The burdens attributable to primary headache disorders in children and adolescents in Iran: estimates from a schools-based study.

BACKGROUND: We recently found headache disorders to be highly prevalent among children (aged 6-11 years) and adolescents (aged 12-17) in Iran (gender- and age-adjusted 1-year prevalences: migraine 25.2%, tension-type headache 12.7%, undifferentiated headache [UdH] 22.1%, probable medication-overuse headache [pMOH] 1.1%, other headache on ≥ 15 days/month [H15+] 3.0%). Here we report on the headache-attributed burden, taking evidence from the same study. METHODS: In a cross-sectional survey, following the generic protocol for the global schools-based study led by the Global Campaign against Headache, we administered the child and adolescent versions of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) structured questionnaire in 121 schools, purposively selected to reflect the country's diversities. Pupils self-completed these in class, under supervision. Headache diagnostic questions were based on ICHD-3 criteria but for the inclusion of UdH (defined as mild headache with usual duration < 1 h). Burden enquiry was across multiple domains. RESULTS: The analysed sample (N = 3,244) included 1,308 (40.3%) children and 1,936 (59.7%) adolescents (1,531 [47.2%] male, 1,713 [52.8%] female). The non-participating proportion was 3.4%. Mean headache frequency was 3.9 days/4 weeks, and mean duration 1.8 h. Estimated mean proportion of time in ictal state was 1.1% (1.4% for migraine, 16.5% for pMOH). Symptomatic medication was consumed on a mean of 1.6 days/4 weeks. Lost school time averaged 0.4 days/4 weeks overall (2%, assuming a 5-day week), but was eleven-fold higher (4.3 days; 22%) for pMOH. For most headache types, days of reported limited activity were several-fold more than days lost from school (45% for pMOH, 25% for other H15+). Almost one in 12 parents (7.9%) missed work at least once in 4 weeks because of their son's or daughter's headache. Emotional impact and quality-of-life scores reflected these measures of burden. CONCLUSIONS: Headache, common in children and adolescents in Iran, is associated with symptom burdens that may be onerous for some but not for most. However, there are substantial consequential burdens, particularly for the 1.1% with pMOH and the 3.0% with other H15+, who suffer educational disturbances and potentially major life impairments. These findings are of importance to educational and health policies in Iran.

The effect of salt substitution on frequency and severity of headache: results from the SSaSS cluster-randomised controlled trial of 20,995 participants.

BACKGROUND: Headache is one of the most common neurological symptoms. Headache disorders are associated with a high global burden of disease. Prior studies indicate that short-to-medium term sodium reduction reduces headache symptom. This study evaluated the effects of long-term reduced-sodium, added-potassium salt on headache frequency and severity in rural China. METHODS: The Salt substitute and stroke study (SSaSS) was an open-label cluster-randomised trial in rural China designed to evaluate the effect of salt substitution on mortality and cardiovascular events. Participants included adults with a history of prior stroke and those aged ≥60 years with uncontrolled high blood pressure (BP). Villages were randomly assigned in a 1:1 ratio either to intervention with salt substitute (75% sodium chloride and 25% potassium chloride by mass) or to control with continued use of regular salt (100% sodium chloride). In this pre-specified analysis, between-group differences in headache frequency and severity were evaluated. The study was registered with ClinicalTrials.gov (identifier number: NCT02092090). RESULTS: A total of 20,995 participants were included in the trial (mean age 64.3 years, 51% female, mean follow-up 4.7 years). At final follow-up at the end of the study, headache outcome data including frequency and severity of headaches was available for 16,486 (98%) of 16,823 living participants. Overall, 4454/16,486 (27%) individuals reported having headache: 27.4% in the intervention group (2301/8386) vs 26.6% in the control group (2153/8100) (RR 1.04, 95% CI: 0.93, 1.16, p = 0.48). There was no difference in headache severity between intervention and control groups (p = 0.90). CONCLUSION: Long term salt substitution did not reduce the frequency or severity of headaches in this population.

The effect of blood pressure lowering medications on the prevention of episodic migraine: A systematic review and meta-analysis.

