The aim of this review was to evaluate the evidence for midodrine as a treatment for patients with postural orthostatic tachycardia syndrome (POTS). We conducted a systematic review of the literature to identify studies which evaluate midodrine treatment in patients with POTS. Random-effects meta-analysis was used to determine the effect of midodrine on symptoms compared with placebo and beta-blockers. A total of 14 studies with 968 patients were included which took place between 2000 and 2017. The proportion of patients who clinically benefited from POTS from 10 studies ranged from 46.2% to 91.3%. Meta-analysis of midodrine versus control for studies of children showed that midodrine had significantly increased odds of symptom response (RR, 1.52; 95% confidence interval, 1.09-2.13, P = 0.01, I 2 = 78%, 4 studies). The pooled result comparing midodrine with beta-blockers in pediatric populations showed that there was a 1.16-fold increase in odds for symptom response compared with beta-blockers (RR, 1.16; 95% confidence interval, 1.02-1.32, P = 0.02, I 2 = 0%, 4 studies). Hypertension was reported in 3 studies to occur in 8.2% of patients (7/85). Gastrointestinal disturbance was reported in 4 studies and it occurred in 3.4% of patients (6/175). The evidence for midodrine efficacy in patients with POTS is limited, particularly in adults. Additional studies are needed to better understand which patients may benefit the most. Midodrine may be considered as a second-line or third-line therapy in patients who remain symptomatic particularly if an enhancement of vascular tone or preload is desired. The use of midodrine in older patients with hypertension should be discouraged.

Median arcuate ligament syndrome (MALS) is a rare condition caused by compression of the celiac artery by the median arcuate ligament. The surgical treatment for MALS is a median arcuate ligament release (MALR). While outcomes of MALR are well described in adults, pediatric data remain limited. Leveraging our extensive institutional experience, we sought to address this gap by reporting the largest single-institution cohort of pediatric patients undergoing MALR at a standalone children's hospital. We performed a single-institution retrospective review of all patients who underwent laparoscopic MALR between January 2013 and December 2024 at a standalone children's hospital. We performed descriptive statistics and univariate analyses, with the primary outcome measure of freedom from treatment failure after MALR, defined as any symptom improvement after MALR without symptom recurrence. Median arcuate ligament release was performed in 286 patients. Median age at surgery was 17.1 years. All cases were performed laparoscopically with one conversion to an open operation (0.3%). Mean postoperative length of stay was 1.5 days. Freedom from treatment failure was achieved in 61.2% of patients. Complications occurred in 2.4% of patients. Our single-institution retrospective review describes the largest series of MALR at a freestanding children's hospital. We demonstrate a 61.2% freedom from treatment failure rate with minimal complications, supporting MALR as a safe therapeutic option for pediatric MALS. However, the substantial rate of postoperative symptom persistence or recurrence highlights the need for careful patient selection and thorough preoperative counseling regarding expected outcomes.

The authors compared palpitations, presyncope, syncope, and postural orthostatic tachycardia syndrome (POTS) prevalence among patients with hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD). A retrospective analysis of patients referred for cardiac evaluation at the New York Institute of Technology Ehlers-Danlos Syndrome/Hypermobility Treatment Center between January 2019 and November 2023 was conducted. hEDS and HSD patients underwent cardiac evaluation and were stratified by median age into younger (<35 years) and older (≥35 years) groups. Symptom prevalence was compared between hypermobile patients overall and by age cohort. Data were presented as mean ± SD; P < .05 was considered statistically significant. One hundred-nine patients (75 hEDS, 34 HSD) underwent cardiac evaluation: 75 hEDS (71 females/4 males; age 33.9 + 11.6 years) and 34 HSD (29 females/ 5 males; age 40.0 + 13.8 years). POTS (48% vs 23.5%, P = .016) was significantly more prevalent in the hEDS group; palpitations, presyncope, and syncope were common in both groups. No significant differences were observed in Cohort 1 (age less than 35 years). In Cohort 2 (age ≥35 years), presyncope (100% vs 82.6%, P = .04) differed; palpitations, syncope, and POTS were similar. POTS was prevalent in patients younger than 35 years with hEDS (58.3% vs 29.6%, P = .022) and HSD (45.5% vs 13.0%, P = .042). Patients with h EDS exhibited greater symptoms than HSD patients, and symptoms were particularly more pronounced with age. POTS prevalence decreased with age in both groups. Larger prospective studies are needed to explore underlying mechanisms.

