International Headache Society global practice recommendations for the acute pharmacological treatment of migraine.

BACKGROUND: In an effort to improve migraine management around the world, the International Headache Society (IHS) has here developed a list of practical recommendations for the acute pharmacological treatment of migraine. The recommendations are categorized into optimal and essential, in order to provide treatment options for all possible settings, including those with limited access to migraine medications. METHODS: An IHS steering committee developed a list of clinical questions based on practical issues in the management of migraine. A selected group of international senior and junior headache experts developed the recommendations, following expert consensus and the review of available national and international headache guidelines and guidance documents. Following the initial search, a bibliography of twenty-one national and international guidelines was created and reviewed by the working group. RESULTS: A total of seventeen questions addressing different aspects of acute migraine treatment have been outlined. For each of them we provide an optimal recommendation, to be used whenever possible, and an essential recommendation to be used when the optimal level cannot be attained. CONCLUSION: Adoption of these international recommendations will improve the quality of acute migraine treatment around the world, even where pharmacological options remain limited.

Comparative effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies and onabotulinumtoxinA in chronic migraine: A multicenter, real-world study in Taiwan.

OBJECTIVE: To compare the real-world effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) and onabotulinumtoxinA in chronic migraine (CM) patients. METHODS: This multicenter study involved retrospective analysis of prospectively collected data of CM patients treated with CGRP mAbs or onabotulinumtoxinA, including difficult-to-treat (DTT) patients (i.e., ≥3 preventive failures). Treatment outcomes were determined at 6 months based on prospective headache diaries and Migraine Disability Assessment (MIDAS). RESULTS: The study included 316 (55 M/261F, mean age 44.4 ± 13.5 years) and 333 (61 M/272F, mean age 47.9 ± 13.4 years) CM patients treated with CGRP mAbs or onabotulinbumtoxinA, respectively. At 6 months, CGRP mAb treatment was associated with a greater decrease in monthly migraine days (MMDs) (-13.0 vs. -8.7 days/month, p < 0.001) and a higher ≥50% responder rate (RR) (74.7% vs. 50.7%, p < 0.001) compared with onabotulinumtoxinA injections. The findings were consistent in DTT patients (-13.0 vs. -9.1 MMDs, p < 0.001; ≥50% RR: 73.9% vs. 50.3%, p < 0.001) or those with medication-overuse headache (MOH) (-13.3 vs. -9.0 MMDs, p < 0.001; ≥50% RR: 79.0% vs. 51.6%, p < 0.001). Besides, patients receiving CGRP mAbs had greater improvement (-42.2 vs. -11.8, p < 0.001) and a higher ≥50% RR (62.0% vs. 40.0%, p = 0.001) in MIDAS scores and a lower rate of adverse events (AEs) (6.0% vs. 21.0%, p < 0.001). However, none of the patients discontinued treatment due to AEs. CONCLUSIONS: In this multicenter, real-world study, CGRP mAbs were more effective than onabotulinumtoxinA in CM patients, even in DTT or MOH patients. All of these injectables were well tolerated. Further prospective studies are needed to verify these findings.

Dynamic changes in glymphatic function in reversible cerebral vasoconstriction syndrome.

BACKGROUND: The pathophysiology of the reversible cerebral vasoconstriction syndrome (RCVS) remains enigmatic and the role of glymphatics in RCVS pathophysiology has not been evaluated. We aimed to investigate RCVS glymphatic dynamics and its clinical correlates. METHODS: We prospectively evaluated the glymphatic function in RCVS patients, with RCVS subjects and healthy controls (HCs) recruited between August 2020 and November 2023, by calculating diffusion-tensor imaging along the perivascular space (DTI-ALPS) index under a 3-T MRI. Clinical and vascular (transcranial color-coded duplex sonography) investigations were conducted in RCVS subjects. RCVS participants were separated into acute (≤ 30 days) and remission (≥ 90 days) groups by disease onset to MRI interval. The time-trend, acute stage and longitudinal analyses of the DTI-ALPS index were conducted. Correlations between DTI-ALPS index and vascular and clinical parameters were performed. Bonferroni correction was applied to vascular investigations (q = 0.05/11). RESULTS: A total of 138 RCVS patients (mean age, 46.8 years ± 11.8; 128 women) and 42 HCs (mean age, 46.0 years ± 4.5; 35 women) were evaluated. Acute RCVS demonstrated lower DTI-ALPS index than HCs (p < 0.001) and remission RCVS (p < 0.001). A continuously increasing DTI-ALPS trend after disease onset was demonstrated. The DTI-ALPS was lower when the internal carotid arteries resistance index and six-item Headache Impact test scores were higher. In contrast, during 50-100 days after disease onset, the DTI-ALPS index was higher when the middle cerebral artery flow velocity was higher. CONCLUSIONS: Glymphatic function in patients with RCVS exhibited a unique dynamic evolution that was temporally coupled to different vascular indices and headache-related disabilities along the disease course. These findings may provide novel insights into the complex interactions between glymphatic transport, vasomotor control and pain modulation.

