEMP and SVH were 30%, 80%, 78%, respectively. Magnetic resonance imaging brain was normal in all patients. Patients were followed up over 6 months to 8 years with no change in the final diagnosis. VM can rarely present as an acute peripheral vestibulopathy with findings that mimic vestibular neuritis and should be considered in the differential diagnosis of acute prolonged vertigo.
 
Study design flow. MBS: most bothersome migraine-associated symptom; e-TNS: external trigeminal nerve stimulation.
Inclusion and exclusion criteria.
Study participant flow. mITT: modified intention-to-treat.
Objective The main objective of this study was to obtain efficacy data for external trigeminal nerve stimulation (e-TNS) in the acute treatment of migraine in patients using the device at home. Methods This was a single-center, open-label trial conducted at the Rochester Clinical Research Center (Rochester, NY, USA). Patients who met International Classification of Headache Disorders, Third Edition, criteria for migraine with and without aura for ≥1 year and having between 2 and 8 moderate or severe attacks per month were recruited. Patients were advised to treat one migraine attack of moderate to severe intensity that started less than 4 h earlier and was not treated with an acute migraine medication, with a 2-h e-TNS session. Primary outcome measures were pain freedom at 2 h and most bothersome migraine-associated symptom (MBS) freedom at 2 h. Secondary outcome measures were pain relief at 2 h, the absence of migraine-associated symptoms at 2 h, the use of rescue medication between 2 and 24 h, and sustained pain freedom at 24 h. Results Fifty-nine subjects were included in the study, and among them, 48 subjects were eligible for the modified intention-to-treat analysis. After 2 h of e-TNS, 35.4% of the subjects were pain-free, 60.4% were MBS-free, 70.8% had pain relief, and 45.8% were free from all migraine-associated symptoms. Half of the subjects took rescue medication between 2 h and 24 h, and sustained pain freedom at 24 h was achieved for 25.0% of the subjects. Regarding safety, 15 patients reported adverse events, all minor and fully reversible, mainly forehead paresthesia. Conclusions This study shows that e-TNS with the Cefaly® Acute Device is effective, well-tolerated, and safe for the acute treatment of migraine in patients using the device at home. A large, multicenter, randomized, sham-controlled trial is needed to confirm this finding.
 
Background Parenteral non-steroidal anti-inflammatory drugs (NSAIDs) are important alternatives to oral NSAIDs, especially in patients with severe migraine who have emesis or gastroparesis. With increasing research on using parenteral NSAIDs for acute migraine, it is critical to examine the quality of these studies. Our goal was to assess the adherence of these trials to the International Headache Society (IHS) controlled trial guidelines for acute treatment of migraine. Methods We queried PubMed for clinical trials investigating parenteral NSAIDs for acute treatment of migraine in adult patients. We developed a 14-point scoring system based on the essential components of the IHS guidelines. To date, four versions of the IHS’s Guidelines for controlled trials of acute treatment of migraine attacks have been published. Each trial was evaluated with the appropriate edition of the guidelines. Results We identified 216 studies and assessed 27 eligible clinical trials. The mean score was 6.7 ± 2.1 (2–11). Most trials followed the IHS migraine diagnosis criteria (85.2%), but only six (22.2%) selected patients based on the recommended headache frequency. Most trials were randomized (88.8%), but fewer were double-blinded (74.1%) or placebo-controlled (11.1%). Almost every trial clearly explained the pain scale (96.3%), and three-quarters (77.8%) assessed headache-associated symptoms. However, no trial utilized the recommended primary endpoint: pain-freedom at 2-hours. Conclusions Most clinical trials on parenteral NSAIDs for acute migraine did not fully adhere to the IHS recommendations. Future studies should pay special attention to the IHS guideline to improve the quality of clinical trials for the acute treatment of migraine.
 
Norm-based SF-36 scores at visits 1 and 2, according to therapy. General population score !50 on each item. PF: physical functioning; RP: physical role; BP: bodily pain; GH: general health perceptions; VT: vitality; SF: social functioning; RE: emotional role; MH: mental health.
Descriptive analysis of the patients.
Background The quality of life of migraine patients, particularly mental domains, is severely diminished despite the preventive therapies available. We aimed to evaluate whether citalopram plus nadolol is superior to nadolol alone in terms of quality of life (QOL) in migraine patients. Methods Adult patients with episodic migraine (≥ 3 headache days per month) were allocated by simple randomization to nadolol 40 mg daily plus citalopram 10 mg daily or to nadolol alone. Baseline visit confirmed the entry criteria and patients filled out a generic QOL (SF-36) as well a migraine-specific questionnaire (MSQoL), a measure of migraine-related disability (MIDAS), a headache calendar and Beck inventory for depression and anxiety. This battery was again completed after 16 weeks of therapy. Results A total of 92 patients from a general neurology clinic completed the study, 85% females with migraine without aura. Fourty-four (47.83%) patients were allocated to nadolol therapy, and 48 (52.17%) to the combination of nadolol plus citalopram. After therapy, both groups had a similar gain in quality of life (SF-36 and MSQOL), but combination therapy was not superior to nadolol. Despite this improvement, all SF-36 domains remained below the population norms in both groups. Conclusion Adding systematically citalopram 10 mg daily to a conventional migraine preventive drug (nadolol) does not result in an additional improvement in the QOL of migraine patients.
 
