The aim of this study was to evaluate the association of oral menopausal hormone therapy (estrogen only [E-only] or estrogen and progestin [E+P]), as compared to placebo on postmenopausal headache severity among females with and without a history of migraine in the Women's Health Initiative Hormone Therapy (WHI-HT) trials. Migraine is three times more common among females than males and is a major source of pain and disability among women throughout the life course. Previous observational research found a positive association between menopausal hormone therapy (MHT) use and migraine prevalence, but the longitudinal association of MHT with postmenopausal migraine severity is unclear. We examined changes in self-reported headache severity between baseline and year 1 in 22,876 females (average age 64 years) across the United States enrolled in the WHI-HT trials between 1993 and 1998. We conducted a secondary, stratified analysis of data of two parallel, randomized, placebo-controlled clinical trials to estimate the association of MHT and headache severity overall and stratified by history of migraine at baseline. Additionally, we assessed the association between MHT and headache trajectory, based on whether headaches worsened over the follow-up period. At baseline, the prevalence of a lifetime migraine diagnosis was 10%. Among participants with a history of migraine, randomization to E-only MHT was not associated with more severe headache at 1 year (adjusted odds ratio [aOR] = 1.14, 95% confidence interval [CI]: 0.90-1.44), or worsening headache trajectory (adjusted risk ratio [aRR] = 0.98, 95% CI: 0.71-1.34) after 1 year. Randomization to E+P MHT was modestly associated with more severe headache, although estimates did not reach statistical significance (aOR = 1.21, 95% CI: 0.98-1.50). E+P MHT was significantly associated with worsening headache trajectory (aRR= 1.53, 95% CI: 1.14-2.03). Among those without a migraine history, E-only MHT was not strongly associated with moderate-to-severe headache severity (aOR: 1.11, 95% CI: 1.01-1.21) or worsening headache trajectory (aRR = 1.08 95% CI: 0.96-1.22) after 1 year. However, E+P MHT was associated with modestly increased odds of moderate-to-severe headache severity (aOR = 1.14, 95% CI: 1.06-1.23) and a higher likelihood of worsening headache trajectory (aRR = 1.18, 95% CI: 1.07-1.30) after 1 year. In this study of MHT in the WHI hormone therapy trial participants, E-only MHT was not associated with increased odds of more severe postmenopausal headache severity. Among those with a history of migraine, E+P MHT was associated with more severe and worsening postmenopausal headache. Further research on the effect of newer MHT formulations on postmenopausal headache is warranted. Menopausal hormone therapy is widely used, but its impact on headache severity, especially among those with a history of migraine, is unclear. We analyzed data from randomized trials and found that estrogen‐only therapy was not linked to worse headaches, while combined estrogen plus progestin therapy was associated with worsening headaches, particularly among women with prior migraine. These findings suggest that menopausal hormone therapy types differ in their association with headache outcomes.
Headache is one of the most frequent reasons for emergency department (ED) visits, and distinguishing primary from secondary headache remains challenging. Blood biomarkers may improve early risk stratification. This study evaluates serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) as potential biomarkers in patients presenting with non-traumatic headache to the ED. Secondary analysis of a prospective multicenter case-control study at University Hospital Basel and Aarau, Switzerland. Patients presenting with acute non-traumatic headache were included. Final headache diagnoses were adjudicated by two board-certified neurologists. Blood samples obtained at ED presentation were analyzed for sNfL and sGFAP, excluding patients with conditions known to affect biomarker levels. Primary headache samples were matched to serious secondary headache samples. Biomarker levels were expressed as age-, BMI-, and sex-adjusted Z-scores. A total of 82 patients were analyzed (42 serious secondary, 40 primary headache). Median[IQR] sNfL Z-scores were significantly higher in serious secondary compared with primary headache (0.8 [0.0-1.8] vs. 0.2 [-0.3-0.8]; p < 0.01). sGFAP Z-scores showed an even greater difference (1.2 [-0.1-2.3] vs. -0.2 [-0.7-0.2]; p < 0.001). Both biomarkers demonstrated a specificity of 85%, but sGFAP showed higher sensitivity (57% vs. 43%), NPV (65% vs. 59%), and PPV (80% vs. 75%). In multivariable analysis adjusted for clinical risk factors, sGFAP remained independently associated with serious secondary headache (OR 1.9, 95%-CI 1.2-3.4), whereas sNfL did not. sGFAP may represent a promising biomarker to support differentiation between primary and non-traumatic serious secondary headache in the ED, warranting validation in larger cohorts.