Noninvasive investigations of human glymphatic dynamics in a diseased model.

OBJECTIVES: To explore human glymphatic dynamics in a diseased model via a noninvasive technique. METHODS: Patients with reversible vasoconstriction syndrome (RCVS) presenting with blood-brain barrier disruption, i.e., para-arterial gadolinium leakage on 3-T 3-dimensional isotropic contrast-enhanced T2-fluid-attenuated inversion recovery (CE-T2-FLAIR) magnetic resonance imaging (MRI), were prospectively enrolled. Consecutive 9-min-CE-T2-FLAIR for 5-6 times (early panel) after intravenous gadolinium-based contrast agent (GBCA) administration and one time-varying deferred scan of noncontrast T2-FLAIR (delayed panel) were performed. In Bundle 1, we measured the calibrated signal intensities (cSIs) of 10 different anatomical locations. In Bundle 2, brain-wide measurements of para-arterial glymphatic volumes, means, and medians of the signal intensities were conducted. We defined mean (mCoIs) or median (mnCoIs) concentration indices as products of volumes and signal intensities. RESULTS: Eleven subjects were analyzed. The cSIs demonstrated early increase (9 min) in perineural spaces: (cranial nerve [CN] V, p = 0.008; CN VII + VII, p = 0.003), choroid plexus (p = 0.003), white matter (p = 0.004) and parasagittal dura (p = 0.004). The volumes, mCoIs, and mnCoIs demonstrated increasing rates of enhancement after 9 to 18 min and decreasing rates after 45 to 54 min. The GBCA was transported centrifugally and completely removed within 961-1086 min after administration. CONCLUSIONS: The exogenous GBCA leaked into the para-arterial glymphatics could be completely cleared around 961 to 1086 min after administration in a human model of BBB disruption. The tracer enhancement started variously in different intracranial regions but was eventually cleared centrifugally to brain convexity, probably towards glymphatic-meningeal lymphatics exits. CLINICAL RELEVANCE STATEMENT: Glymphatic clearance time intervals and the centrifugal directions assessed by a noninvasive approach may have implications for clinical glymphatic evaluation in the near future. KEY POINTS: • This study aimed to investigate the human glymphatic dynamics in a noninvasive diseased model. • The intracranial MR-detectable gadolinium-based contrast agents were removed centrifugally within 961 to 1086 min. • The glymphatic dynamics was demonstrable by enhancing MRI in an in vivo diseased model noninvasively.

Sex differences in the clinical manifestations related to dependence behaviors in medication-overuse headache.

OBJECTIVE: The present study aimed to compare sex differences in the clinical manifestations related to dependence behaviors in medication-overuse headache (MOH). METHODS: Consecutive patients with newly diagnosed chronic migraine (CM) with and without MOH based on the Third Edition of International Classification of Headache Disorders (ICHD-3) were enrolled prospectively from the headache clinic of a tertiary medical center. Demographics and clinical profiles were collected by using a questionnaire, which included current use of tobacco, alcohol, and caffeinated beverages, the Leeds Dependence Questionnaire (LDQ), the Severity of Dependence Scale (SDS), the Headache Impact Test-6 (HIT-6), and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: In total, 1419 CM patients (1135F/284 M, mean age 41.7 ± 13.9 years) were recruited, including 799 with MOH (640F/159 M, mean age 42.5 ± 13.2 years) (56.3%). Smoking was associated with an increased risk for MOH in men (odds ratio [OR] = 3.60 [95% confidence interval = 1.73-7.50], p = 0.001), but not in women (OR = 1.34 [0.88-2.04], p = 0.171) (p = 0.021 for interaction). Hypnotic use ≥ 3 days/week was a risk factor for MOH (OR = 2.55 [95% confidence interval = 2.00-3.24], p < 0.001), regardless of sex. By using receiver operating characteristics (ROC) curves, the cutoff scores of the LDQ for MOH were determined at 7 for women and 6 for men, and those for the SDS were 5 and 4, respectively (area under curve all ≥ 0.83). Among patients with MOH, the male sex was associated with a shorter latency between migraine onset and CM onset (12.9 ± 11.1 vs. 15.4 ± 11.5 years, p = 0.008), despite less average headache intensity (6.7 ± 1.9 vs. 7.2 ± 1.9, p = 0.005), functional impacts (HIT-6: 63.4 ± 8.3 vs. 65.1 ± 8.0, p = 0.009), and sleep disturbances (PSQI: 10.9 ± 4.4 vs. 12.2 ± 4.3, p = 0.001). CONCLUSIONS: The current study identified an association between smoking and MOH in men, as well as sex-specific cutoffs of the LDQ and the SDS, for MOH. MOH was characterized by a shorter latency between migraine onset and CM onset in men and a more severe phenotype in women. Sex should be considered as an important factor in the evaluation of MOH.