Casuistic from the ELSA-Brasil study. ELSA-Brasil: Brazilian Longitudinal Study of Adult Health.
Distribution of serum adiponectin (a) and leptin levels (b) at the baseline of ELSA-Brasil, according to migraine status in all sample (N ¼ 257).
Distribution of serum adiponectin (a) and leptin levels (b) at the baseline of ELSA-Brasil, according to migraine status in 122 women.
Distribution of serum adiponectin (a) and leptin levels (b) at the baseline of ELSA-Brasil, according to migraine status in 135 men.
Background Relationships of adipokines (ADP) with migraine are not well-established. We examined the relationship of adiponectin and leptin with migraine by aura symptoms. Methods In a baseline cross-sectional data of Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), associations of ADP levels and migraine were assessed in a sample of 257 nondiabetic subjects, free from cardiovascular disease. Associations of ADP tertiles (dependent variable) and migraine status were tested using logistic regression models. Categories of migraine were created as follows: no headache (reference), migraine with aura (MA), and migraine without aura (MO) in all sample and by sex. Odds ratio (OR) with respective 95% confidence interval (CI) adjusted for age, sex, body mass index, and metabolic syndrome. Results Among participants (46 years ± SD: 4.8), 47.5% were women and 36.2% had migraine (16.7% MA). Median values of leptin (ng/mL) increased gradually across subgroup: no headache: 9.5 (interquartile range (IQR): 5.5–15.7) versus MO: 17.0 (IQR: 10.9–34.2) versus MA: 20.9 (IQR: 11.7–29.3), overall p value <0.0001, but not for adiponectin levels. After full adjustment, the third of leptin was positively associated with MA (OR 2.89 (1.00–8.4)) and the second of adiponectin was associated with MO (OR 2.76; 95% CI: 1.09–6.96, p = 0.03). Positive associations with MA, second (OR 3.81; 95% CI: 1.07–13.59; p = 0.04) and third tertile of leptin (6.54; 95% CI: 1.74–24.57, p = 0.005), were also observed in women, but not in men. Conclusions Positive associations between ADP and migraine, particularly between MA and leptin levels in women, raise the possibility of adipocytokines and play a role in migraine pathophysiology.
 
Introduction Migraine is a polygenic multifactorial disorder with a neuronal initiation of a cascade of neurochemical processes leading to incapacitating headaches. Headaches are generally unilateral, throbbing, 4–72 h in duration, and associated with nausea, vomiting, photophobia, and sonophobia. Chronic migraine (CM) is the presence of a headache at least 15 days per month for ≥3 months and has a high global impact on health and economy, and therapeutic guidelines are lacking. Methods Using the Grading of Recommendations, Assessment, Development, and Evaluations system, we conducted a search in MEDLINE and Cochrane to investigate the current evidence and generate recommendations of clinical practice on the identification of risk factors and treatment of CM in adults. Results We recommend avoiding overmedication of non-steroidal anti-inflammatory drugs (NSAIDs); ergotamine; caffeine; opioids; barbiturates; and initiating individualized prophylactic treatment with topiramate eptinezumab, galcanezumab, erenumab, fremanezumab, or botulinum toxin. We highlight the necessity of managing comorbidities initially. In the acute management, we recommend NSAIDs, triptans, lasmiditan, and gepants alone or with metoclopramide if nausea or vomiting. Non-pharmacological measures include neurostimulation. Conclusions We have identified the risk factors and treatments available for the management of CM based on a grading system, which facilitates selection for individualized management.
 
Mean systolic blood pressure over the first 4 hours post-dose following sumatriptan on Day 1 and rimegepant þ sumatriptan on Day 5.
Demographics and other baseline characteristics. y
Pharmacokinetics of rimegepant on Day 4 and rimegepant þ sumatriptan on Day 5.
Objective This randomized, partially-blinded, placebo-controlled study evaluated hemodynamic effects, pharmacokinetic interactions, and safety of concomitant administration of oral rimegepant and subcutaneous sumatriptan. Methods Healthy non-smokers aged ≥18 and ≤40 years (men) or ≥18 and ≤50 years (women) were enrolled. On Day 1, subjects received 12 mg of sumatriptan as 2 subcutaneous 6 mg injections separated by 1 hour. From Days 2 to 4, subjects received rimegepant or placebo once daily (randomized 6 to 1, rimegepant to placebo). On Day 5, subjects received rimegepant or placebo, followed 2 hours later by 2 subcutaneous 6 mg injections of sumatriptan, separated by 1 hour. Sumatriptan was administered at the same times as on Day 1. Results All 42 dosed subjects were analyzed. There were no significant differences in the time-weighted average of mean arterial pressure, diastolic blood pressure, or systolic blood pressure between treatment with rimegepant + sumatriptan and sumatriptan alone. Co-administration of rimegepant and sumatriptan had no effect on the pharmacokinetics of either drug. Overall, 93% (39/42) of subjects experienced ≥1 adverse event; injection site reaction was most common (60% [29/42]). Conclusions Concomitant administration of oral rimegepant and subcutaneous sumatriptan to healthy adults was without hemodynamic or pharmacokinetic interaction and was safe and well tolerated.
 
Background Ubrogepant is metabolized by cytochrome P450 3A4 (CYP3A4) and is a P-glycoprotein (P-gp) substrate. Objective To assess effects of multiple-dose moderate-strong CYP3A4 and strong P-gp inhibitors and inducers on ubrogepant pharmacokinetic (PK) parameters. Methods Two phase 1, open-label, fixed-sequence, single-center, crossover trials enrolled healthy adults to receive ubrogepant 20 mg with/without verapamil 240 mg (a moderate CYP3A4 inhibitor) or ketoconazole 400 mg (a strong CYP3A4 and P-gp transporter inhibitor) (Study A), or ubrogepant 100 mg with/without rifampin 600 mg (a strong CYP3A4 inducer and P-gp inducer) (Study B). Outcomes included ubrogepant PK parameters (area under plasma concentration-time curve, time 0 through infinity [AUC 0-∞ ], peak plasma concentration [C max ]), and safety (treatment-emergent adverse events [TEAEs]). PK parameters were compared between ubrogepant with/without coadministered medications using linear mixed-effects models. C max and AUC 0-∞ least-squares geometric mean ratios (GMR) of ubrogepant with/without coadministration were constructed. Results Twelve participants enrolled in Study A and 30 in Study B. AUC 0-∞ and C max GMR (90% CI) were 3.53 (3.32–3.75) and 2.80 (2.48–3.15), respectively, for ubrogepant with verapamil; 9.65 (7.27–12.81) and 5.32 (4.19–6.76) with ketoconazole; and 0.22 (0.20–0.24) and 0.31 (0.27–0.36) with rifampin. TEAEs were predominantly mild; no treatment-related serious TEAEs or TEAE-related discontinuations occurred. Conclusion The PK of ubrogepant were significantly affected by the concomitant use of CYP3A4 moderate-strong inhibitors and strong inducers.
 