Prospective studies of the risk of headache with low levels of physical activity are limited. Pandemic-related lifestyle changes and the potential headache risk associated with Coronavirus Disease (COVID-19) and SARS-CoV-2 vaccination may complicate this association. Our study aims to investigate the potential risk of new bothersome headache in relation to physical activity and explore the impact of COVID-19 and SARS-CoV-2 vaccines on this association. This prospective cohort study utilized questionnaires from the Norwegian Mother, Father, and Child Cohort Study (MoBa). Logistic regression analyses were conducted to estimate the adjusted odds ratio (aOR) for new-onset headache according to physical activity levels. Models were adjusted for gender, age, body mass index, education level, smoking, alcohol intake, anxiety/depression, and COVID-19 and SARS-CoV-2 vaccination prior to February 2022. The potential impact of COVID-19 disease was investigated in a stratified analysis. Both low level of physical activity and inactivity were significantly associated with new bothersome headache when compared to moderate to high activity levels (low activity: aOR 1.22, 95% CI 1.13 to 1.30; inactive: aOR 1.26, 95% CI 1.05 to 1.51). The corresponding adjusted absolute risk differences were 1.9% (95% CI 1.2 to 2.6) and 2.3% (95% CI 0.4 to 4.3), respectively. Findings persisted across COVID-19 status strata, without significant interactions. Our findings underscore the potential role of physical activity in mitigating new bothersome headache also for headache associated with COVID-19. Encouraging regular physical activity may serve as a preventive measure for headache in a pandemic setting.
Primary headaches in children impair daily functioning, yet data from Jordan, particularly regarding their effect on school functioning, have not been systematically evaluated. The objective of this study is to assess the clinical characteristics of pediatric primary headaches in central Jordan and their association with school functioning. A cross-sectional study included children aged 5 to 18 years diagnosed with primary headaches at three public hospitals. Data were collected using a structured, culturally adapted questionnaire incorporating items from the validated Arabic PedsQL 4.0 school-functioning scale. Descriptive, univariable, and multivariable analyses were performed to identify factors associated with impaired school functioning. A total of 147 children were included (51% male; 61.2% aged 10-14 years). Migraine was most common (60.5%), followed by tension-type headache (23.8%). Common triggers included stress, noise, and sleep disturbance. Unfavorable lifestyle factors-increased screen time, skipped meals, low hydration, and limited physical activity-were prevalent. More than 92% of participants had impairment in at least one school-functioning domain. Poor academic performance and lower parental education were significantly associated with lower scores. In multivariable analysis, poorer academic performance and lower paternal education remained independently associated with worse school-functioning scores, whereas headache type and frequency were not significant predictors. Most patients used simple analgesics (paracetamol in 93%), whereas migraine-specific rescue medications and preventive therapies were rarely used. Primary headaches in children are associated with substantial impairment in school functioning. Educational and family-related factors appear more influential than headache-specific variables. Addressing modifiable lifestyle and contextual factors may improve outcomes.