BACKGROUND: Currently, only a few specific blood pressure-lowering medications are recommended for migraine prevention. Whether benefits extend to other classes or drugs is uncertain. METHODS: Embase, MEDLINE, and the Cochrane Central Registry of Controlled Trials were searched for randomized control trials on the effect of blood pressure-lowering medications compared with placebo in participants with episodic migraine. Data were collected on four outcomes - monthly headache or migraine days, and monthly headache or migraine attacks, with a standardised mean difference calculated for overall. Random effect meta-analysis was performed. RESULTS: In total, 50 trials (70% of which were crossover) were included, comprising 60 comparisons. Overall mean age was 39 years, and 79% were female. Monthly headache days were fewer in all classes compared to placebo, and this was statistically significant for all but one class: alpha-blockers -0.7 (95% CI: -1.2, -0.1), angiotensin-converting enzyme inhibitors -1.3 (95% CI: -2.9, 0.2), angiotensin II receptor blockers -0.9 (-1.6, -0.1), beta-blocker -0.4 (-0.8, -0.0) and calcium channel blockers -1.8 (-3.4, -0.2). Standardised mean difference was significantly reduced for all drug classes and was separately significant for numerous specific drugs: clonidine, candesartan, atenolol, bisoprolol, metoprolol, propranolol, timolol, nicardipine and verapamil. CONCLUSION: Among people with episodic migraine, a broader number of blood pressure-lowering medication classes and drugs reduce headache frequency than those currently included in treatment guidelines.Trial Registration: The study was registered at PROSPERO (CRD42017079176).

Evaluating the efficacy of CGRP mAbs and gepants for the preventive treatment of migraine: A systematic review and network meta-analysis of phase 3 randomised controlled trials.

BACKGROUND: Several novel treatments targeting the calcitonin gene-related peptide pathway have been developed for migraine. We evaluated the efficacy of these medications, including atogepant, rimegepant, erenumab, eptinezumab, fremanezumab, and galcanezumab, for the prevention of migraine via network meta-analysis. METHODS: Databases, including MEDLINE via PubMed, EMBASE, and Cochrane central, were systematically reviewed, and all eligible phase 3 randomised controlled trials were included. RESULTS: Nineteen studies (n = 14,584 participants) were included. Studies included episodic (n = 11) and chronic (n = 4) migraine or both (n = 4). All interventions, except for eptinzumab 30 mg, significantly reduced mean monthly migraine days compared to placebo. All medications had a higher ≥50% responder rate than placebo and results were statistically significant in those with the subcutaneous or intravenous route of administrations, but not with the oral one. All medications significantly reduced mean monthly headache days, although no data for this outcome was available for rimegepant, and mean monthly acute medication days, with no data for eptinezumab. CONCLUSION: The results show that medications targeting calcitonin gene-related peptide were effective in preventing migraine compared to placebo. Considering limitations of single studies, different populations such as episodic and chronic migraine, and the absence of head-to-head trials, all novel treatments decreased mean monthly migraine and headache days, and showed higher 50%, 75% and 100% responder rates than placebo.Trial registration: PROSPERO registration: CRD42022310579.

Efficacy, safety and indirect comparisons of lasmiditan, rimegepant, and ubrogepant for the acute treatment of migraine: A systematic review and network meta-analysis of the literature.

BACKGROUND: We performed a random-effects network meta-analysis to study the efficacy and safety of newly developed drugs for the acute treatment of migraine attacks. METHODS: MEDLINE via PubMed, Embase and The Cochrane Register of Controlled Trials were searched from inception to 11 February 2022. Phase 3 randomized controlled trials examining all formulations of lasmiditan, rimegepant and ubrogepant for the acute treatment of adults with migraine, were included. Data were extracted following the PRISMA guidelines. RESULTS: Seven studies (SAMURAI, SPARTAN, CENTURION, Study 302, Study 303, ACHIEVE I and II) involving n = 12,859 patients were included. All treatments were superior in efficacy to placebo. Lasmiditan 200 mg showed the highest two-hour pain freedom, while two-hour freedom from most bothersome symptom was equally achieved by the higher doses of lasmiditan (100 and 200 mg), rimegepant and the higher doses of ubrogepant (50 and 100 mg). The odds of treatment-emergent adverse events were greatest with all doses of lasmiditan. CONCLUSION: Lasmiditan 200 mg was the most effective intervention in the treatment of migraine attacks, although it was associated with high degrees of dizziness, nausea and somnolence. Rimegepant showed slightly lower, but similar efficacy rates to lasmiditan. Ubrogepant had overall the best tolerability profile. These conclusions are limited by the absence of head-to-head comparisons, limitations of individual trials and of the meta-analysis methodology itself.PROSPERO trial registration: CRD42022308224.