Flow-diagram of patient inclusion.
Primary and secondary outcomes for all time points: (a) NDI, (b) headaches days/month, (c) PHQ-9, and (d) MIDAS. Figures display means (SEM). NDI: Neck Disability Index; PHQ: Personal Health Questionnaire; MIDAS: Migraine Disability Assessment Score.
Reduction in headache days according to stratification based on palpation of the upper cervical spine at baseline.
Primary and secondary outcomes for all time points.
Objectives The main objective of this study was to compare the effectiveness of aerobic exercise with physiotherapy. A second objective was to evaluate whether patients with pain referred to the head during manual palpation will benefit more from physiotherapy than patients with local or no pain. Methods A total of 103 patients with migraine received physiotherapy ( n = 79) or supervised aerobic exercise ( n = 24) according to their preference as an add-on treatment. Both groups had the same contact time with a specialized physiotherapist. The primary outcome measure was headache frequency during the 4 weeks after the intervention. Eighty-seven patients were analyzed at the primary end point ( n = 69 in the physiotherapy group; n = 18 in the aerobic exercise group). A follow-up assessment was conducted 3 months after the final intervention. Results During the initial assessment of the upper cervical spine, 17 patients reported no pain, 45 local pain, and 25 referred pain to the head. Patients in the physiotherapy group had a mean reduction of 1.8 days (standard deviation (SD) 6.07), while patients in the aerobic exercise group had a mean reduction of 1.2 days (SD 4.27) at the primary end point. This difference was not statistically significant ( p = 0.8). The largest improvement was noted in the group that showed referred pain to the head and received physiotherapy (2.13 days (SD 7.82)). Only patients in the physiotherapy group reported a subjectively perceived general improvement. Conclusions Patients had a strong preference for physiotherapy. Both groups showed small reductions in headache frequency. Effects were superior after physiotherapy but not statistically significant. Patients with pain referred to the head responded best to a physiotherapy intervention.
 
Days and dose of Lithium Treatment cohorts.
New daily persistent headache (NDPH) is an uncommon, treatment-resistant primary headache disorder that was first describe by Vanast in 1986 as a benign syndrome. Elevated TNF-alpha levels on CSF of NDPH patients as a possible cause of this disease. TNF-alpha inhibitors like doxycycline, venlafaxine and montelukast have been used in the past with relative good success. Lithium, used in Cluster Headache, has anti-inflammatory effects by inhibition of glycogen synthase kinase-3 (GSK3). This mechanism of action reduces production of inflammatory IL-6, IL-1 beta and TNF-alpha production by microglia, astrocytes and other immune cells. We report a NDPH patient that responded successfully to the administration of lithium after trying multiple treatments. We propose lithium, a TNF-alpha Inhibitor, as an effective treatment for refractory cases of NDPH.
 
International headache society members per million habitants in Latin America (colour coded). The highest density was found in Dominican Republic. There are no registered IHS members in 13 countries in the region. IHS: International Headache Society.
Survey response rates per country.
Related concepts when diagnosing medication overuse headache.
Top-usage of different therapeutic approaches. Bottom-withdrawal pattern preferences.
Introduction Headache epidemiological studies in Latin America are scarce, and available data suggest that medication overuse headache is an existing health concern in the region. Materials and Methods A survey empirically constructed to assess the management of medication overuse headache was sent to all the International Headache Society (IHS) members from Latin American countries. Results We found no IHS members in 13 countries of Latin America. In countries with active members, the median number of IHS members per million inhabitants was significantly less when compared to Western Europe. Although the International Classification of Headache Disorders-3-beta (ICHD-3-beta) criterion was the most frequently used tool for medication overuse headache diagnosis, 41% of responders considered the diagnostic criterion ‘ambiguous’ and only 67% found them ‘very useful’. With respect to preferred treatment patterns, an important lack of uniformity, and a very limited usage of therapeutic approaches widely employed in other regions, characterized the responses. Conclusion There is an urgent need to reach a consensus and establish region-specific strategies for the management of medication overuse headache as well as other headache disorders in this region. Development of headache specialized educational programmes, and participation of Latin American health providers in the IHS, should be incentivized.
 
Location of the otic ganglion in the left infratemporal fossa. The OG is situated directly medial to the mandibular nerve under the foramen ovale. OG: otic ganglion.
Illustration of the roots and branches of the otic ganglion, with permission from Senger et al. 10
(a) Photograph showing an anatomic preparation of the left OG. (b) An enlargement of the same preparation with the measured distance between the inferior aspect of the FO and the OG (0.59 mm in this preparation). FO: foramen ovale; OG: otic ganglion.
Illustration showing the assumed mechanism underlying how a block of the SPG works. SPG: sphenopalatine ganglion.
Background The otic ganglion (OG) is a cranial parasympathetic ganglion located in the infratemporal fossa under the foramen ovale (FO) and adjacent to the medial part of the mandibular nerve. Parasympathetic innervation of intracranial vessels from the OG has been shown both in animal and human models and evidence suggests that the OG plays an important role in the cranial vasomotor response. We review the evidence that positions the OG as a viable target for headache disorders. The OG is a small structure and not detectable on medical imaging. The FO is easily identifiable on CT scans and the mandibular nerve on MRI, hence, the position of the OG may be predicted if the mean distance from the FO is known. Objective The objective is to describe the average distance between the FO and the OG in a sample of 18 infratemporal fossae from 21 cadavers. Methods A total of 21 high definition photographs of 21 infratemporal fossae from 18 cadavers were analyzed. The distance between the inferior edge of the medial part of the FO to the OG was measured. Results Four photographs of infratemporal fossae of four cadavers were excluded due to the inability to localize the inferior edge of the FO. A total of 15 infratemporal fossae from 17 cadavers were measured. The mean distance from the FO to the OG was 4.5 mm (SD 1.7), range 2.1–7.7 mm. Conclusions We have described the average distance from the OG to an easily identifiable anatomical landmark that is visible in CT scans, the FO. This anatomical study may aid in the development of strategies to localize the OG in order to explore its role as a therapeutic target for headache disorders.
 