Cluster headache (CH) has historically been considered a male-dominated disorder, suggesting a role for androgens in its pathophysiology. We aimed to evaluate hormone profiles and symptoms of androgen deficiency in CH. In this prospective, matched case-control study with a nested repeated-measures component, fasted morning blood samples were collected in 30 males with chronic CH (CCH), 33 males with episodic CH (ECH; both during episode and remission), and in 30 age-matched male headache-free controls (HCs). Surveys assessing symptoms of androgen deficiency (Quantitative Androgen Deficiency of Aging Males [QADAM], Aging Males' Symptoms [AMS]) were collected simultaneously. Steroid hormone profiles were compared among groups. The primary outcome was total testosterone (tT) including biochemical hypogonadism (tT ≤ 10.5). Secondary outcomes were hormonal pathways and individual hormones. Data were collected between October 2022 and April 2025. Biochemical hypogonadism was observed in 20% of participants with CCH (n = 6), in 9% with ECH (n = 3), and in 7% of HCs (n = 2). None of the HCs had severe hypogonadism, in contrast to those with CH (CCH, n = 3/6; ECH, n = 1/3). AMS and QADAM scores indicated more symptoms of androgen deficiency in participants with hypogonadism, in ECH (AMS: B = 9.59 [95% CI = 5.69-13.50], p < 0.001; QADAM: B = -5.25 [95% CI = -7.39 to -3.11], p < 0.001) and CCH (AMS: B = 8.78 [95% CI = 4.45-13.12], p < 0.001; QADAM: B = -4.59 [95% CI = -6.97 to -2.22], p < 0.001) compared to HCs. In the unadjusted model, we observed a lower, albeit non-statistically significant, mean tT in participants with CCH versus HCs (CCH: B = -2.35 nmol/L [95% CI = -4.79 to 0.09], p = 0.059). In the adjusted model, the differences attenuated, suggesting a strong effect of body mass index and age on the mean tT (CCH: B = -0.93 nmol/L [95% CI = -3.81 to 1.95], p = 0.524; ECH: B = 0.55 nmol/L [95% CI = -2.05 to 3.15], p = 0.674). Measures of hormonal pathways and individual hormones did not differ among groups. Biochemical hypogonadism was observed in one out of five males with CCH versus one out of 20 in the ECH and HCs. Apart from one case, gonadotrophin concentrations were not increased, suggesting a central origin. In the crude data we observed a lower, albeit non-statistically significant, mean tT in males with CCH, but this appeared to be mainly driven by body mass index and age, because it attenuated after correction. Clinical symptoms of androgen deficiency were more prevalent in CH compared to HCs, independent of hypogonadism. Physicians should be aware of potential increased risk and symptoms of (central) hypogonadism in CCH. Further investigation should explore shared underlying mechanisms and testosterone supplementation in CH. It is thought that there may be a link between cluster headache (CH) in males and low testosterone. In this study, we compared hormone levels and symptoms of low testosterone in men with chronic and episodic CH to headache‐free controls (males). No differences in hormone levels were found between groups, but low testosterone levels were found in 20% of patients with chronic CH, and males with CH reported more symptoms of low testosterone than headache‐free controls.
Adolescent patients with major depressive disorders (MDD) frequently co-occur with headache, contributing to substantial disease burden and social functional impairment. Repetitive transcranial magnetic stimulation (rTMS) has been supported for MDD and pain conditions, but clinical evidence for a combined affect and pain network targeting strategy in comorbid phenotypes remains limited. A 16-year-old male student presented with a 2-year history of depression accompanied by paroxysmal headache. We administered a dual-target rTMS protocol targeting the dorsolateral prefrontal cortex and primary motor cortex. After 2 weeks of treatment (40 sessions), the patient's depressive and headache symptoms improved significantly. This case suggests that an intensified dual-target rTMS approach engaging both affect regulation and pain modulation targets may be feasible for adolescents with comorbid depression and headache. Prospective studies are needed to determine optimal parameters, durability, and safety. Not applicable.
BackgroundGlutathione (GSH) and glutamate (Glu) have been individually implicated in migraine pathophysiology, but their ratio as a marker of oxidative-excitatory balance in the thalamus-a key pain-processing hub-remains unexplored. This study investigated thalamic GSH/Glu ratios across primary headache subtypes and evaluated their diagnostic utility.MethodsThis cross-sectional study included 131 participants: 36 healthy controls (HC), 17 migraine with aura (MwA), 46 migraine without aura (MwoA), and 32 tension-type headache (TTH). Single-voxel proton magnetic resonance spectroscopy was performed at 3T using a MEGA-PRESS sequence targeting bilateral thalami. Metabolite concentrations were quantified with LCModel and corrected for partial volume effects using an established tissue correction framework. Group differences were analyzed using ANOVA with Tukey HSD correction; diagnostic performance was assessed using ROC analysis with bootstrap resampling.ResultsThe GSH/Glu ratio differed significantly across groups (F = 9.41, p < 0.001, η2 = 0.183), confirmed by bootstrap validation. MwA (0.250 ± 0.038, p < 0.001, Cohen's d = 1.47) and MwoA (0.280 ± 0.052, p = 0.006, d = 0.79) showed significantly lower ratios than HC (0.320 ± 0.055), whereas TTH (0.318 ± 0.068) did not differ from HC. This reduction was driven by decreased GSH levels, with Glu concentrations unchanged across groups. Exploratory ROC analysis yielded apparent AUCs of 0.874 for GSH and 0.758 for the GSH/Glu ratio; these estimates require independent validation.ConclusionsMigraine is characterized by reduced thalamic GSH levels and decreased GSH/Glu ratios, reflecting diminished antioxidant buffering capacity against normal excitatory neurotransmission. This metabolic alteration distinguishes migraine from TTH, supporting distinct pathophysiological mechanisms.
