Citations

Abstract Background Wide-spread mast cell (MC)-associated symptoms and MC activation syndrome (MCAS) are often reported in patients with hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). The goal of this study was to develop a novel MC score based on 11 self-reported MC-related conditions with clinical and research utility to better understand MC symptoms in hEDS and HSD patients. Methods From November 1, 2019, to June 13, 2025, patients ( n =2,141) filled out an Intake Questionnaire at the Mayo Clinic Florida EDS Clinic that included 11 self-reported questions related to categories of MC-related conditions for a MC score ranging from 0/11 to 11/11. Based on the MC score distribution in hEDS and HSD patients, a MC score of 0-1 was considered a low MC score and ≥5 was considered a high MC score. Symptoms/comorbidities were compared between patients with high vs. low MC scores. Results From the 2,141 hEDS/HSD patients, 535 (25.0%) had a MC score ≥5 (Hi MC). MCAS-specific symptoms such as nausea and vomiting were reported more often in hEDS/HSD patients with a high vs. low MC score ( p <0.0001). Random clinical blood tryptase and urinary MC markers were not elevated in patients with high MC scores ( n =50/group), although high MC scores were found to significantly reduce urinary creatinine levels indicating that the protein used to normalize data was affected by MC activity. In contrast, random blood IgE, tryptase and major basic protein (MBP) by ELISA were increased in patients with high MC scores (e.g., IgE hEDS p =0.0004, HSD p =0.003). Of note, the percentage of patients reporting abuse or post-traumatic stress disorder was nearly doubled in patients with high vs. low MC scores (Abuse and PTSD: hEDS p < 0.0001; HSD p < 0.0001). Overall, 109/135 (80.7%) in hEDS and 129/135 (95.6%) in HSD reported more symptoms/comorbidities if they had a high MC score. Conclusions We found that hEDS/HSD patients with high MC scores self-reported more widespread symptoms/comorbidities and higher MC-related blood markers than patients with low MC scores indicating the utility of this tool to evaluate the level of widespread MC activity in hEDS, HSD and other patients.

Background Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSDs) are heritable connective tissue disorders characterized by widespread fragile soft connective tissue affecting the skin, ligaments, joints, vasculature, and internal organs. Although hEDS and HSD are autosomal-dominant conditions and would be expected to display a 1:1 sex ratio, studies report higher prevalence in women. Objectives The purpose of this exploratory study was to determine whether self-reported sexual problems differed between females and males diagnosed with hEDS or HSD compared with controls with chronic pain but no hypermobility. Methods In this exploratory retrospective study, we examined 1,407 patients diagnosed with hEDS or HSD according to the 2017 diagnostic criteria for eight indicators of sexual problems based on a validated screening tool. Results Patients in each diagnosis primarily self-reported as White, non-Hispanic females (90%). Of the 1,407 patients who attended the EDS Clinic, 976 (69%) were diagnosed with HSD, 240 (17%) with hEDS, and 191 (14%) were chronic pain controls with neither diagnosis. For HSD, 937 (96%) were females vs. 39 (4%) males (24:1 females to males), while for hEDS, 210 (88%) were females vs. 30 (13%) males (7:1 females to males), and controls were 165 (86%) females vs. 26 (14%) males (6:1 females to males). Females with hEDS reported significantly higher rates of sexual issues than chronic pain controls, including sexual problems (69%, p = 0.018), problems with sexual interest (41%, p = 0.023), sexual pain (45%, p = 0.006), and orgasm difficulty (34%, p = 0.022) compared with males with hEDS or males or females with HSD. In contrast, males diagnosed with hEDS did not report any sexual problems over controls, and males and females diagnosed with HSD reported only one issue—more problems with sexual interest—compared with controls (females p = 0.019, males p = 0.018). However, the small number of males in this study limits conclusions that can be drawn for them. Conclusions This study is unique because we examine sex differences in sexual problems in patients with hEDS and HSD. Our findings indicate a higher percentage of sexual problems in females with hEDS than chronic pain controls without hypermobility, but this was not observed for females with HSD.