Introduction Post-traumatic headaches (PTH) are common following mild traumatic brain injury (mTBI). There is evidence of altered central pain processing in adult PTH; however, little is known about how children with PTH process pain. The anterior cingulate cortex (ACC) plays a critical role in descending central pain modulation. In this study, we explored whether the functional connectivity (FC) of the ACC is altered in children with PTH. Methods In this case-control study, we investigated resting-state FC of 5 ACC seeds (caudal, dorsal, rostral, perigenual, and subgenual) in children with PTH ( n = 73) and without PTH ( n = 29) following mTBI, and healthy controls ( n = 27). Post-concussion symptoms were assessed using the Post-Concussion Symptom Inventory and the Child Health Questionnaire. Resting-state functional Magnetic Resonance Imaging (fMRI) data were used to generate maps of ACC FC. Group-level comparisons were performed within a target mask comprised of pain-related regions using FSL Randomise. Results We found decreased FC between the right perigenual ACC and the left cerebellum, and increased FC between the right subgenual ACC and the left dorsolateral prefrontal cortex in children with PTH compared to healthy controls. The ACC FC in children without PTH following mTBI did not differ from the group with PTH or healthy controls. FC between rostral and perigenual ACC seeds and the cerebellum was increased in children with PTH with pre-injury headaches compared to those with PTH without pre-injury headaches. There was a positive relationship between PTH severity and rostral ACC FC with the bilateral thalamus, right hippocampus and periaqueductal gray. Conclusions Central pain processing is altered in children with PTH. Pre-existing headaches help to drive this process. Trial registration The PlayGame Trial was registered in ClinicalTrials.gov database ( ClinicalTrials.gov Identifier: NCT01874847).
 
Medication overuse headache (MOH) is defined as headache occurring ≥15 days/month developing as a consequence of regular overuse of acute or symptomatic headache medication for more than 3 months. MOH is present in more than 50% of patients with chronic migraine (CM). Although, studies have shown a positive impact for MOH patients of early introduction of preventive treatment and withdrawal of overused medication, uncertainties remain. The main purpose of this systematic review and meta-analysis is to assess the relative impact of topiramate, botulinum toxin type A, and human monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) or its receptor (CGRPr) among MOH patients with CM. The PRISMA guideline for conducting systematic review will be followed. CENTRAL, MEDLINE, Embase and Web of Science databases will be searched. RCTs reporting outcomes such as change in migraine/headache frequency, change from MOH to no MOH, and ≥50% response rate will be included. The effect will be measured as mean difference (MD) for continuous data and odds ratio (OR) for dichotomous data. Heterogeneity across studies will be assessed using the Cochrane I ² statistics. The Cochrane RoB2 tool will be used to assess risk of bias, and the quality of evidence for outcomes will be rated according to five factors defined in Cochrane GRADE approach. The revision of the included articles, data extraction, risk of bias assessment, and quality rating of evidence will be independently done by two reviewers. Any discrepancies will be resolved through consensus with the third reviewer.
 
Background The majority of CGRP monoclonal antibodies for migraine prevention are administered subcutaneously. Therefore, we attempted to calculate the pooled placebo response with subcutaneous placebo injections in this systematic review and meta-analysis. Methods We identified 16 randomized controlled trials that met our inclusion and exclusion criteria through a comprehensive search in five electronic databases (PubMed Central, EMBASE, MEDLINE, Cochrane library and clinicaltrials.gov ). The risk of bias was assessed for all included studies. Random effects model was used to calculate pooled mean monthly migraine days and 50% response rates. Results A total of 4240 subjects were included from 16 studies in this meta-analysis. The pooled mean monthly migraine day reduction with subcutaneous placebo injections was 2.15 (95% CI: 1.60–2.69). The pooled proportion of patients achieving a 50% reduction in mean monthly headache days was 26% (95% CI: 20%–31%). Placebo response accounted for more than 50% of therapeutic gain in our study. Conclusion A substantial placebo response was noted with subcutaneous injections in migraine CGRP monoclonal antibody clinical trials. This meta-analysis may serve as a reference point to calculate sample size in clinical trials using subcutaneous interventions for migraine prevention. We registered our study at PROSPERO (CRD42020185300).
 
Flow chart illustrating inclusion procedure.
Characteristics of the study population. a
Characteristics of the study population according to referral diagnosis. a
Background Migraine is underdiagnosed especially by general practitioners and non-neurologists. In our experience, validated screening and diagnosing tools for migraine are generally not used outside neurology. The three-item identification of migraine (ID-Migraine™) is a short and validated screening/diagnosing tool; positive predictive value for migraine is 93% if at least two out of nausea, photophobia, or disability are present. Aim To investigate the diagnostic yield of ID-Migraine™ when applied to the information provided in the referral letters. Methods Retrospective analysis of 95 referral letters of patients referred for undetermined headache who were finally diagnosed with migraine at our Tertiary Care Headache Center. Results Median age was 34 years, and 75% were women. Migraine was suspected by the referring physician in 33% of patients, whereas the remainder were classified as unclear. ID-Migraine™ criteria were fulfilled in 59% of patients with referral diagnosis of suspected migraine and 23% of patients with unclear headache, respectively. Clinical characteristics associated with migraine suspicion were photophobia and other visual symptoms. Conclusion Applying ID-Migraine™ in primary care, emergency departments, or in specialists’ consultations outside neurology might lead to an increased frequency of migraine recognition. Knowledge about and access to those criteria should be increased, especially in the primary care setting.
 
Distribution of all headaches reported.
Headache patterns: all combinations of laterality, regionality and temporal profile reported. All uni-and bilaterally restricted headaches were counted as one region. For all uni-and bilateral headaches with a larger distribution, all regions involved were counted separately: for contiguous headaches 2 regions and for hemicranial headaches 3, leading to a total of 44 regions.
Symptoms reported in GCA cohort.
Aim To help clinicians in the diagnostic approach of giant cell arteritis (GCA) by providing a better knowledge on headache patterns in GCA. Methods Cross-sectional data of a cohort of 30 known GCA patients regarding symptoms, clinical signs, laboratory and pathology data were collected retrospectively. Results Headache was experienced by the majority of our cohort (26/30; 87%) and the most common pattern reported was a continuous, unilateral pain centered in or around the temporal area (13/26; 50% of all headaches). Pain confined to the occiput or frontal areas of the head was rarely reported as well as migrainous or cluster-like headaches. Conclusion This data suggests that the headache pattern in GCA is heterogeneous, but that the most common pattern is a continuous, unilateral, temporal headache. Several other patterns were infrequently reported and these should question the clinical diagnosis of GCA. A large prospective study will be necessary to further elaborate these findings.
 