Social risk factors are key determinants of migraine occurrence and progression. This study assessed the association between the social risk profile (SRP) and the prevalence of self-reported severe headache or migraine and all-cause mortality in US adults, and developed machine learning prediction models to explore feature contributions to internal risk stratification. Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2004, weighted multivariate logistic regression evaluated the SRP-migraine association, and a weighted Cox proportional hazards model assessed the influence of SRP on all-cause mortality among migraine patients. The Boruta and Lasso algorithms selected predictive features for nine machine learning classifiers to predict migraine risk and four survival models to assess mortality risk. SMOTE was applied within cross-validation folds to address class imbalance. SHAP values were utilized to identify the most critical features. Among 11,861 participants, 2,355 self-reported severe headache or migraine; 2,351 were included in the mortality analysis after excluding 4 individuals with missing survival status. Over a median follow-up of 206 months (IQR: 187-224), 471 deaths occurred. Higher SRP scores were associated with lower migraine prevalence (OR = 0.44, 95% CI: 0.34-0.57) and lower all-cause mortality (HR = 0.31, 95% CI: 0.19-0.50). XGBoost achieved the best performance for migraine prediction (AUC = 0.732, 95% CI: 0.712-0.753), while Random Survival Forest performed best for mortality prediction (AUC = 0.882). SHAP analysis identified age, SRP, and cotinine as key predictors. Decision curve and calibration analyses demonstrated acceptable internal performance, supported by ten-fold cross-validation. SRP is an independent predictor of migraine risk and long-term survival. The machine learning analysis provides exploratory insights into feature importance for risk stratification within the development sample, while the regression-based association estimates support the epidemiological significance of social determinants in migraine.
Menopause is associated with neuroendocrine changes and a variety of climacteric symptoms. While hormone replacement therapy (HRT) remains a standard treatment, safety concerns increase global interest in non-hormonal alternatives like ERr 731®, an extract from Rheum rhaponticum to alleviate climacteric complaints. To evaluate the long-term effectiveness of ERr 731® in reducing menopausal climacteric symptoms during a 12-week randomized controlled (RCT) trial followed by a 52-week open-label observational study (OS). One hundred and twelve perimenopausal women (aged 45-55 years) with climacteric complaints (Menopausal Rating Scale (MRS) ≥18) participated in this RCT while eighty-nine of these study participants continued in the OS. During the RCT patients received either ERr 731® (4 mg daily) or a placebo. During the OS, all participants received ERr 731® and were assessed every 13 weeks for headache/migraine, dizziness, paresthesia, fluor vaginalis, and general well-being. Descriptive statistics and exploratory t-tests compared symptom severity between day 0 and day 84 as well as day 364. During the RCT, climacteric complaints were significantly reduced in the ERr 731® group compared to placebo. Symptom severity also decreased across all domains from baseline to week 52 of the OS. Headache/migraine and paresthesia improvements were notable. Since all participants received ERr 731® during the OS, no significant differences between the prior ERr 731® and placebo groups were present (p > 0.05). Dizziness reduction remained significant between groups (p = 0.0086). General well-being improved markedly, with >90% of participants reporting to be "good" or "very good spirits" at week 52. ERr 731® demonstrated sustained symptom relief and improved well-being over 52 weeks, supporting its role as a non-hormonal option for managing climacteric complaints in perimenopausal women.