Background High-quality research studies on therapeutic approaches for migraine management in pediatrics are scarce. Therefore, we conducted a systematic review of current clinical practice guidelines for the diagnosis and management of migraine in children and adolescents to identify areas of consensus and disagreement, as well as critical gaps, paving the way for future updates and improvements. Methods We searched PubMed, WOS, and SCOPUS for guidelines published in the English language in the last 10 years focused on the diagnosis and management of migraine in children and adolescents. Results Following a systematic search, eight eligible guidelines were identified. These guidelines were authored by the American Academy of Neurology (AAN), the European Headache Federation/European Academy of Neurology (EHF/EAN), the International Headache Society (IHS), National Institute for Health and Care Excellence (NICE), the Danish Headache Society, and the German Migraine and Headache Society and the German Society of Neurology. There was a broad consensus on considering the International Classification of Headache Disorders-3rd edition as the diagnostic reference. As regards management, paracetamol and ibuprofen were considered first line in the acute management of migraine, with sumatriptan and zolmitriptan nasal sprays rated as second line. Injectable medications for acute management were overlooked in most guidelines. On the other hand, targeted age groups, dosing, and preventive treatment choices showed areas of variability. Various non-pharmacological measures gained attention in all guidelines. Notably, CGRP antagonists and non-invasive neuromodulation techniques were identified as major gaps. Conclusion The current systematic review highlights areas of agreement and disagreement between existing guidelines on the management of childhood and adolescent migraine and emphasizes the current gaps and opportunities, thus offering a solid foundation for future studies and guidelines.

Background/Objective: It remains unknown whether patients with the more common forms of hypermobility carry an elevated risk for the development of intracranial/cervical artery abnormalities. The objective of this study was to determine the prevalence of unruptured intracranial aneurysms, spontaneous cervical artery dissections, and fibromuscular dysplasia in patients with hypermobile Ehlers–Danlos Syndrome (hEDS) and hypermobility spectrum disorders (HSD) who presented to an academic headache clinic. Methods: This is a retrospective cohort study. We used an electronic medical record to look for all patients seen at the Mayo Clinic Florida Headache Center and EDS Clinic between 2019 and 2025 with a diagnosis of hEDS or HSD and neuroimaging of both the intracranial and cervical arteries. Results: There were 103 patients who met the inclusion criteria. There was no statistically significant difference between hEDS and HSD patients in developing cerebral/cervical arterial anomalies. Of the sample, 95% of the hypermobile patients with abnormal neuroimaging also had migraine. A total of eleven (10.7%) patients (hEDS + HSD) were diagnosed with unruptured intracranial aneurysms. Trends included age less than 50 years, small aneurysms in the anterior circulation, and having migraine with aura. Five (4.8%) patients were diagnosed with spontaneous cervical artery dissection with trends for HSD, over the age of 50 years, vertebral artery involvement and a history of migraine without aura. Six (5.8%) patients were diagnosed with fibromuscular dysplasia with trends for HSD, over the age of 50 years, carotid artery involvement and a history of migraine with aura. Conclusions: This is the first study to identify that patients with the more common type of EDS, HSD and hEDS, and a possible concomitant history of migraine have a heightened risk for the development of unruptured intracranial aneurysms, spontaneous cervical artery dissections, and fibromuscular dysplasia. Our findings suggest the need for targeted screening with intracranial and extracranial arterial imaging for this unique patient population.