Association between impaired dynamic cerebral autoregulation and BBB disruption in reversible cerebral vasoconstriction syndrome.

BACKGROUND: Half of the sufferers of reversible cerebral vasoconstriction syndrome (RCVS) exhibit imaging-proven blood-brain barrier disruption. The pathogenesis of blood-brain barrier disruption in RCVS remains unclear and mechanism-specific intervention is lacking. We speculated that cerebrovascular dysregulation might be associated with blood-brain barrier disruption in RCVS. Hence, we aimed to evaluate whether the dynamic cerebral autoregulation is altered in patients with RCVS and could be associated with blood-brain barrier disruption. METHODS: A cross-sectional study was conducted from 2019 to 2021 at headache clinics of a national tertiary medical center. Dynamic cerebral autoregulation was evaluated in all participants. The capacity of the dynamic cerebral autoregulation to damp the systemic hemodynamic changes, i.e., phase shift and gain between the cerebral blood flow and blood pressure waveforms in the very-low- and low-frequency bands were calculated by transfer function analysis. The mean flow correlation index was also calculated. Patients with RCVS received 3-dimensional isotropic contrast-enhanced T2 fluid-attenuated inversion recovery imaging to visualize blood-brain barrier disruption. RESULTS: Forty-five patients with RCVS (41.9 ± 9.8 years old, 29 females) and 45 matched healthy controls (41.4 ± 12.5 years old, 29 females) completed the study. Nineteen of the patients had blood-brain barrier disruption. Compared to healthy controls, patients with RCVS had poorer dynamic cerebral autoregulation, indicated by higher gain in very-low-frequency band (left: 1.6 ± 0.7, p = 0.001; right: 1.5 ± 0.7, p = 0.003; healthy controls: 1.1 ± 0.4) and higher mean flow correlation index (left: 0.39 ± 0.20, p = 0.040; right: 0.40 ± 0.18, p = 0.017; healthy controls: 0.31 ± 0.17). Moreover, patients with RCVS with blood-brain barrier disruption had worse dynamic cerebral autoregulation, as compared to those without blood-brain barrier disruption, by having less phase shift in very-low- and low-frequency bands, and higher mean flow correlation index. CONCLUSIONS: Dysfunctional dynamic cerebral autoregulation was observed in patients with RCVS, particularly in those with blood-brain barrier disruption. These findings suggest that impaired cerebral autoregulation plays a pivotal role in RCVS pathophysiology and may be relevant to complications associated with blood-brain barrier disruption by impaired capacity of maintaining stable cerebral blood flow under fluctuating blood pressure.

Noninvasive Characterization of Human Glymphatics and Meningeal Lymphatics in an in vivo Model of Blood-Brain Barrier Leakage.