Patients with chronic migraine (CM) frequently demonstrate resistance to conventional medical therapies, likely attributable to the multifactorial pathophysiology underlying their pain. Transcranial direct current stimulation (tDCS) has recently emerged as a promising non-invasive neuromodulation technique for migraine prophylaxis. In this study, we evaluate the efficacy of a tDCS protocol in treating CM patients, both with and without medication-overuse headache (MOH). Thirty patients diagnosed with chronic migraine (CM) underwent treatment with tDCS (2 mA, 20 min/session) targeting the anodal right dorsolateral prefrontal cortex (DLPFC) and cathodal occipital region for three days each week over two weeks, followed by once-weekly sessions for an additional six weeks. The tDCS demonstrated significant efficacy in pain reduction for CM patients, regardless of MOH comorbidity. After eight weeks, tDCS had significantly reduced severe migraine days (VAS score > 7), awakening migraine episodes, and mean headache intensity and duration. The maximum effects were observed for headache duration and the number of severe headache days. A reduction of more than 50% in the mean headache duration was achieved in 80% of participants. Similarly, 70% of patients demonstrated >50% decrease in severe headache days (VAS >7). Treatment was well-tolerated, with no serious adverse effects reported during the study period. TDCS appears to be an effective, well-tolerated, non-invasive treatment for CM patients, including cases with MOH. The significant reductions in headache duration, intensity, and frequency suggest that tDCS may be a valuable option for those resistant to standard medical therapies. Iranian Registry of Clinical Trials IRCT20140624018213N2. Registered 17 June 2026. Retrospectively registered.
Vasculitic disorders can present with overlapping clinical and radiologic features, complicating diagnosis and management. Differentiating between Behçet disease-associated vasculitis and giant cell arteritis (GCA) is particularly challenging but essential for appropriate treatment. A 49-year-old woman with a history of recurrent venous and arterial thrombosis and suspected Behçet disease presented with severe temporal headache and acute focal neurological deficits. Neuroimaging revealed a chronic ischemic infarct with occlusion of the right internal carotid artery and collateral circulation, without evidence of active intracranial vasculitis. Laboratory studies demonstrated elevated inflammatory markers. Vascular imaging showed inflammatory changes involving the superficial temporal artery. Based on the presence of temporal headache, raised inflammatory markers, imaging evidence of superficial temporal artery inflammation, and exclusion of alternative causes, a diagnosis of giant cell arteritis was considered most likely in the setting of a complex vasculitic background. High-dose systemic corticosteroid therapy was initiated. The patient showed marked clinical improvement following treatment, with resolution of headache and stabilization of neurological deficits. She continues under multidisciplinary follow-up for monitoring of disease activity and thrombotic risk. This case highlights the diagnostic challenges of overlapping vasculitic syndromes and emphasizes the importance of integrating clinical findings, imaging results, and therapeutic response in guiding management of suspected giant cell arteritis.
BackgroundRimegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist approved for both acute and preventive treatment of episodic migraine. Real-world data on its preventive use remain limited, particularly in patients with multiple prior preventive failures. This study evaluated the effectiveness and tolerability of rimegepant in routine clinical practice, focusing on a highly treatment-resistant population.MethodsWe conducted a prospective, multicenter real-world cohort study within the GEMA (GEpants in MigrAine) Project across nine tertiary Headache Units in Spain. Adults initiating rimegepant for migraine prevention were consecutively enrolled and followed for up to 6 months. The primary endpoint was the 3-month change in monthly headache days (MHD). Secondary endpoints included the change in monthly migraine days (MMD), response rates, predictors of response, and tolerability. Baseline characteristics, prior preventive failures, medication overuse, adverse events, and patient-reported outcomes (Headache Impact Test-6 (HIT-6), HADS, and Insomnia Severity Index) were recorded.ResultsIn total, 150 patients completed 3-month follow-up and 64 reached 6 months. The cohort was predominantly female (85.3%), with 70.7% episodic migraine, a median age of 48 years (interquartile range (IQR) = 39-57), and a median of 6 prior preventive failures (IQR = 4-8), reflecting high treatment resistance. At 3 months, median MHD decreased from 12 to 7.5 and MMD from 10 to 6 (p < 0.05), with significant improvement in HIT-6. Overall, 36% and 43% achieved ≥ 50% reduction in MHD and MMD, respectively (≥ 75%: 15% and 20%). Among patients with 6-month data, further reductions were observed (MHD, 6 days; MMD, 5 days), with ≥ 50% response rates increasing to 48% and 58%. Clinical responders showed greater improvements in anxiety and depressive symptoms. Medication overuse, chronic migraine, and prior exposure to anti-CGRP monoclonal antibodies and onabotulinumtoxinA were independent predictors of poorer outcomes, with response declining with increasing prior anti-CGRP exposure, although a relevant proportion still achieved meaningful benefit. Rimegepant was well tolerated, with predominantly mild adverse events (nausea 13%, constipation 8%) and low discontinuation (7% at 3 months), and with nausea being the most frequent cause.ConclusionsRimegepant showed meaningful preventive effectiveness and good tolerability in routine clinical practice, including in highly treatment-resistant patients with prior anti-CGRP monoclonal antibody exposure. The response was influenced by baseline disease burden and prior treatment exposure. These findings suggest that earlier use of rimegepant in the treatment course may be associated with greater clinical benefit.