Autonomic dysfunction, characterized by orthostatic intolerance and presyncope, is understudied in youth. Mental health comorbidities are commonly reported and sometimes blamed for the onset of autonomic dysfunction; however, no studies have yet examined this relationship. This study aimed to establish the prevalence rate of mental health diagnoses in a pediatric sample of patients with autonomic dysfunction, characterize the temporal relationship between autonomic and mental health symptom onset, and understand patients' perspectives on this relationship. Pediatric patients completed surveys at autonomic dysfunction clinic follow-up appointments. Surveys obtained patient self-reported metal health conditions, autonomic symptoms, and patient-perceived timelines. Patients then described their understanding of the relationship between their mental and physical health. Authors analyzed qualitative data using content analysis. Of 142 patients approached, 127 completed surveys (response rate 88.8%; Mean age = 16.1); 70.1% reported a mental health diagnosis, and 4.7% suspected a mental health condition. Anxiety was the most reported concern (72.4%). Patients reported mental health concerns preceding (37.6%), co-occurring (12.2%), or succeeding (38.1%) their autonomic dysfunction symptoms. Qualitative responses revealed patients perceived bidirectional or unidirectional relationships between mental health and autonomic dysfunction, although some patients were uncertain. Patients described varied relationships between mental health symptoms and autonomic dysfunction, emphasizing the individualized nature of these experiences. Although the rate of mental health diagnoses was pointedly high, temporal associations appeared patient-specific rather than consistent across the sample. Providers should consider routine screening and treatment of mental health concerns as part of comprehensive care for youth with autonomic dysfunction.

Autonomic dysfunction, or dysautonomia, is increasingly being recognized as a complication of concussion. While the symptoms can overlap with other postconcussion sequelae, it is important to distinguish the patient suffering from postconcussion dysautonomia in order to provide proper symptomatic management and aid in recovery. This narrative review will summarize the available, high-quality literature regarding autonomic testing abnormalities in patients with a history of concussion, interpret these findings in the context of the sympathetic and parasympathetic divisions of the autonomic nervous system, and discuss an approach to managing postconcussion dysautonomia.

Postural orthostatic tachycardia syndrome (POTS) is a debilitating autonomic disorder characterized by excessive orthostatic tachycardia and significant functional impairment. Conventional therapies, including beta-blockers, often provide incomplete relief or are poorly tolerated. Ivabradine, a selective If channel inhibitor, reduces heart rate without affecting blood pressure or myocardial contractility, making it a promising option, particularly in post-COVID-19 POTS. This systematic review and meta-analysis evaluated the efficacy and safety of ivabradine in patients with POTS. PubMed, Embase, and the Cochrane Library were searched through August 2025 in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO CRD420251073600). Eligible studies included randomized controlled trials, observational studies, and case series reporting ivabradine outcomes in POTS. Primary outcomes were changes in standing and supine heart rate; secondary outcomes included symptom burden, quality of life, and adverse events. A random-effects model was used, heterogeneity was assessed through sensitivity analyses, and certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development, and Evaluation. Nine studies involving 245 patients were included. Ivabradine significantly reduced standing heart rate (-18.5 bpm; 95% confidence interval -23.3 to -13.8) and supine heart rate (-9.7 bpm; 95% confidence interval -13.4 to -6.1). Symptom improvement particularly palpitations, lightheadedness, and exercise intolerance was consistently reported across classic, pediatric, hyperadrenergic, and post-COVID-19 subgroups. Adverse events were infrequent and mild, most commonly transient visual disturbances, with no reports of severe bradycardia or hypotension. Heterogeneity was high, largely driven by pediatric and post-COVID-19 cohorts. In conclusion, ivabradine seems to provide meaningful heart rate reduction and symptomatic improvement in POTS with a favorable safety profile. However, evidence is limited by small, heterogeneous, predominantly observational studies, underscoring the need for large, multicenter randomized controlled trials.