OBJECTIVE: To evaluate human glymphatics and meningeal lymphatics noninvasively. METHODS: This prospective study implemented 3-dimensional (3D) isotropic contrast-enhanced T2 fluid-attenuated inversion recovery (CE-T2-FLAIR) imaging with a 3T magnetic resonance machine to study cerebral glymphatics and meningeal lymphatics in patients with reversible cerebral vasoconstriction syndrome (RCVS) with (n = 92) or without (n = 90) blood-brain barrier (BBB) disruption and a diseased control group with cluster headache (n = 35). The contrast agent gadobutrol (0.2mmol/kg [0.2ml/kg]) was administered intravenously in all study subjects. RESULTS: In total, 217 patients (182 RCVS, 35 cluster headache) were analyzed and separated into 2 groups based on the presence or absence of visible gadolinium (Gd) leakage. Para-arterial tracer enrichment was clearly depicted in those with overt BBB disruption, while paravenous and parasinus meningeal contrast enrichment was evident in both groups. Paravenous and parasinus contrast enrichment remained in RCVS patients in the remission stage and in cluster headache patients, suggesting that these meningeal lymphatic channels were universal anatomical structures rather than being phase- or condition-specific. Additionally, we demonstrated nodular leptomeningeal enhancement in 32.3% of participants, which might represent potential lymphatic reservoirs. Four selected RCVS patients who received consecutive contrasted 3D isotropic FLAIR imaging after gadobutrol administration showed that the Gd persisted for at least 54 minutes and was completely cleared within 18 hours. INTERPRETATION: This large-scale in vivo study successfully demonstrated the putative human para-arterial glymphatic transports and meningeal lymphatics by clear depiction of para-arterial, parasinus, and paravenous meningeal contrast enrichment using high-resolution 3D isotropic CE-T2-FLAIR imaging noninvasively; this technique may serve as a basis for further studies to delineate clinical relevance of glymphatic clearance. ANN NEUROL 2021;89:111-124.

Pain sensitivities predict prophylactic treatment outcomes of flunarizine in chronic migraine patients: A prospective study.

BACKGROUND: We aimed to assess the differences in quantitative sensory testing between chronic migraine and healthy controls and to explore the association between pain sensitivities and outcomes in chronic migraine following preventive treatment. METHODS: In this prospective open-label study, preventive-naïve chronic migraine and healthy controls were recruited, and cold, heat, mechanical punctate, and pressure pain thresholds over the dermatomes of first branch of trigeminal nerve and first thoracic nerve were measured by quantitative sensory testing at baseline. Chronic migraines were treated with flunarizine and treatment response was defined as ≥50% reduction in the number of monthly headache days over the 12-week treatment period. RESULTS: Eighty-four chronic migraines and fifty age-and-sex-matched healthy controls were included in the analysis. The chronic migraine had higher cold pain thresholds over the dermatomes of the first branch of trigeminal nerve and the first thoracic nerve (p < 0.001 and < 0.001), lower pressure pain thresholds over the dermatomes of the first thoracic nerve (p = 0.003), heat pain thresholds over the dermatomes of the first branch of the trigeminal nerve and the first thoracic nerve (p < 0.001 and p = 0.015) than healthy controls. After treatment, 24/84 chronic migraine had treatment response. The responders with relatively normal pain sensitivity had higher heat pain thresholds over the dermatome of the first branch of the trigeminal nerve (p = 0.002), mechanical punctate pain thresholds over the dermatomes of the first branch of the trigeminal nerve (p = 0.023), and pressure pain thresholds over the dermatomes of the first branch of the trigeminal nerve (p = 0.026) than the hypersensitive non-responders. Decision tree analysis showed that patients with mechanical punctate pain threshold over the dermatomes of the first branch of the trigeminal nerve > 158 g (p = 0.020) or heat pain threshold over the dermatome of the first branch of the trigeminal nerve > 44.9°C (p = 0.002) were more likely to be responders. CONCLUSIONS: Chronic migraine were generally more sensitive compared to healthy controls. Preventive treatment with flunarizine should be recommended particularly for chronic migraine who have relatively normal sensitivity to mechanical punctate or heat pain.Trial registration: This study was registered on ClinicalTrials.gov (Identifier: NCT02747940).

Most bothersome symptoms in patients with migraine: A hospital-based study in Taiwan.

OBJECTIVE: To investigate the distribution, clinical associations, and treatment responses for the most bothersome symptoms of migraine in a large sample of patients with migraine in Taiwan. BACKGROUND: The most bothersome symptom is recently recommended as a co-primary endpoint in clinical trials of acute treatment of migraine. However, most clinical trials and observational studies have been conducted in the United States and Europe, with photophobia representing the most common most bothersome symptom. METHODS: Patients who were newly diagnosed with migraine by headache specialists in Taipei Veterans General Hospital were recruited. All participants completed a questionnaire for headache profile, including the most bothersome symptom. Clinical associations of the most bothersome symptoms and response rates to previous acute treatments were analyzed. RESULTS: Among the recruited 1188 patients with migraine (female 79.4%, mean age 39.0 ± 12.1 years) in this cross-sectional study, nausea (n = 729/1188, 61.4%) was the most common symptom that was most bothersome, followed by phonophobia (n = 280/1188, 23.6%), and photophobia (n = 122/1188, 10.3%). The frequency ranking was the same regardless of sex and age. Compared to migraine without aura, migraine with aura was associated with photophobia (adjusted odds ratio [OR] = 2.97, 95% confidence interval [CI] 1.76-5.0, p < 0.001). Chronic migraine was associated with phonophobia (adjusted OR = 1.51, 95% CI 1.13-2.01, p = 0.005), but there was a lower chance for nausea (adjusted OR = 0.68, 95% CI 0.53-0.88, p = 0.004), as the most bothersome symptom. Patients with different most-bothersome symptoms responded similarly to previous acute treatments, with an overall response rate of 52.2% (n = 550/1053). CONCLUSION: Patients with migraine in Taiwan reported a distinct ranking of the most bothersome symptom. However, the response rates of the most bothersome symptom and headache were similar, which supports the most bothersome symptom as an outcome measure for acute treatment of migraine. Further studies recruiting different populations are required to investigate regional differences in most bothersome symptoms.