Safety and tolerability of monoclonal antibodies targeting the CGRP pathway and gepants in migraine prevention: A systematic review and network meta-analysis.

BACKGROUND: Direct comparisons of the tolerability and safety of migraine preventive treatments targeting the calcitonin gene-related peptide pathway are lacking. This study aimed to compare the safety and tolerability of anti-calcitonin gene-related peptide monoclonal antibodies and gepants in migraine prevention. METHODS: A network meta-analysis of phase 3 randomized controlled trials assessing the safety and tolerability of anti-calcitonin gene-related peptide monoclonal antibodies (erenumab, eptinezumab, fremanezumab, or galcanezumab) and gepants (atogepant, rimegepant) in migraine prevention was performed. Primary outcomes were treatment-emergent adverse events and serious adverse events. Secondary outcomes included any adverse events, adverse events leading to treatment discontinuation and individual adverse events. RESULTS: We included 19 randomized controlled trials, comprising 14,584 patients. Atogepant 120 mg (OR 2.22, 95% CI [1.26, 3.91]) and galcanezumab 240 mg (OR 1.63, 95% CI [1.33, 2.00]) showed the largest odds of treatment-emergent adverse events compared to placebo. While eptinezumab 30 mg had greater odds of adverse events leading to treatment discontinuation (OR 2.62, 95% CI [1.03,6.66]). No significant differences in serious adverse events were found between active treatments and placebo. Eptinezumab was associated with the lowest odds of treatment-emergent adverse events and serious adverse events compared to placebo, whereas erenumab was associated with the lowest odds of any adverse events and quarterly fremanezumab with the lowest odds of treatment discontinuation due to adverse events. CONCLUSION: Monoclonal antibodies targeting the calcitonin gene-related peptide pathway and gepants are a safe and well tolerated option for migraine prevention.

Migraine management: Non-pharmacological points for patients and health care professionals.

Migraine is a highly prevalent disorder with an enormous burden on societies. Different types of medications are used for controlling both acute attacks and prevention. This article reviews some non-pharmacological recommendations aiming to manage migraine disorder better and prevent headache attacks. Different triggers of migraine headache attacks, including environmental factors, sleep pattern changes, diet, physical activity, stress and anxiety, some medications, and hormonal changes, are discussed. It is advised that they be identified and managed. Patients should learn the skills to cope with the trigger factors that are difficult to avoid. In addition, weight control, management of migraine comorbidities, lifestyle modification, behavioural treatment and biofeedback, patient education, using headache diaries, and improving patients' knowledge about the disease are recommended to be parts of migraine management. In addition, using neuromodulation techniques, dietary supplements such as riboflavin, coenzyme Q10 and magnesium, and acupuncture can be helpful. Non-pharmacological approaches should be considered in migraine management. Furthermore, the combination of pharmacological and non-pharmacological approaches is more effective than using each separately.

The impact of Coronavirus disease 2019 (COVID-19) pandemic on migraine disorder.

OBJECTIVE: To evaluate the impact of the Coronavirus disease of 2019 (COVID-19) pandemic on patients with migraine. METHODS: Self-reported data from a migraine tracking smartphone application, Migraine Buddy, were used. Data were collected from users who reported at least one attack in the Jan, Feb, Mar and Apr of 2018, 2019 and 2020. In addition, a survey was conducted to evaluate the impact of COVID-19 on migraine management. RESULTS: On average, data from 124,717 users per month (mean age 36.3 ± 10.9 years and 89% female) were collected. Overall, the mean frequency of migraine headache was higher in 2020 than in 2019 and higher in 2019 than in 2018. The four commonest headache triggers in 2018, 2019 and 2020 were stress in 39.7, 38.4 and 36.1%, lack of sleep in 25, 25 and 22.8%, neck pain, 20, 20.4 and 19.3 and anxiety in 19, 18.4 and 18.4% of participants, respectively. 1689 users participated in the survey and they reported that they preferred face-to-face (54.29%) to telehealth (11.9%) consultations. CONCLUSION: An increase in migraine frequency from 2018 to 2020 was reported by the users of the mobile phone. This could reflect a real increase or change in reporting habits. Stress, lack of sleep, neck pain and anxiety were the commonest attack triggers. The frequency of these triggers decreased slightly in 2020 compared to 2019 and 2018. An increase in telehealth consultations with specialists was reported in the survey but migraine patients preferred face-to-face consultations.