Pelvic venous disorders (PeVD) are recognised causes of chronic pelvic pain; emerging evidence suggests that venous outflow obstruction or reflux can also provoke orthostatic intolerance (OI) by infra-diaphragmatic pooling and reduced preload. Diagnostic and therapeutic frameworks for this overlap remain poorly defined. We systematically searched PubMed, Ovid MEDLINE, Scopus, and Cochrane to 20 May 2025. Two reviewers extracted data; risk of bias used design-specific validated tools. Sixteen studies met criteria (4 case reports, 7 case series, 2 single-arm cohorts, 2 case-control, 1 cross-sectional), comprising 964 participants (93% female; age 7-67 years). Case-control data suggested left common iliac or left renal-vein compression is more prevalent in patients with postural tachycardia syndrome than in controls. Paediatric series linked left renal-vein entrapment with orthostatic symptoms and proteinuria. Imaging confirmation used duplex ultrasound, CT, CT-venography, intravascular ultrasound, and dynamic MRA with 4D-flow. Eleven studies reported interventions (iliac stenting, ovarian/internal-iliac embolization, superficial venous ablation, renal-vein transposition or robotic auto-transplantation). Orthostatic symptoms generally improved; cohorts using the Orthostatic Hypotension Questionnaire showed ∼50% mean reduction, and several stented patients no longer met POTS criteria. Follow-up was typically ≤12 months. Overall risk of bias was high for single-arm cohorts and moderate for case-control studies. Available evidence supports a biologically plausible link between pelvic venous obstruction and OI suggests PeVD-directed procedures can ameliorate OI in selected patients. Prospective, multicentre studies with standardized imaging thresholds, objective autonomic endpoints, and longer follow-up are needed to define patient selection and comparative effectiveness.

Tachycardia upon standing implicates cardiovascular dysreflexia, potentially resulting from impaired autonomic regulation. However, the pathophysiology of POTS remains unclear. Here, we evaluated the central nervous system in postural orthostatic syndrome (POTS). The purpose of this study was to evaluate brain tissue changes, functional networks (the central autonomic network), and cerebral hemodynamic status in patients with POTS using magnetic resonance imaging (MRI) and autonomic reflex challenges. Individuals with POTS and age- and sex-matched healthy controls were enrolled. Brain MRI data were collected with a 3.0-T scanner at rest and during functional MRI using 3 autonomic reflex challenges: passive leg raise, mental arithmetic, and isometric handgrip reflex. 38 participants were enrolled (18 patients with POTS and 20 controls). No significant differences emerged in age, sex, or body mass index between patients with POTS and controls (P > .05). Patients with POTS had higher anxiety and depression symptoms. Although global screening indicators of cognitive function were preserved (Montreal Cognitive Assessment test: POTS vs controls, 28 ± 1 vs 29 ± 1; P = .2), executive function was slowed in POTS (Trail Making Test Part B: POTS vs controls, 44 ± 12 vs 67 ± 34; P = .008). Brain tissue structural changes (P < .005) and reduced cerebral blood flow appeared in patients with POTS compared with controls (P < .005). Furthermore, impaired neural responses were seen in patients with POTS during passive leg raise, mental arithmetic, and isometric handgrip reflex challenges (P < .005), despite preserved peripheral reflex function (P > .05). Patients with POTS show evidence of brain tissue structural changes, impaired central neural responses, and reduced cerebral blood flow in autonomic regulatory sites during cardiovascular reflex testing. These findings indicate that central autonomic control deficits may help explain cardiovascular dysreflexia in POTS.