Diagnosis and classification of headache associated with sexual activity using a composite algorithm: A cohort study.

BACKGROUND: To differentiate primary headache associated with sexual activity from other devastating secondary causes. METHODS: In this prospective cohort, we recruited consecutive patients with at least 2 attacks of headache associated with sexual activity from the headache clinics or emergency department of a national medical center from 2005 to 2020. Detailed interview, neurological examination, and serial thorough neuroimaging including brain magnetic resonance imaging and magnetic resonance angiography scans were performed on registration and during follow-ups. Patients were categorized into four groups, i.e. primary headache associated with sexual activity, reversible cerebral vasoconstriction syndrome, probable reversible cerebral vasoconstriction syndrome, and other secondary headache associated with sexual activity through a composite clinic-radiological diagnostic algorithm. We compared the clinical profiles among these groups, including sex, age of onset, duration, quality, and clinical course ("chronic" indicates disease course ≥ 1 year). In addition, we also calculated the score of the reversible cerebral vasoconstriction syndrome2, a scale developed to differentiate reversible cerebral vasoconstriction syndrome from other intracranial vascular disorders. RESULTS: Overall, 245 patients with headache associated with sexual activity were enrolled. Our clinic-radiologic composite algorithm diagnosed and classified all patients into four groups, including 38 (15.5%) with primary headache associated with sexual activity, 174 (71.0%) with reversible cerebral vasoconstriction syndrome, 26 (10.6%) with probable reversible cerebral vasoconstriction syndrome, and 7 (2.9%) with other secondary causes (aneurysmal subarachnoid hemorrhage (n = 4), right internal carotid artery dissection (n = 1), Moyamoya disease (n = 1), and meningioma with hemorrhage (n = 1)). These four groups shared similar clinical profiles, except 26% of the patients with primary headache associated with sexual activity had a 3 times greater chance of running a chronic course (≥ 1 year) than patients with reversible cerebral vasoconstriction syndrome. Of note, the reversible cerebral vasoconstriction syndrome2 score could not differentiate reversible cerebral vasoconstriction syndrome from other groups. CONCLUSION: Our composite clinic-radiological diagnostic algorithm successfully classified repeated headaches associated with sexual activity, which were predominantly secondary and related to vascular disorders, and predicted the prognosis. Primary headache associated with sexual activity and reversible cerebral vasoconstriction syndrome presented with repeated attacks of headache associated with sexual activity may be of the same disease spectrum.

Post-reversible cerebral vasoconstriction syndrome headache.

BACKGROUND: Chronic headache may persist after the remission of reversible cerebral vasoconstriction syndrome (RCVS) in some patients. We aimed to investigate the prevalence, characteristics, risk factors, and the impact of post-RCVS headache. METHODS: We prospectively recruited patients with RCVS and collected their baseline demographics, including psychological distress measured by Hospital Anxiety and Depression scale. We evaluated whether the patients developed post-RCVS headache 3 months after RCVS onset. The manifestations of post-RCVS headache and headache-related disability measured by Migraine Disability Assessment (MIDAS) scores were recorded. RESULTS: From 2017 to 2019, 134 patients with RCVS were recruited, of whom, 123 finished follow-up interviews (response rate 91.8%). Sixty (48.8%) patients had post-RCVS headache. Migrainous features were common in post-RCVS headache. Post-RCVS headache caused moderate-to-severe headache-related disability (MIDAS score > 10) in seven (11.7%) patients. Higher anxiety level (odds ratio 1.21, p = 0.009) and a history of migraine (odds ratio 2.59, p = 0.049) are associated with post-RCVS headache. Survival analysis estimated that 50% post-RCVS headache would recover in 389 days (95% confidence interval: 198.5-579) after disease onset. CONCLUSIONS: Post-RCVS headache is common, affecting half of patients and being disabling in one-tenth. Higher anxiety level and migraine history are risk factors. Half of the patients with post-RCVS headache would recover in about a year.