BackgroundEvidence supporting calcitonin gene-related peptide monoclonal antibody (CGRP mAb) use in adolescents with migraine is limited. Rapid recovery for daily school functioning is particularly important during this stage of life. We aimed to evaluate early functional outcomes in daily and school activities, as well as headache-related outcomes after initiating CGRP mAb therapy in Japanese adolescents with migraine.MethodsThis single-center retrospective cohort study included patients aged 15-17 years who received CGRP mAb therapy (galcanezumab, fremanezumab or erenumab) for migraine between May 2021 and July 2025. The primary outcome was time to clinically meaningful improvement on the Headache Impact Test-6 (HIT-6) scores, comprising a reduction of ≥ 6 points from baseline, and was analyzed using the Kaplan-Meier method. Secondary outcomes included tracking longitudinal HIT-6 trajectories with mixed-effects models for repeated measures, exploratory univariable comparisons for early response (≥ 6-point reduction within 10-14 weeks), questionnaire-based daily functioning assessments, and safety evaluations.ResultsOf 34 adolescents who initiated CGRP mAb therapy, 33 participated in HIT-6 analyses. The cumulative response rate began increasing immediately after treatment initiation, reaching 68.3% (95% confidence interval = 44.6-81.8%) within the 10-14-week period; approximately half of the responders achieved meaningful improvement by weeks 4-6. Mixed-effects models for repeated measures analyses adjusted for baseline HIT-6 scores showed a least-squares mean change of -9.4 points at 12 weeks (95% confidence interval = -14.2 to -4.6; p < 0.001), with benefits sustained over follow-up. Among questionnaire respondents (n = 27), school attendance or concentration in the classroom was the most affected activity before treatment (70.4%) and 88.9% indicated that their primary treatment goals were mostly or partially achieved. Adverse events were reported by 40.7% of participants, primarily injection-site reactions (29.6%), none of which led to therapy discontinuations or modifications.ConclusionsIn this real-world adolescent cohort, CGRP mAb therapy was associated with early and clinically meaningful improvements in headache-related impact and self-reported functioning. Safety and tolerability findings are particularly notable given the limited evidence in this age group. Further prospective controlled studies are warranted to validate these findings and to identify predictors of early functional response.
Traumatic brain injury (TBI) is a global health crisis affecting approximately 27 million individuals annually. Nearly half of TBI survivors develop chronic neuropathic pain, with post-traumatic headache representing the most prevalent pain syndrome. Despite substantial advances in understanding TBI pathophysiology, no unified mechanistic framework links acute neuroinflammation to the chronification of post-TBI pain, and no FDA-approved treatment currently targets TBI-specific neuropathic pain. This review synthesizes the cellular and molecular mechanisms underlying neuroinflammation and pain following TBI, with emphasis on the roles of microglia, astrocytes, regulatory T cells, and mast cells in sustaining central sensitization. Proinflammatory cytokines, most notably interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6), drive nociceptor sensitization through prostaglandin-dependent and receptor-mediated signaling cascades, with IL-1β having the strongest and most direct evidence for nociceptor sensitization. Dysregulation of calcitonin gene-related peptide (CGRP) and substance P exacerbates post-traumatic headache through trigeminovascular sensitization. The review further integrates evidence on epigenetic modifications, ferroptosis, complement system activation, and descending pain modulatory circuit disruption as contributors to pain chronicity. The three key conclusions of this review are: (1) neuroinflammation and central sensitization, driven by glial activation and cytokine signaling, are the primary sustaining forces of chronic post-TBI pain; (2) epigenetic reprogramming and dysregulation of descending pain modulatory pathways drive long-term pain persistence; and (3) therapeutics including CGRP antagonists, adenosine A3 receptor (A3AR) agonists, GABAergic modulators, and emerging natural compounds such as palmitoylethanolamide (PEA) and myrcene show mechanistic promise. Translating these findings into clinical practice requires addressing TBI heterogeneity, validating pain-specific biomarkers, and designing adequately powered trials for this population.