Body Mass Index and its Association with Migraine Characteristics in Female Patients.

BACKGROUND: Migraine is a debilitating neurological disorder with a high prevalence. This study was conducted to evaluate the relationship between body mass index (BMI) and disability, severity, frequency and duration of headaches in female migraine patients. METHODS: This cross-sectional study was designed to address the characteristics of migraine attacks (duration of each attack, frequency, and severity) and MIDAS (Migraine Disability Assessment) score in female migraineurs. The diagnosis of migraine was based on ICHD-3 beta criteria. Verbal rating scale (VRS) was used for headache severity. Height and weight were measured to calculate the BMI. Mann-Whitney and Kruskal-Wallis tests were used for comparison of means, and analysis of covariance (ANCOVA) test was used for adjustment of the confounding factors. RESULTS: In the current study, 170 female migraine patients with a mean (±SD) age of 34.0 ± 8.0 years were enrolled. There were significant differences between the three groups (18.5 ≤ BMI< 25, 25 ≤ BMI < 30 and 30 ≤ BMI) in terms of headache frequency, duration and severity as well as total MIDAS score (P<0.001). These differences remained significant after adjustment for age. CONCLUSION: This study revealed that migraineurs with higher BMI experienced higher headache frequency, severity and duration as well as higher disability score.

The effect of Quercus brantii gall extract on burn wound healing in rat.

OBJECTIVES: The aim of the present study was to evaluate the effect of Quercus brantii galls extract on the rat skin burn wound healing. MATERIALS AND METHODS: Ethanol extract of the galls of Q. brantii was used to treat the induced burn wounds on the back of 32 Wistar rats divided into 4 groups. The groups were treated by placebo, 1%, 2% and 4% concentration gall extract gels for 14 days and the efficacy of treatment was assessed based on reduction of burn wound area, as well as histological and molecular characteristics. RESULTS: The mean wound surface in the 14th day, in all groups treated by Q. brantii gall extracts were larger than control group and the differences were statistically significant (P=0.043). The mean histological wound healing scores were not statistically different. Analysis of nitric oxide and platelet derived growth factor concentration in wound fluids in the 5th day of study showed that there was not any significant difference between groups (P=0.468 and 0.312 respectively). Fibroblast growth factor (bFGF) concentration in the wound fluids, was significantly higher in group treated with 1% gall extract gel in comparison to the control group (P=0.026). CONCLUSION: Our results could not prove the significant positive effect of Q. brantii galls extract on the burning wound healing. More studies with more groups treated with different doses of the Q. brantii extract are recommended.

Association between Ala379Val polymorphism of lipoprotein-associated phospholipase A2 and migraine without aura in Iranian population.

BACKGROUND: Migraine is a common neurovascular disorder with multifactorial and polygenic inheritance. The aim of this study was to investigate the association of a migraine without aura and Ala379Val polymorphism of lipoprotein-associated phospholipase A2 (Lp-PLA2) gene in the Iranian population. METHODS: In this study, 103 migraine patients and 100 healthy controls were enrolled. DNA samples were extracted and the Ala379Val polymorphism of Lp-PLA2 gene was investigated. To assess severity of a headache, patients filled out the headache impact test (HIT-6) and migraine severity (MIGSEV) questionnaires. RESULTS: Allele V had significantly lower frequency in the case group than control subjects [P = 0.001, odds ratio (OR) = 0.25, confidence interval (CI): 0.15-0.40]. The frequency of migraine patients that were a carrier of V allele (V/V and A/V) was statistically significant lower than the control group (P = 0.003, OR = 2.39, CI: 1.35-4.23). There was no significant difference of alleles frequency between three grades of MIGSEV (P = 0.316). Furthermore, total HIT-6 score was not significantly different between different genotypes (P = 0.466). CONCLUSION: Our results showed that Ala379Val gene polymorphism of LP-PLA2 is associated with lower risk of migraine but not with severity of headaches in an Iranian population.