Temporal Profile of Blood-Brain Barrier Breakdown in Reversible Cerebral Vasoconstriction Syndrome.

Background and Purpose- Reversible cerebral vasoconstriction syndrome (RCVS) has a unique temporal course of vasoconstriction. Blood-brain barrier (BBB) breakdown is part of the pathophysiology of RCVS, but its temporal course is unknown. We aimed to investigate the temporal profile of BBB breakdown and relevant clinical profiles in a large sample size. Methods- In this prospective observatory bicenter study, patients who underwent contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging within 2 months from onset were included. The presence and extent of BBB breakdown were evaluated using contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging. Contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging data were analyzed using a semiautomated segmentation technique to quantitatively measure the area of Gadolinium leakage into cerebrospinal fluid space. The univariable and multivariable linear regressions were performed to investigate the independent effect of time from onset with adjustment for other covariates. Results- In the 186 patients with angiogram-proven RCVS included in this analysis, BBB breakdown was observed in 52.6%, 56.8%, 30.3%, 40.0%, and 23.8% in the first, second, third, fourth, and ≥fifth week after onset. The extent of BBB breakdown peaked at first and second week, whereas the peak of vasoconstriction was observed at the third week after onset. Multivariable analysis showed the second week from onset (ß, 3.35 [95% CI, 0.07-6.64]; P=0.046) and blood pressure surge (ß, 3.84 [95% CI, 1.75-5.92]; P<0.001) were independently associated with a greater extent of BBB breakdown. A synergistic effect of time from onset and blood pressure surge was found (P for interaction=0.006). Conclusions- Frequency and extent of BBB breakdown are more prominent during the early stage in patients with RCVS, with an earlier peak than that of vasoconstriction. The temporal course of BBB breakdown may provide a pathophysiologic background of the temporal course of neurological complications of RCVS.

Mechanical punctate pain threshold is associated with headache frequency and phase in patients with migraine.

OBJECTIVE: Previous studies regarding the quantitative sensory testing are inconsistent in migraine. We hypothesized that the quantitative sensory testing results were influenced by headache frequency or migraine phase. METHODS: This study recruited chronic and episodic migraine patients as well as healthy controls. Participants underwent quantitative sensory testing, including heat, cold, and mechanical punctate pain thresholds at the supraorbital area (V1 dermatome) and the forearm (T1 dermatome). Prospective headache diaries were used for headache frequency and migraine phase when quantitative sensory testing was performed. RESULTS: Twenty-eight chronic migraine, 64 episodic migraine and 32 healthy controls completed the study. Significant higher mechanical punctate pain thresholds were found in episodic migraine but not chronic migraine when compared with healthy controls. The mechanical punctate pain thresholds decreased as headache frequency increased then nadired. In episodic migraine, mechanical punctate pain thresholds were highest (p < 0.05) in those in the interictal phase and declined when approaching the ictal phase in both V1 and T1 dermatomes. Linear regression analyses showed that in those with episodic migraine, headache frequency and phase were independently associated with mechanical punctate pain thresholds and accounted for 29.7% and 38.9% of the variance in V1 (p = 0.003) and T1 (p < 0.001) respectively. Of note, unlike mechanical punctate pain thresholds, our study did not demonstrate similar findings for heat pain thresholds and cold pain thresholds in migraine. CONCLUSION: Our study provides new insights into the dynamic changes of quantitative sensory testing, especially mechanical punctate pain thresholds in patients with migraine. Mechanical punctate pain thresholds vary depending on headache frequency and migraine phase, providing an explanation for the inconsistency across studies.

Narrative Review: Headaches After Reversible Cerebral Vasoconstriction Syndrome.