Reports of severe mixed connective tissue disease (MCTD) or macrophage activation syndrome (MAS)-associated cardiac involvement are limited. A 37-year-old woman with MCTD was transferred to a local hospital with fever and headache. She was diagnosed with meningitis and treated with glucocorticoid (GC) pulse therapy (methylprednisolone 1,000 mg/day for 3 days), followed by GC tapering. Despite a normal left ventricular ejection fraction on admission, her left ventricular ejection fraction abruptly declined to 7%, and she subsequently developed cardiogenic shock. She then experienced sudden cardiac arrest, which required initiation of veno-arterial extracorporeal membrane oxygenation and insertion of an Impella CP. Intravenous cyclophosphamide (1,000 mg) was administered for suspected myocarditis, although endomyocardial biopsy showed no specific positive staining. Cardiac function did not improve after immunosuppressive therapy. Therefore, plasma exchange was performed five times considering for MAS, which resulted in recovery of the left ventricular ejection fraction to 71%. Veno-arterial extracorporeal membrane oxygenation was successfully ceased, followed by veno-venous extracorporeal membrane oxygenation and mechanical ventilation to facilitate respiratory recovery for 39 days. The etiology of the myocardial dysfunction remains unclear; however, both cytokine-mediated myocardial dysfunction associated with MAS and immune-mediated microvascular injury could not be excluded. We successfully managed with combined immunosuppressive therapy, including GC, intravenous cyclophosphamide, and plasma exchange, under mechanical circulatory support.
Broadly neutralizing antibodies (bnAbs) are a promising tool for HIV prevention and treatment. Here we conducted a first-in-human, phase 1 trial of the bispecific 10E8.4/iMab antibody, which consists of a 10E8.4 arm binding the HIV-1 envelope glycoprotein membrane-proximal external region and an ibalizumab (iMab) arm binding the human CD4 molecule. 10E8.4/iMab was administered intravenously (IV) or subcutaneously (SC). Safety/tolerability within 2 weeks of 10E8.4/iMab administration (primary outcome) and the pharmacokinetics (PK), antiviral activity, induction of anti-10E8.4/iMab antibodies, longitudinal CD4+ and CD8+ T cell counts and long-term safety (secondary outcomes) were evaluated. 54 participants living with HIV (PLWH) or without HIV (PLWoH) received 10E8.4/iMab or placebo. In arm 1, PLWoH received 10E8.4/iMab 0.3 mg kg-1 IV, 1 mg kg-1 SC, or 1 mg kg-1 IV (n = 3 each). In arm 2, PLWoH received 10E8.4/iMab 3 mg kg-1 IV, 10 mg kg-1 IV or 30 mg kg-1 IV (n = 6 each). In arms 3/3a, PLWH received 10E8.4/iMab 10 mg kg-1 IV (n = 3) or 30 mg kg-1 IV (n = 6). In arm 4, PLWoH were randomized to receive 10E8.4/iMab or placebo 2.5 mg kg-1 SC or 10 mg kg-1 SC (n = 9 each). Participants in arms 1-3 were not randomized. No treatment-related serious adverse events (AEs) or AEs ≥ grade 3 were reported. The most common solicited AEs were tenderness (10/54, 18.5%), fatigue (18/54, 33.3%) and headache (12/54, 22.2%). Related grade 2 local and systemic solicited AEs occurred in one and six participants, respectively. Three of nine PLWH developed a generalized rash 8-12 days after infusion that resolved within 9-16 days. The primary objective of the study to evaluate the safety/tolerability of 10E8.4/iMab was met. These data support further study of 10E8.4/iMab to expand HIV treatment and prevention options. ClinicalTrials.gov: NCT03875209 .