Occupation of the right maxillary sinus with distortion of its walls by mass protruding into the nasal fossa with complete obliteration of the middle infundibulum and reabsorption of the turbinate, all compatible with fungal sinusitis.
A symptomatic cluster headache (CH), caused by fungal maxillary sinus infection fulfilling the criteria of International Headache Society (ICDH-3) for CH is presented. A 35-year-old man without previous headaches reported episodes of pain in the right fronto-orbitary region, with severe eyelid oedema, photophobia, frontal sweating, lacrimation, conjunctival injection and rhinorrhoea, which lasted for 2–3 h. A brain magnetic resonance imaging (MRI) showed occupation of the right maxillary sinus, a mycetoma due to Aspergillus fumigatus. Although rare, secondary causes must be discarded before the diagnosis of a primary CH is made. Imaging study should always be performed, even though no atypical feature was present and ICDH-3 were fulfilled.
 
Study population identification. a MIDAS: Migraine Disability Assessment, validated questionnaire.
Baseline treatments by disability grade. Disability grade based on MIDAS score: Little to no disability (0-5 days), mild (6-10 days), moderate (11-20 days), severe (21þ days). MIDAS: Migraine Disability Assessment, validated questionnaire.
Baseline treatments by provider specialty. Provider specialty: Specialty of provider completing the MIDAS questionnaire. MIDAS: Migraine Disability Assessment, validated questionnaire.
Baseline clinical characteristics.
Background Better understanding of migraine treatment in US clinical practice could be facilitated by availability of Migraine Disability Assessment (MIDAS) questionnaire results collected in routine care. We present results for migraine patients with MIDAS collected in routine clinical practice through an electronic medical record (EMR) system that presented the MIDAS questionnaire as an electronic form during the patient office encounter. The purpose of this retrospective observational study was to gain better understanding of migraine disability and migraine treatment patterns in US real-world clinical practice. Methods In this EMR database study, patients were required to have 12 months baseline time for review of patient and clinical characteristics. Adult patients with documentation of migraine with subsequent MIDAS questionnaire data collected between March 2017 and September 2018 were included. Based on MIDAS responses patients were categorized into grade I—little or no disability, grade II—mild disability, grade III—moderate disability, and grade IV—severe disability. Results This study included 2731 migraine patients with MIDAS results. Overall, 2309 (84.5%) were female with an average age of 46.7 years. Distribution by disability grade was 1161 (42.5%) little or no disability, 424 (15.5%) mild disability, 477 (17.5%) moderate disability, and 669 (24.5%) severe disability. Compared to overall, a larger proportion of patients with severe disability had baseline treatment with acute (71.3% vs. 67.6%) or preventive medications (70.4% vs. 62.0%) and to be on 3+ acute (9.4% vs. 7.0%) or 3+ preventive therapies (17.0% vs. 14.5%). Conclusion Availability of MIDAS results in usual care provides additional insight into migraine care.
 
Univariate comparison of clinical and radiological characteristics among CVST patients with isolated headache and those with other symptoms + headache.
Association of isolated headache and poor outcome, E-ICH and D-ICH, and hospital stay in patients with CVST.
We aimed to evaluate the clinical characteristics and outcome, hospital stay, and intracranial hemorrhage (ICH) development of patients with cerebral venous sinus thrombosis (CVST) who presented with isolated headache. In a retrospective study, consecutive patients with a definite diagnosis of CVST referred to Namazi hospital (Shiraz University of Medical Sciences) from 2012 to 2016 were included. Clinical, radiological, and prognostic characteristics and outcome on discharge (using modified Rankin Scale (mRS)) were compared between the CVST patients who presented with isolated headache and other CVST patients through univariate analyses. The associations of isolated headache with poor outcome (mRS > 2), presence or development of ICH, and duration of hospital stay were assessed through multivariable analyses. Of the 174 patients, 45 (26.0%) presented with isolated headache. Presence of isolated headache was more frequent in men ( p value = 0.048) and patients with thrombophilia ( p value = 0.040). Lateral sinus involvement was more common in patients with isolated headache ( p value = 0.005). After adjustment for other variables, the isolated headache was significantly associated with shorter hospital stay (odds ratio (OR): 0.85, confidence interval (CI): 0.73–0.99) and lower risk of early ICH (OR: 0.314, CI: 0.132–0.749). Although poor outcome was significantly less frequent in patients with isolated headache on univariate analysis ( p value < 0.001), this association was not significant in multivariable analysis (OR: 0.324, CI: 0.035–2.985). CVST patients with isolated headache had lower ICH events and shorter hospital stay. CVST should be considered as a possible differential diagnosis in certain patients who present only with headache, particularly those with diffuse progressive headache, or underlying provocative conditions.
 
This figure shows the biphasic cerebral blood flow change according to each phase of migraine attack proposed by Olesen et al. 5 During the aura phase, hypoperfusion initially occurs representing suppression of neural activity, that is, CSD. During the headache phase, subsequent hyperperfusion is caused by trigeminal nerve activation, which causes neurogenic inflammation and increases vasoactive neuropeptides, such as astrocyte-derived vasodilator, CGRP, and substance P. Vasogenic leakage of blood plasma proteins and blood vessels extension leads to focal hyperperfusion of affected hemisphere. CSD: cortical spreading depression; CGRP: calcitonin gene-related protein; CBF: cerebral blood flow.
The aim of this article is to provide neuroimaging data on cases with familial hemiplegic migraine (FHM). A 14-year-old male presented normal diffusion-weighted magnetic resonance imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) findings during his first hemiplegic migraine attack. However, magnetic resonance angiography (MRA) showed diffuse narrowing of the right middle cerebral artery. Cerebral blood flow–single-photon emission computed tomography showed right hypoperfusion. A follow-up study showed no abnormal findings. His mother had normal DWI, FLAIR, and MRA findings during her migraine attack. Both patients were diagnosed with FHM2 (p.R763H mutation in ATP1A2). This study highlights the importance of neurovascular examinations during the FHM2 headache phase. Further cases are required to clarify the pathophysiology of migraine.
 