PURPOSE OF REVIEW: Reversible cerebral vasoconstriction syndrome (RCVS) is a disorder with distinct features: recurrent thunderclap headaches with reversible vasoconstriction of intracranial arteries. Substantial studies regarding outcomes after RCVS were conducted, showing favorable functional outcomes in most patients despite the potentially life-threatening complications of RCVS, including ischemic stroke, intracranial hemorrhage, or convexity subarachnoid hemorrhage. However, patients may report headaches after the resolution of RCVS while relative studies were scarce. RECENT FINDINGS: Two prospective studies from different cohorts consistently revealed that RCVS recurred in at least 5% of patients. Patients with prior migraine history and patients whose thunderclap headaches are elicited by sexual activity or exertion are at higher risk for RCVS recurrence. On the other hand, several retrospective studies and case reports reported that chronic headaches are common in RCVS patients after the resolution of acute bouts. The chronic headaches after RCVS are sometimes disabling in certain patients. Headaches after RCVS are not uncommon but usually overseen. Medical attention and examinations are warranted in patient with RCVS who reported recurrence of thunderclap headaches or chronic headaches after RCVS.

TRPM8 genetic variant is associated with chronic migraine and allodynia.

BACKGROUND: Many single nucleotide polymorphisms (SNPs) have been reported to be associated with migraine susceptibility. However, evidences for their associations with migraine endophenotypes or subtypes are scarce. We aimed to investigate the associations of pre-identified migraine susceptibility loci in Taiwanese with migraine endophenotypes or subtypes, including chronic migraine and allodynia. METHODS: The associations of six SNPs identified from our previous study, including TRPM8 rs10166942, LRP1 rs1172113, DLG2 rs655484, GFRA1 rs3781545, UPP2 rs7565931, and GPR39 rs10803531, and migraine endophenotypes, including chronic migraine and allodynia were tested. Significant associations in the discovery cohort were validated in the replication cohort. The adjusted odds ratios (aOR) were calculated after controlling for confounders. RESULTS: In total, 1904 patients (mean age 37.5 ± 12.2 years old, female ratio: 77.7%) including 1077 in the discovery cohort and 827 in the replication cohort were recruited. Of them, 584 (30.7%) had chronic migraine. Of the 6 investigated SNPs, TRPM8 rs10166942 T allele-carrying patients were more likely to have chronic migraine than non-T allele carriers in both discovery and replication cohorts and combined samples (33.7% vs. 25.8%, p = 0.004, aOR = 1.62). In addition, T allele carriers reported more allodynic symptoms than non-T allele carriers (3.5 ± 3.7 vs. 2.6 ± 2.8, p < 0.001). However, allodynia severity did not differ between episodic and chronic migraine patients. No further correlations between genetic variants and endophenotypes were noted for the other SNPs. CONCLUSIONS: TRPM8 may contribute to the pathogenesis of chronic migraine. However, our study did not support allodynia as a link between them. The underlying mechanisms deserve further investigations.

Treatment in the emergency department.

As a common headache disorder, migraine is also a common cause for emergency department (ED) visiting, which leads to tremendous medical and economic burden. The goals of migraine management in ED are resolving headache and migraine-related most bothersome symptoms rapidly, preventing ED revisiting due to headache relapse, and referring patients at risk, e.g., patients with chronic migraine and/or medication-overuse headache, to specialists. In this chapter, we elucidated the algorithm which was particularly adapted to ED settings for the diagnosis and treatment of migraine. We reviewed a plentiful amount of high-quality clinical trials, especially those conducted in populations derived from ED, to provide readers insights into the optimized treatment options for migraine in ED.

The normative values of pain thresholds in healthy Taiwanese.

OBJECTIVE: Quantitative sensory testing is widely used in clinical and research settings to assess the sensory functions of healthy subjects and patients. It is of importance to establish normative values in a healthy population to provide reference for studies involving patients. Given the absence of normative values for pain thresholds in Taiwan, the aim of this study was to report the normative values for future reference in the Taiwanese population and compare the differences between male and female participants. METHODS: Healthy adults without any chronic or acute pain condition were recruited. The pain thresholds were assessed over the cephalic (supraorbital area and masseter muscle) and extracephalic (medio-volar forearm and thenar eminence) areas. The heat, cold, mechanical punctate, and pressure pain thresholds were measured with a standardized protocol. Comparisons between male and female participants were performed. RESULTS: One hundred and thirty healthy participants (55 males: 30.4 ± 7.4 years; 75 females: 30.5 ± 8.1 years) finished the assessments. Male participants were less sensitive to mechanical stimuli, including pressure over masseter muscle (male vs. female: 178.5 ± 56.7 vs. 156.6 ± 58.4 kPa, p = .034) and punctate over medio-volar forearm (male vs. female: 116.4 ± 45.2 vs. 98.7 ± 65.4 g, p = .011), compared to female participants. However, female participants were less sensitive to cold stimuli, indicated by lower cold pain thresholds over the supraorbital area (male vs. female: 18.6 ± 8.4 vs. 13.6 ± 9.3°C, p = .004), compared to male participants. No significant differences were found between sexes in other pain threshold parameters. CONCLUSIONS: We provided the normative values of healthy male and female adults in Taiwan. This information is crucial for comparison in future pain-related studies to identify potential hypoalgesia or hyperalgesia of tested subjects.