ABSTRACT Chimeric antigen receptor T-cell (CART) and T-cell engager (TCE) therapies targeting B-cell maturation antigen (BCMA) are transforming the treatment landscape for relapsed multiple myeloma (MM). However, despite impressive initial response rates, most patients eventually relapse. To investigate this unmet medical need, we applied whole-genome sequencing (WGS) to MM cells from cohorts of 102 relapsed patients treated with anti-BCMA CART and TCE therapies. Several genomic alterations were associated with clinical outcomes, particularly primary refractoriness, including high genomic complexity and mutations in genes regulating plasma cell identity, which predicted resistance to therapy. Single-cell RNA sequencing further revealed that MM cells from refractory patients exhibited high proliferation signatures and reduced expression of TNFRSF17 (encoding BCMA), while were less enriched for plasma cell–associated transcriptional programs, a phenomenon we term “plasma cell identity escape.” This profile was strongly associated with immune dysregulation of CD8 T cells including increased activation and exhaustion. This evolution of MM toward a more proliferative and lineage-divergent state, refractory to the anti-BCMA T-cell redirecting therapies, was functionally validated in preclinical MM mouse models. Collectively, our results comprehensively define the cellular and molecular mechanisms underlying primary resistance to anti-BCMA therapies.

Objectives Heritable connective tissue disorders (HCTDs), including hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobile spectrum disorder (HSD), have complex clinical manifestations, but the prevalence of left common iliac vein (LCIV) compression in these groups is not well known. This study aimed to compare the prevalence of significant LCIV compression in patients with hEDS, HSD, and healthy controls. Methods This retrospective, IRB-approved, single-center study analyzed 109 patients (25 hEDS, 64 HSD, 20 controls) who underwent contrast-enhanced abdominal and pelvic CT imaging from 2020 to 2023. LCIV compression was measured on axial CT, with >50% luminal narrowing defined as significant. Statistical analyses included chi-square tests, odds ratios, and t -tests. Interrater reliability was evaluated using intraclass correlation coefficients. Results Significant LCIV compression occurred in 68.0% of hEDS, 65.6% of HSD, and 35.0% of controls ( p = 0.034). Both hEDS ( p = 0.027) and HSD ( p = 0.015) groups had significantly higher compression rates than controls, with no statistically significant difference between the two clinical groups ( p = 0.831). Odds of compression were nearly fourfold greater in hEDS (OR 3.95) and HSD (OR 3.54) compared to controls. Conclusion LCIV compression is significantly more prevalent in patients with hEDS and HSD than in healthy controls, warranting further investigation of its clinical significance.

Migraine is one of the most disabling diseases worldwide, especially when it transforms into chronic migraine, which is often associated with medication overuse and can become resistant or even refractory to treatments. Molecular, neuroimaging and neurophysiological changes have been described in chronic migraine, some of which might not be fully reversible with preventive treatment. For these reasons, we should aim to prevent this transition, and initiate preventive treatment before disease becomes refractory and burden increases. Preventive migraine treatments are often delayed because of access to care, stigma leading to undertreatment and patients’ reluctance as a result of fear of side effects and, in some cases, fear of being labeled as chronically ill. With the availability of effective and well-tolerated preventive treatments, we must shift our mindset and take advantage of new opportunities to initiate preventive treatment earlier. In this International Headache Society position statement, we propose a migraine preventive strategy under the idea of shifting from reactive treatment once disability is established (prevention of attacks), to proactive, individualized prevention initiated early with safe, effective and tolerable therapies (prevention of disease progression). This approach is based on 1) promoting the early initiation of effective and tolerable preventive therapies, starting from two to four monthly migraine days in line with the majority of current guidelines and recommendations and 2) fostering longitudinal studies to gather more evidence on the potential benefit of early prevention, with the final goal of improving patient outcomes, promoting excellent migraine care, enhancing individual and social well-being, and, ultimately, preventing migraine progression and preserving brain health.