Association between promoter region of the uPAR (rs344781) gene polymorphism in genetic susceptibility to migraine without aura in three Iranian hospitals.

INTRODUCTION: Migraine is a chronic neurological disorder. Inflammation has a key role in migraine pathophysiology. Urokinase plasminogen activator receptor (uPAR) directly involves in inflammatory conditions by facilitating migration of inflammatory cells to different tissues. The aim of this study was to investigate whether uPAR rs344781, common genetic polymorphism in the uPAR promoter region, might be associated with migraine without aura susceptibility in an Iranian population. METHODS: We enrolled 103 newly diagnosed patients with migraine and 100 healthy controls. Peripheral blood sample was used for DNA extraction and uPAR rs344781 gene polymorphism was determined. Patients filled HIT-6 as a tool to evaluate headache severity. RESULTS: The genotype frequency of uPAR is significantly different between migraine patients and control subjects. Heterozygote genotype (AG) was statistically more frequent in the patients than the controls (P=0.001; OR=2.67, 95% CI=1.51-4.7). Also G allele was more frequent in the patients. Total HIT-6 score was not significantly different between heterozygote and homozygote patients (55.50±2.22 vs. 49.60±3.68 respectively, P=0.075). CONCLUSION: In conclusion, our study showed a significant association between uPAR rs344781 gene promoter polymorphism and migraine without aura susceptibility but not with headache severity.

Reliability and validity of the migraine disability assessment scale among migraine and tension type headache in Iranian patients.

INTRODUCTION: MIDAS is a valid and reliable short questionnaire for assessment of headache related disability. Linguistic validation of Persian MIDAS and assessment of psychometric properties between tension type headache (TTH) and migraine were the aims of this study. METHODS: Patients with migraine or TTH were included. At the first visit, we administered a headache symptom questionnaire, MIDAS, and SF-36. Patients filled out MIDAS in second and third visit within three and eight weeks after base line visit. Internal consistency (Cronbach α ) and test-retest reproducibility (Spearman correlation coefficient) were used to assess reliability. Convergent validity and MIDAS capability to differentiate between chronic and episodic headaches (migraine and TTH) were also assessed. RESULTS: The 267 participants had episodic migraine (EM-64%), chronic migraine (CM-13.5%), episodic TTH (ETTH-13.5%), and chronic TTH (CTTH-9). Internal consistency reliability was 0.8 for the entire sample, 0.72 for TTH, and 0.82 for migraine. Test-retest reliability for all questions between visit 1 and visit 2 varied from 0.54 to 0.71. Convergent validity was assessed using SF-36 as an external referent. Patients with episodic headaches (EM and ETTH) had significantly lower MIDAS scores than chronic headaches (CM and CTTH). CONCLUSION: Persian MIDAS is a valid and reliable questionnaire for migraine and TTH that can differentiate between episodic headache and chronic headache.

Vitamin D status in migraine patients: a case-control study.

BACKGROUND: There have been few studies on the relation between vitamin D and migraine. We investigated the prevalence of vitamin D deficiency in migraine patients and compared it with a control group. We also evaluated the relationship of vitamin D deficiency with severity of migraine. METHODS: 105 newly diagnosed migraine patients and 110 controls, matched for age, sex, socioeconomic status, education, and sun exposure, were enrolled during the spring of 2011. 25-Hydroxy vitamin D [25(OH)D] plasma levels were measured by chemiluminescence immunoassay. RESULTS: The mean ± SE concentration of 25(OH)D was 13.55 ± 0.91 ng/mL in cases and 13.19 ± 1.19 ng/mL in controls. There was no significant difference in 25(OH)D concentration between cases and controls. We found no relationship between severity of headache and 25(OH)D status. CONCLUSIONS: We did not find any association between migraine and vitamin D status; also, severity of headaches was not related to 25(OH)D level. Further studies with larger sample sizes are required to confirm our results.