Introduction Detailed Emergency Department attendance data for migraine are needed for service redesign. Methods A service evaluation was undertaken, classifying adult emergency department headache attendances using the International Classification of Headache Disorders migraine C-E criteria, evaluating attendance characteristics. Results Migraine/Probable migraine diagnosis was documented in 58% but coded in 24% attendances by ED clinicians. 29% of patients used no analgesia before attending, 43% attended ≥4 days after onset and 19% arrived by ambulance. Conclusion This evaluation highlights sub-optimal acute management and discrepancy between migraine coding and diagnosis contributing to underreporting. We recommend further evaluation of identified cohorts and headache proforma use.
 
Objective The objective of this prospective audit was to determine the long term outcome of patients diagnosed with chronic migraine who were treated with onabotulinumtoxinA for the prevention of chronic migraine. Background While long term and real-world studies have confirmed the safety and efficacy of onabotulinumtoxinA in CM, there remains limited information from large patient numbers on the number of cycles and duration of onabotulinumtoxinA needed to successfully convert chronic migraine to episodic migraine, development of resistance to treatment and sustainability of response after stopping treatment. Methods A total of 655 adult patients diagnosed with chronic migraine who received onabotulinumtoxinA at the Hull Migraine Clinic were followed up prospectively for a minimum of 2 years. OnabotulinumtoxinA was delivered as per the PREEMPT study protocol and patients were asked to keep a headache diary for at least 30 days prior to and continuously after receiving onabotulinumtoxinA. The primary outcome assessed in this prospective real-world audit was either the number of patients who achieved a ≥50% reduction in headache days or migraine days or an increment in crystal clear days twice that of baseline in a 30-day period. Patients were also assessed for analgesic medication overuse. Results Treatment data were available for 655 patients who commenced treatment between July 2010 and October 2016 and followed for at least 2 years (24–70 months), with the last follow-up taking place in September 2018. Of the 655 patients, 380 patients responded to treatment after two cycles and went on to receive the third cycle. Of these, 152 patients were still on active treatment at 2 years. A further 61 patients had relapsed and were on treatment at 2 years. Of the 228 patients who stopped treatment, 112 were successfully converted to episodic migraine and showed a sustained response, 28 reverted to chronic migraine after the initial response despite continuing treatment (developed resistance), 14 were lost to follow up and 61 patients after achieving remission relapsed after a mean of 9 months (range 4–24 months) and recommenced treatment with onabotulinumtoxinA. Conclusion After a minimum of 2 years, 29.4% of patients with chronic migraine who initially responded to treatment were successfully converted to episodic migraine and maintained a sustained response. Forty percent of the initial cohort of responders continued therapy with onabotulinumtoxinA to manage their chronic migraine.
 
Background Signs of distinct brain dysfunction in patients where migraine intersects with vertigo (i.e. vestibular migraine (VM)), remain elusive. As migraine and vertigo can both independently modulate attentional processes, here we seek the utility of the attentional network to functionally differentiate patients. Methods We used the Attentional Network Task (ANT) to elucidate three separate functional networks: Alerting, orienting and resolving conflict. 120 participants had to attend to the direction of a target visual stimulus, while other parameters were simultaneously manipulated. Reaction times across the networks were assessed in, (i) 30 healthy controls, (ii) 30 VM patients, (iii) 30 patients with migraine without vertigo, and (iv) 30 patients with benign paroxysmal positional vertigo (BPPV) but no migraine. Results Patients with VM (mean = 737.1 ms, SEM = 28), migraine (mean = 735.3 ms, SEM = 36.4), and BPPV (mean = 720.3 ms SEM = 24.3) all exhibited significantly delayed ANT reaction times compared to healthy controls (mean = 661.3 ms, SEM = 23.4). Specific attentional network deficits were observed for resolving conflict in VM, alerting in migraine and orienting in BPPV. Conclusion VM patients displayed deficits in executive function characterized by an inability to focus attentional resources and suppress peripheral distractors, whereas migraineurs without vertigo exhibited changes in the alerting network that reflects hypervigilance.
 
Background The aim of this work is to analyze reports of migraine attacks collected online in the citizen science project CLUE with respect to gender- and migraine type-specific differences in drug effectiveness and pain perception. Citizen science project data collection opens the possibility to examine these differences based on a large number of individual attacks instead of a simple survey of patients. Methods One thousand three hundred and ninety four participants reported 47,274 migraine attacks via an online platform and smartphone apps. The reports contained information on the acute medications taken, the evaluation of their effect, and information on pain parameters such as pain intensity, origin, and localization. Chi-square tests were used to investigate whether the effect of acute medications and pain parameters differed when collated by gender and migraine type (migraine with and without aura). Results Our participants rated the effectiveness of triptans as significantly better than that of ibuprofen. For triptans, significant differences in effectiveness were found when migraine types were distinguished, but no difference was found between genders. For ibuprofen, there were no differences between migraine types but significant differences between gender groups. Examination of pain parameters reveals differences between groups in pain intensity, pain origin, and pain location. The differences are statistically significant, but the effects are small. Conclusions Despite some methodological limitations, web-based data collection is able to support findings from clinical trials in a real-world setting. Due to the high numbers of participants included and attacks reported, even small differences in medication efficacy and pain parameters between the groups considered can be demonstrated to be statistically significant.
 
We describe a patient affected by migraine with visual and somatosensory aura, whose symptoms were consistently attenuated by noninvasive peripheral vagal nerve stimulation (nVNS) in multiple prospectively recorded attacks. When compared with the current standard of care, nVNS significantly reduced the duration of visual aura in all the attacks (n = 5) and prevented the somatosensory aura in three of the five attacks. The overall duration of nVNS-treated auras was 19.0 ± 4.2 min, significantly shorter than the duration of aura in attacks treated with standard of care (103.8 ± 10.3 min). This single-case study requires confirmation in a larger sample size, but we believe that this first report is suggestive of likely efficacy given the relatively high number of treated attacks and the consistent effect of nVNS.
 