Salivary Testosterone Levels and Pain Perception Exhibit Sex-Specific Association in Healthy Adults But Not in Patients With Migraine.

This study investigated the sex-specific associations between pain perception and testosterone levels in healthy controls (HCs) and patients with migraine. Male and female HCs and migraine patients were recruited. A series of questionnaires were completed by the participants to evaluate their psychosocial profiles, which included data on mood, stress, and sleep quality. Heat pain thresholds and suprathreshold pain ratings at 45 °C (referred to as the pain perception score [PPS]) were assessed using the Thermode system. Salivary testosterone levels were analyzed using a commercial enzyme-linked immunosorbent assay kit. A total of 88 HCs (men/women: 41/47, age: 29.9 ± 7.7 years) and 75 migraine patients (men/women: 30/45, age: 31.1 ± 7.7 years) completed all assessments. No significant differences were observed in either the psychosocial profiles or heat pain thresholds and PPSs between the sexes in the control and migraine groups. A positive correlation between testosterone levels and PPSs was identified in the male controls (r = .341, P = .029), whereas a negative correlation was identified in the female controls (r = -.407, P = .005). No such correlations were identified in the migraine group. This study confirms that a negative association is present between PPSs and testosterone levels in female controls, which is in line with the findings that testosterone is associated with reduced pain perception. Our study is the first to demonstrate a sex-specific association between PPSs and testosterone levels in HCs. Moreover, this study also revealed that the presence of migraine appears to disrupt this association. PERSPECTIVE: This study revealed that testosterone levels demonstrate opposite associations with pain perception in healthy men and women. However, the presence of migraine appears to disrupt this sex-specific association.

A genome-wide association study identifies novel loci of vertigo in an Asian population-based cohort.

The contributing genetic factors of vertigo remain poorly characterized, particularly in individuals of non-European ancestries. Here we show the genetic landscape of vertigo in an Asian population-based cohort. In a two-stage genome-wide association study (Ncase = 6199; Ncontrol = 54,587), we identify vertigo-associated genomic loci in DROSHA and ZNF91/LINC01224, with the latter replicating the findings in European ancestries. Gene-based association testing corroborates these findings. Interestingly, both genes are enriched in cerebellum, a key structure receiving sensory input from the vestibular system. Subjects carrying risk alleles from lead SNPs of DROSHA and ZNF91 incur a 1.74-fold risk of vertigo than those without. Moreover, composite clinical-polygenic risk scores allow differentiation between patients and controls, yielding an area under receiver operating characteristic curve of 0.69. This study identified novel genomic loci for vertigo in an Asian population-based cohort, which may help identifying high risk subjects and provide mechanistic insight in understanding the pathogenesis of vertigo.

Clinical Utility of Leeds Dependence Questionnaire in Medication-Overuse Headache.

Dependence behaviors are common in patients with medication-overuse headache (MOH). This prospective study aimed to characterize dependence behaviors in MOH by using Leeds dependence questionnaire (LDQ), and to determine the clinical utility of LDQ in the diagnosis of MOH. In total, 563 consecutive chronic migraine (CM) patients (451F/112M, mean age 41.7 ± 12.0 years) were recruited, including 320 with MOH (56.8%) (254F/66M, mean age 42.3 ± 11.6 years). LDQ scores were positively correlated with the monthly frequency of acute medication use (Spearman's rho = 0.680, p < 0.001). When compared with patients without, those with MOH scored higher on LDQ (13.0 ± 7.6 vs. 3.9 ± 5.1, p < 0.001). By using a receiver operating characteristics curve, the cutoff value of LDQ was determined at 7 (sensitivity = 77.5%, specificity = 77.4%, area under curve = 0.85) for a diagnosis of MOH. An LDQ score of ≥7 was predictive of MOH (odds ratio = 11.80, 95% confidence interval = 7.87-17.67, p < 0.001). In conclusion, the presence of MOH in patients with CM is associated with more severe dependence behaviors. An LDQ score of ≥7 is useful in the detection of MOH in CM patients.