Reliability and Validity of the Persian HIT-6 Questionnaire in Migraine and Tension-type Headache.

OBJECTIVE: Headache Impact Test (HIT-6) measures the impact headaches in a 1-month period. We validated the Persian translation of HIT-6, compared the HIT-6 psychometric analysis between migraine and tension-type headache (TTH) patients, and evaluated the capability of HIT-6 to differentiate between TTH, chronic migraine, and episodic migraine. METHODS: Qualified participants, including 274 patients diagnosed with migraine or TTH, were required to complete HIT-6, SF-36v2, and a symptoms questionnaire on their first visit. At 3 and 8 weeks from first visit, participants completed HIT-6. Internal consistency (Cronbach's α) and test-retest reproducibility (Pearson's correlation coefficient) were used to assess reliability. Convergent validity was also assessed. RESULTS: Tension-type headache, episodic, and chronic migraines included 24.5%, 61.9%, and 13.6% of the participants, respectively. Internal consistency among all patients, TTH, and migraine in the first visit were 0.74, 0.77, and 0.73, respectively. Test-retest reliability for HIT-6 between visit 1 and 2 showed a moderate level of correlation (r = 0.50). Convergent validity and also item total correlation were acceptable. There was no significant difference in HIT-6 total score between TTH and migraine. CONCLUSION: Persian HIT-6 is a valid and reliable questionnaire for the evaluation of headache. However, it cannot differentiate between chronic migraine, episodic migraine, and TTH in Iranian population.

Pistacia atlantica Resin Has a Dose-Dependent Effect on Angiogenesis and Skin Burn Wound Healing in Rat.

Objectives. The aim of the present study was to evaluate the effect of Pistacia atlantica resin extract on the rat skin burn wound healing. Methods. Thirty-two Wistar rats were divided into four groups and treated by vehicle, 5%, 10%, and 20% concentration of Pistacia atlantica resin extract for 14 days (G1, G2, G3, and G4, resp.). The efficacy of treatment was assessed based on reduction of burn wound size and histological and molecular characteristics. Results. α -Pinene (46.57%) was the main content of essential oil of resin. There were no statistically significant differences between groups according to wound size analysis. The mean histological wound healing scores were not statistically different. Capillary counts of G2 and G3 were significantly higher than those of the G1 (P = 0.042 and 0.032, resp.). NO concentration in wound fluids on the 5th day of study was not significantly different between groups (P = 0.468). But bFGF concentration in G2 and G3 and PDGF concentration in G3 were significantly higher in comparison to G1 (P = 0.043, 0.017, and 0.019, resp.). Conclusion. Our results revealed that Pistacia atlantica resin extract has a concentration-dependent effect on the healing of burn wounds after 14 days of treatment by increasing the concentration of bFGF and PDGF and also through improving the angiogenesis.

The psychometric properties of the persian migraine-specific quality of life questionnaire version 2.1 in episodic and chronic migraines.

BACKGROUND: Migraine-specific quality of life (MSQ) is a valid and reliable questionnaire. Linguistic validation of Persian MSQ questionnaire, analysis of psychometric properties between chronic and episodic migraine patients, and capability of MSQ to differentiate between chronic and episodic migraines were the aims of this study. METHOD: Participants were selected from four different neurology clinics that were diagnosed as chronic or episodic migraine patients. Baseline data included information from MSQ v. 2.1, MIGSEV, SF-36, and symptoms questionnaire. At the third week from the baseline, participants filled out MSQ and MIGSEV. Internal consistency (Cronbach alpha) and test-retest reproducibility (intraclass correlation coefficients) were used to assess reliability. Convergent and discriminant validities were also assessed. RESULTS: A total of 106 participants were enrolled. Internal consistencies of MSQ among all patients, chronic and episodic migraines, were 0.92, 0.91, and 0.92, respectively. Test-retest correlation of MSQ dimensions between visits 1 and 2 varied from 0.41 to 0.50. Convergent, item discriminant, and discriminant validities were approved. In all visits MSQ scores were lower in chronic migraine than episodic migraine; however, the difference was not statistically significant. CONCLUSION: Persian translation of MSQ is consistent with original version of MSQ in terms of psychometric properties in both chronic and episodic migraine patients.