Gender and age of the participants.
Increased resting-state functional connectivity in migraine patients with respect to healthy controls. a
Rather than a localized alteration, increased visual reactivity in migraine patients seems to result from a complex interaction between several brain structures, mostly involving the ventral attention network. The hub of this network is the right temporo-parietal junction. In this report, complementing our previous findings, we describe the differences in seed-to-voxel resting-state functional connectivity seeded in the right temporo-parietal junction (right angular gyrus) between migraine patients and healthy controls. Resting-state functional MRIs of episodic migraine without aura patients in the interictal period (n = 19) and matched healthy controls (n = 19) were analysed. With the seed placed in the right temporo-parietal junction (right angular gyrus), seed-to-voxel connectivity was compared between groups. Electrophysiological, voxel-based morphometry (both groups) and specific region of interest (ROI)-to-ROI functional connectivity (migraine patients) data have already been published. Migraine patients showed a higher positive interaction between the right temporo-parietal junction and both temporal poles and a higher negative interaction between this same region and bilateral areas of the visual cortex. On the basis of our results, and because of their established properties as multisensory integration hubs, it is likely that the right temporo-parietal junction and both temporal poles are involved in the altered processing of sensory stimulus commonly observed in migraine patients. Therefore, more attention should be paid to these regions for migraine research in the future.
 
Introduction A better understanding of etiology might improve poor outcomes of trochlear headaches (TRHs). Aims To study clinical spectrum, etiology, and therapeutic response of TRH. Methods Fifty-three TRH patients seen in a single center between 2015 and 2020 were included, excluding Trigeminal Autonomic Cephalalgia (TAC). Results Mean age was 36.45 years (range 11–85 years), with 77.35% being females. Twenty-five patients had continuous trochlear headache (CTRH) and 28 episodic trochlear headache (ETRH). Tension-type headache (TTH) occurred in 9 ETRH patients and 24 of 25 CTRH patients, and migraine-like headaches occurred in 19 ETRH patients and 8 CTRH (trochlear migraine) patients. Prior history of headaches was noted in 22 of 28 ETRH and 11 of 25 CTRH patients. Twenty-eight responded to migraine/TTH prophylaxis, 25 being nonresponders (partial/no response). Fourteen of 25 nonresponders, 4 of 28 responders (4 of 4 secondary and 5 of 9 idiopathic trochleitis (IT), 3 of 9 primary TRH (PTRH), and 6 of 28 ETRH) had autoantibodies, that is, 11 antinuclear antibodies (ANAs) and 7 antithyroid antibodies. Ten of 14 (71.42%) antibody-positive nonresponders improved with immunosuppressants including steroids/hydroxychloroquine and only 11 required local injections. Finally, 38 patients had good response, 13 partial, and 2 no response. The etiology and refractoriness of IT can be attributed to underlying autoimmunity and a minor contribution by primary headaches, vice versa being the case for PTRH and ETRH. Refractory TRHs should be evaluated for underlying autoimmunity and primary headaches. Conclusion Identification and treatment of underlying autoimmunity and primary headaches can help improve outcome of TRH.
 
Clinical characteristics. 
Screening autonomic function testing. 
Background and purpose Orthostatic headache is a hallmark of patients with spontaneous intracranial hypotension (SIH) but may also occur in patients with postural tachycardia syndrome (POTS). Our aim was to compare the clinical symptoms and findings of autonomic function testing in patients with SIH and POTS. Methods This was a retrospective analysis of the clinical symptoms and findings of autonomic function testing, including sympathetic vasoconstrictor and parasympathetic cardiac function as well as head-up tilt in patients with SIH and POTS. Results Nine patients with confirmed SIH and 48 with POTS (neuropathic N = 35, hyperadrenergic N = 5, deconditioned N = 8) were included. SIH patients experienced on average a shorter disease duration than patients with POTS. Orthostatic headache was present in all patients with SIH and 27% of patients with POTS. There was a broad overlap of other clinical symptoms of orthostatic intolerance. Screening autonomic function testing revealed normal sympathetic and parasympathetic function in all patients. All patients with SIH showed an excessive clinically symptomatic heart rate increase during standing, fulfilling the diagnostic criteria for POTS. Conclusion Clinical symptoms and results of autonomic function testing overlap in SIH and POTS. Hence, patients with prominent orthostatic headache fulfilling the diagnostic criteria for POTS should also be evaluated for further testing of a spinal cerebrospinal fluid leak, in the absence of a history of lumbar puncture.
 
Brain MRI showing meningeal hypertrophy and enhancement. Representative slices of the gadolinium-enhanced T1 sequence are shown. (a) Hypertrophy and enhancement of meninges along the right convexity. (b) The arrow points to a focal hypertrophic meningeal nodule that compresses the right optic nerve just prior to entering the orbit.
Short-lasting unilateral neuralgiform headache with autonomic symptoms (SUNA) is a rare form of trigeminal autonomic cephalalgia. SUNA is frequently associated with a trigeminal neurovascular conflict and rarely occurs secondary to other intracranial pathology. We report a patient with SUNA that was associated with ipsilateral meningeal inflammation caused by idiopathic hypertrophic pachymeningitis (HP). During the 9-year follow-up, she experienced multiple episodes of SUNA, most of which occurred during exacerbations of the pachymeningitis. This is the third case of SUNA associated with HP reported in the literature. Based on this observation, we suggest that in patients presenting with SUNA, besides dedicated magnetic resonance imaging (MRI) of the trigeminal nerve, gadolinium-enhanced brain MRI should be performed to rule out HP.
 
Physical activity avoidance and beliefs about physical activity on migraine. Note: Means adjusted for past/month migraine attack frequency. 
Sample characteristics (n ¼ 100).
Differences in PA and migraine characteristics by PA avoidance status. PA avoidance for migraine management
Given the benefits of habitual physical activity for migraine management and overall health, it is important to understand the reasons for low physical activity levels in those with migraine. Beliefs that physical activity can trigger and/or worsen migraine pain may contribute to low physical activity levels via intentional avoidance of physical activity, particularly of higher intensities. This study evaluated intentional avoidance of physical activity at varying intensity levels and its association with (a) leisure-time physical activity levels, (b) beliefs that physical activity will trigger and/or worsen migraine, and (c) migraine characteristics. Participants were women (n = 100) who screened positive for migraine on the IDMigraine and completed an online survey on physical activity and migraine. The majority of the sample (78%) reported avoiding physical activity to manage migraine attacks at least once in the past month, and most reported avoidance of both moderate- and vigorous-intensity activity. Among those who reported avoidance, moderate- and vigorous-intensity physical activity was avoided on an average of 4.0 ± 2.0 and 4.1 ± 2.2 days/week, respectively. More frequent avoidance of vigorous-intensity physical activity (but not moderate-intensity) was significantly correlated with lower vigorous-intensity physical activity indicated by fewer days/week (r = −0.28, p = 0.016) and fewer minutes/day (r = −0.29, p = 0.011). The frequency of physical activity avoidance was significantly correlated with stronger expected likelihood that physical activity, at both intensity levels, will both trigger (r = 0.39–0.43, p < 0.01) and worsen (r = 0.24–0.25, p < 0.05) migraine attacks. Individuals who avoided physical activity reported a significantly higher number of migraine attacks in the past month and were more likely to have chronic migraine, compared to those who did not report avoidance. Intentional avoidance of moderate- and vigorous-intensity physical activity is a common migraine management strategy that is associated with lower levels of vigorous-intensity physical activity, stronger beliefs that physical activity will trigger or worsen migraine, and more frequent migraine attacks. Individuals with migraine who avoid physical activity may benefit from targeted intervention to address beliefs about physical activity and migraine, which has the strong potential to improve both migraine and health outcomes.
 