Nose- and sinus-related neuralgia syndromes (NSNS) constitute a constellation of clinical entities characterized by persistent pain in the distribution of nerves from the nasal cavity and paranasal sinuses. Various characterizations and management approaches have been reported in the literature, yet no universally accepted definition exists. The aim of this study is to provide a narrative synthesis of relevant studies and to propose a structured algorithm for the diagnosis and management of this intriguing clinical entity. A narrative review informed by a structured database search was conducted using Medline (via PubMed), Scopus and manual searching, with no restrictions on publication date. Since Sluder's first description in 1908, a number of related syndromes have been reported in the literature, each with partially overlapping clinical features and diagnostic criteria, including anterior ethmoidal nerve syndrome, anterior ethmoidal neuralgia, sphenopalatine neuralgia, syndrome of the olfactory fissure, nasociliary neuralgia (Charlin's syndrome), collectively reflecting the complex and ambiguous nature of these disorders. While the anterior ethmoidal nerve is central to the syndrome, other nerves innervating the lateral nasal wall and nasal pyramid skin are also implicated in the associated headache. Complex pathophysiological mechanisms contribute to the chronic pain. Clinically, the syndrome is characterized by the absence of a specific sinonasal disease; pain may vary in localization, be uni- or bilateral, and can be associated with mucosal engorgement, intranasal contact points, or a history of facial trauma. A thorough history, clinical examination, nasal endoscopy, imaging of the nasal cavity and paranasal sinuses, recognition of the frequent association with endonasal contact points and the topical anesthetic test remain fundamental to the diagnosis of NSNS. Management options include conservative and surgical approaches. The existing literature on NSNS consists exclusively of small, uncontrolled case series and expert opinion spanning over a century, with no randomized controlled trials or prospective comparative studies, reflecting a persistent evidence gap that limits definitive conclusions about diagnosis and treatment. In this review, a practice-oriented diagnostic and management algorithm is proposed. Prospective controlled studies are needed to validate and refine these recommendations.
Both recovery and strain are highly relevant to worker productivity and cognitive performance. Prior research suggests that survey response times (RTs) may serve as an approximation of everyday processing speed. We examined associations between strain-related experiences and recovery behaviors over a week, a time frame seldom considered prior, and subsequent survey RT-based processing speed. We analyzed approximately 1 year of data from 5,303 workers in a U.S.-based Internet panel study. Participants completed a survey on a biweekly to monthly basis regarding their experiences during the COVID-19 pandemic (April 2020-July 2021). Within individuals, longer survey RTs (indicating slower processing speed) were associated with working 50 or more hours (B = 0.016 log seconds, 95% confidence interval [0.004, 0.025]), having work hours reduced (i.e., job insecurity, B = 0.031, 95% CI [0.016, 0.044]), a positive COVID test (B = 0.041, 95% CI [0.03, 0.055]), fever (B = 0.012, 95% CI [0.003, 0.024]), feelings of fatigue (B = 0.019, 95% CI [0.012, 0.025]), headache (B = 0.018, 95% CI [0.011, 0.027]), body aches (B = 0.017, 95% CI [0.009, 0.025]), higher stress levels (B = 0.006, 95% CI [0.001, 0.01]), and increased depressive symptoms (B = 0.009, 95% CI [0.006, 0.011]) in the week prior. Unexpectedly, for individuals who typically infrequently engaged in general relaxation or socializing, engaging in these activities more often in the prior week was associated with reduced processing speed (B = 0.005, 95% CI [0.002, 0.008] and B = 0.006, 95% CI [0.002, 0.01], respectively). Everyday processing speed, as measured by survey RT, was sensitive to strain and recovery engagement experienced over the week prior. (PsycInfo Database Record (c) 2026 APA, all rights reserved).
Perioperative anaphylactic reactions, especially those induced by colloid solutions like gelatins, can lead to severe hypotension and tissue hypoperfusion, with potential serious complications. We present a rare case of acute cerebral infarction following severe anaphylaxis during sinus lesion resection under general anesthesia. A 16-year-old patient received succinylated gelatin for hypovolemia. Within 7 min, the patient developed profound hypotension (45/25 mmHg), tachycardia (139 bpm), and severe desaturation (63%), necessitating treatment with epinephrine and 35 min of continuous resuscitation Postoperatively, the patient developed headache and memory deficits, prompting an MRI that revealed an acute infarction. Follow-up MRI on postoperative day 27 showed significant lesion resolution accompanied by improvement in neurological symptoms. This case highlights cerebral ischemia as a potential sequela of anaphylaxis-induced hypotension, emphasizing prompt hemodynamic stabilization and neurologic vigilance in perioperative hypersensitivity reactions.