Background: Variable terminology is used in the literature to describe facial synkinesis and hypertonicity following incomplete recovery from facial paralysis and its associated medical and surgical treatments. Study Objectives: Establish a nomenclature consensus for this condition among a group of facial nerve experts. Design Type: Consensus study. Methods: Using modified Delphi methodology, an international, multidisciplinary group of facial nerve experts reviewed the terminology for the name of the clinical condition and treatments of interest. Online surveys and a virtual discussion were performed to establish consensus, defined a priori as agreement by 80% of the group. Results: Twenty-five facial nerve experts established consensus after three Delphi rounds. Consensus terminology for the condition is “facial synkinesis” with 84% agreement. Medical treatment is termed “chemodenervation” with 100% agreement. Surgical treatments including “selective facial neurectomy,” “selective facial neurotomy,” “selective facial myectomy,” and “selective facial myotomy,” were defined and reached agreement of 100%. Conclusions: This international group of facial nerve experts has recommended standardized nomenclature for the condition of facial synkinesis and its various treatments. While “facial synkinesis” reached consensus as the preferred term, some experts noted it may insufficiently describe the full clinical spectrum, which includes muscle hypertonicity, weakness, and spontaneous twitching.

Abstract May-Thurner physiology (MTP) can lead to various congestion syndromes due to compression of the left common iliac vein (LCIV) by the right common iliac artery (RCIA). This compression may result in venous reflux through the lumbar vein, leading to congestion of the spinal epidural venous plexus (EVP), which could contribute to refractory headaches. This case report details the clinical course of a patient with severe refractory new daily persistent headache associated with MTP who underwent ascending lumbar vein (ALV) embolization. The patient is a 59-year-old female with a 3-year history of daily persistent headache which failed multiple migraine prevention therapies and minimally invasive procedures. Imaging studies revealed significant LCIV compression by the RCIA, retrograde ALV flow, and EVP congestion. The patient underwent ALV embolization, resulting in significant symptomatic relief. At the 22-month follow-up, headache severity reduced by 80%, with the patient no longer requiring routine headache medications. Additionally, treatment of associated pelvic congestion syndrome through gonadal vein embolization resolved longstanding associated pelvic pain and pressure. This case highlights the role of venous congestion in refractory headache syndromes and underscores the potential of targeted venous interventions, such as embolization, in their management. The findings expand on emerging evidence linking venous compression syndromes to headache pathophysiology and support exploring interventional strategies as viable treatment options for selected patients. Further research is needed to validate these findings and establish evidence-based guidelines for clinical practice.

Objective: We aimed to estimate the prevalence of cardiovascular diseases (CVDs) and cardiometabolic diseases (CMB) in Brazil, and their relationship with a healthy lifestyle score based on the six pillars of lifestyle medicine proposed by the American College of Lifestyle Medicine. Methods: Data were derived from the 2019 Brazilian National Health Survey, a nationwide cross-sectional study. The prevalence of CVDs/CMB was based on medical-endorsed, self-reported diagnoses and weighted for sample strata. A healthy lifestyle score (0-14 points; the higher the score, the better) incorporates physical activity, diet, sleep, mental health, risky substance use, and social connections. Results: Among 88,531 adults included in the analysis (mean age: 47.1 years; 52.9% female), the weighted prevalence of CVDs/CMB ranged from 1.9% (stroke) to 25.9% (hypertension). Weighted Poisson regression models, adjusted for age, sex, socioeconomic status, and geographic disparities, showed an inverse linear relationship between lifestyle score and CVDs/CMB prevalence. Participants in the highest lifestyle score quartile exhibited lower prevalence for heart diseases [0.48 (95% CI: 0.43, 0.53)], stroke [0.35 (95% CI: 0.29, 0.43)], hypertension [0.85 (95% CI: 0.80, 0.90)], diabetes [0.80 (95% CI: 0.70, 0.91)], dyslipidemia [0.73 (95% CI: 0.66, 0.80)], and obesity [0.81 (95% CI: 0.74, 0.88)], compared to the lowest quartile ( P < 0.001 for all). Conclusions: Higher scores on the six pillars of lifestyle medicine are associated with a lower prevalence of major CVDs/CMB in Brazil.