There is limited evidence supporting the use of lomerizine, a calcium channel blocker approved for migraine prophylaxis in Japan, in children. This study evaluated the prophylactic efficacy of lomerizine in a pediatric population with migraine and identified the baseline factors independently associated with treatment response. This single-center, retrospective cohort study enrolled 83 patients aged ≤18 years prescribed lomerizine for migraine prophylaxis. The primary outcome was headache improvement, defined as a ≥50% reduction in monthly headache days from baseline, assessed at 3-4 and 6-8 months. Multivariable logistic regression included prespecified comorbidity-based covariates: psychosocial factors, neurodevelopmental disorder, and postural orthostatic tachycardia syndrome. Headache improvement was observed in 34 of 80 (42.5%) patients at 3-4 months, and in 36 of 71 (50.7%) patients at 6-8 months. Response rates at 3-4 months and 6-8 months, respectively, were 57.7% and 67.4% among patients without psychosocial factors and 14.3% and 20.0% among those with psychosocial factors. Psychosocial factors were the only variables independently associated with a lower probability of improvement at both time points (3-4 months: adjusted odds ratio, 0.122; 95% confidence interval, 0.036-0.419; < 0.001; 6-8 months: adjusted odds ratio, 0.137; 95% confidence interval, 0.041-0.456; = 0.001). Patients receiving lomerizine experienced clinically meaningful improvement in headache frequency, particularly those without psychosocial comorbidity. Psychosocial comorbidity was the only baseline factor independently associated with a poor treatment response, underscoring the potential importance of routine psychosocial screening and a possible benefit from concurrent psychological interventions; these findings require prospective confirmation.

Multidisciplinary team (MDT) care models are endorsed in the management of multiple chronic health conditions, by international bodies including the World Health Organization. Their growing use reflects recognition of their potential to improve management of complex conditions. MDT care has demonstrated patient acceptability and improved clinical outcomes in chronic conditions such as diabetes, heart failure, and atrial fibrillation. In contrast, MDT care for POTS has a weak recommendation, due to limited, low-quality evidence. Importantly, key concepts such as patient acceptability and management preferences remain unexplored. Patient satisfaction surveys can elicit patient preferences, identify service gaps, and evaluate impact following healthcare delivery. Therefore, we evaluated patient feedback to understand patient perspectives on MDT care after POTS diagnosis.

Pediatric daily headaches are refractory and disabling. However, the influence of the interval between daily headache onset and initial specialist consultation on clinical outcomes remains unknown. This retrospective observational study included 51 children and adolescents presenting with daily headaches. Consultation lag was defined as the interval between the date when the headache first became daily and the initial consultation. The primary outcome was headache improvement (≥50% reduction in monthly headache days) at 3-4 months, and the secondary outcome was improvement at 6-7 months. Multivariate logistic regression and receiver operating characteristic curve analyses were performed. Improvements were observed in 41.2% of patients at 3-4 months and 60.0% at 6-7 months. Each additional week of consultation lag was associated with a 12% decrease in the odds of a 3-4-month improvement (adjusted odds ratio, 0.875; 95% confidence interval [CI], 0.783-0.979; = 0.020). Receiver operating characteristic curve analysis identified an exploratory 5-week threshold (area under the curve, 0.837; 95% CI, 0.711-0.963), with markedly lower odds of early improvement when exceeding this threshold in this cohort (adjusted odds ratio, 0.040; 95% CI, 0.007-0.238; < 0.001). Comorbid postural orthostatic tachycardia syndrome was associated with the absence of 3-4-month improvement ( = 0.003), whereas other comorbidities were not. A shorter consultation lag was independently associated with early improvement in pediatric daily headaches regardless of comorbidities. Patients presenting within this exploratory 5-week window were substantially more likely to improve early in this cohort; however, this threshold requires prospective external validation before it can inform clinical decision-making. These findings support consideration of prompt specialist referral following the onset of daily headache in children.