Timeline of experiments with barometric pressure lowering by 0 hPa (dotted line), 20 hPa (dashed line) and 40 hPa (continuous line). Heart rate was recorded 30 min prior to and throughout the experiment, ear pressure, sensation of head compression and headache were reported on a visual analogue scale (VAS) every minute during the phases 'pre'-'post'.
Craniofacial sensations and heart rate during the control session with no barometric pressure change (a, mean + SEM). (b) Mean values of ear pressure sensation (+SEM). (c) Cumulative values of head compression sensations, subject values are expressed by bars of different grey values. (d) Heart rate (mean + SEM).
Craniofacial sensations and heart rate during transient lowering of barometric pressure by 20 hPa (a). (b) Mean values of ear pressure sensation (+SEM); *significant difference between ratings of 'up' and 'post'. (c) Cumulative values of head compression sensations, subject values are expressed by bars of different grey values; headache is added as open squares. (d) Heart rate (mean + SEM).
Craniofacial sensations and heart rate during transient lowering of barometric pressure by 40 hPa (a). (b) Mean values of ear pressure sensation (+SEM); *significant difference between ratings of 'up' and all other test phases. (c) Cumulative values of head compression sensations, subject values are expressed by bars of different grey values; headache is added as open square. (d) Heart rate (mean + SEM); *significant difference to phase "pre".
Background Changes in atmospheric pressure are suggested to trigger headaches. This pilot study was made to determine craniofacial sensations accompanying short phases of changing barometric pressure. Methods In a crossover design, 15 adult healthy subjects were exposed in a climate chamber to 8 min phases of barometric pressure lowering by 0, 20 and 40 hPa. The subjects rated their sensations of ear pressure, head compression and the occurrence of headache every minute on a visual analogue scale (VAS, range 0–10). Pulse rate was recorded as a parameter for autonomic functions. Results Nearly all subjects experienced ear pressure and half of them compression of their head at variable degrees. These sensations started in most subjects during the phase of lowering barometric pressure and increased to an average rating of about 3 VAS when returning to ambient atmospheric pressure. Heart rate slightly decreased during this phase. Three subjects reported mild to moderate headache for various durations within these phases. Conclusions Changes in barometric pressure can be associated with sensations of ear pressure and head compression and may trigger headaches. The generation of these sensations is discussed with regard to convergent trigeminal innervation of the ear, the paranasal sinuses and the cranial meninges.
 
Coronal T2-weighted images demonstrate a large mass in the central skull base on the right, with predominantly high signal intensity and large flow voids. The mass replaces all the structures of the right middle and inner ear, extending to the petrous apex. It causes superior and medial displacement of the cisternal segment of the right trigeminal nerve (arrow), along with effacement of the CSF around the left trigeminal nerve (arrow).
Coronal and axial post-contrast T1-weighted images show the intense heterogeneous enhancement of the mass in the central skull base on the right, which has mass effect on the pons and right middle cerebellar peduncle. Areas of necrosis are present within the mass.
Background Trigeminal neuralgia can be classical or idiopathic. While trigeminal neuralgia (TN) due to space-occupying lesions is atypical, such lesions rarely cause severe TN secondary to trigeminal nerve irritation. Mass effect from these lesions has been shown to correlate with symptom burden, due to direct or indirect compressive effects. A tethering effect, provoked by an abnormal root-stretching force, theoretically plays a role in trigeminal nerve hyperexcitability. Case The likely etiology in this case presentation is a large glomus tumor invading the middle and posterior cranial fossa. Glomus tumors are uncommon benign tumors of the head and neck derived from neural crest cells. Even more strikingly, a large glomus tumor causes bilateral TN due to direct compression on one side and indirect compression on the contralateral side. Conclusion Although the gold standard in TN management is carbamazepine, other anti-epileptic drugs (AEDs) have been used in the treatment of patients unable to take carbamazepine. A few studies suggest levetiracetam alleviates central and neuropathic pain, supporting the hypothesis that it may be effective in management of TN.
 
Example of location of an electrode from postoperative CT fused to preoperative MRI in (a) axial, (b) sagittal, and (c) coronal planes. Red circle indicates electrode segmentation from CT superimposed on preoperative MRI. 
Individual patient characteristics. a
Background Deep brain stimulation of the posterior hypothalamic area is one of the neuromodulation treatments used for chronic cluster headache, but the number of published patients remains low. Aim The aim of this article was to present the retrospective results of 12 consecutive chronic cluster headache patients treated with deep brain stimulation at Helsinki University Hospital. Materials and Methods All chronic cluster headache patients treated with deep brain stimulation between 2004 and 2012 were included in the study. Patients were interviewed and their hospital files analyzed. Treatment effect was classified as good, partial, or no effect. Results Of the 12 patients, four had a good treatment effect, five had partial, and three had no effect of deep brain stimulation. In contrast to previous studies, our patients reported an almost immediate benefit after the onset of stimulation. Conclusions Deep brain stimulation provides clinically meaningful benefit to a subgroup of chronic cluster headache patients.
 
Top-cited authors
Jean Schoenen
  • University of Liège
Ulrich Danesch
  • Weber & Weber
Arne May
  • University of Hamburg
Nina Graf
  • Universität Bern
Juergen Beck
  • Medical Center – University of Freiburg, Germany