Orthostatic intolerance and postural orthostatic tachycardia syndrome (POTS) are increasingly recognized conditions in pediatrics, often requiring intensive counseling and trials of medications as part of the eventually successful management. Telemedicine offers potential benefits for follow up care in this population. To evaluate clinical outcomes and quality of life (QOL) in pediatric patients with orthostatic intolerance managed through telemedicine follow up, a retrospective chart review was conducted on 220 pediatric patients with significant orthostatic intolerance symptoms who received telemedicine follow up between January 2024 and May 2025. Patients were triaged following initial clinic assessment and managed with lifestyle modifications, iron and vitamin D supplementation when indicated, and potentially medications. QOL was assessed on a 1-10 scale. Baseline and follow up QOL scores were compared over time. The cohort was 94.5% female with a mean age of 15.3 ± 2.0 years; 36.3% of the patients met criteria for a diagnosis of POTS. Over an average follow up of 17.8 months, QOL scores improved significantly from 5.6 at baseline to 7.7 at the last visit (p < 0.005) and 8.2 at best reported visit (p < 0.005). Symptom prevalence decreased notably, particularly lightheadedness, palpitations, and fatigue. Telemedicine follow up for pediatric orthostatic intolerance is associated with significant improvements in symptom burden and quality of life. Frequently scheduled visits can improve follow up rate and compliance as well as support effective use of clinical resources.

Pre-COVID-19 Postural Orthostatic Tachycardia Syndrome (PC-POTS), Long COVID with initial orthostatic hypotension (LC-IOH), and Long COVID-POTS (LC-POTS) are primarily chronic post-viral conditions with debilitating symptoms, despite routine laboratory findings often being normal. We previously identified amyloidogenic fibrinaloid microclot complexes (FMCs) in the insoluble fraction of platelet-poor plasma (PPP-IF) in Long COVID, but it remains unclear whether similar abnormalities occur in PC-POTS and LC-POTS, or whether post-translational modifications (PTMs) contribute to disease mechanisms. Platelet-poor plasma from healthy controls (n = 18), PC-POTS (n = 20), LC-IOH (n = 19), and LC-POTS (n = 18) participants underwent proteomic analysis of the PPP-IF using double trypsin digestion and data-independent LC-MS/MS. Differential protein abundance, PTMs, and amyloidogenicity were compared across groups. Although few proteins were significantly dysregulated, extensive disease-specific PTM alterations were identified across coagulation, immune, and metabolic pathways. LC-IOH demonstrated prominent AGE- and oxidation-related PTMs on fibrinogen subunits, particularly fibrinogen alpha chain (FIBA), resembling diabetic glycation profiles. PC-POTS showed fewer fibrinogen PTMs but marked metabolic and immune dysregulation, including oxidised apoA1 and apoB and complement-associated proteins (C3, C4A/B, IC1), IGG1, and A2MG. LC-POTS shared coagulation-related features with LC-IOH and immune-related features with PC-POTS. Many dysregulated peptides were highly amyloidogenic in silico, consistent with β-sheet-rich FMCs. PTM dysregulation was substantially greater than protein-level changes. This study provides the first evidence that PTMs within the PPP-IF has the potential to distinctly differentiate PC-POTS, LC-IOH, and LC-POTS. Because PC-POTS samples predated SARS-CoV-2, their PTM signatures reflect intrinsic disease biology independent of COVID-19. PTM profiling revealed pro-coagulant fibrinogen changes in LC-IOH and LC-POTS, metabolic-oxidative dysregulation in LC-IOH and PC-POTS, and immune dysregulation in PC-POTS and LC-POTS. These abnormalities were not detectable by routine assays and may contribute to microvascular dysfunction. The findings support disease-specific biomarker development and targeted therapeutic strategies across autonomic and post-viral disorders.

Chiari malformation type 1 (CM-I) is frequently associated with connective tissue disorders (CTDs), particularly Ehlers-Danlos syndrome (EDS), which may increase surgical risk and complicate management. Familial clustering of CM-I and CTDs has been reported, but their prevalence within families remains underexplored. This study aimed to determine the prevalence of CTDs and comorbidities among family members of CM-I patients, comparing familial and sporadic cases. We conducted a retrospective survey-based study of patients who underwent posterior fossa decompression for CM-I between 2008 and 2023 by the senior author. Eligible patients (n = 890) were invited to complete a 10-item questionnaire regarding family history of CM-I, CTDs, and related comorbidities. Responses were stratified into familial (≥1 relative with CM-I) and sporadic groups. Group comparisons were performed using χ 2 or Fisher exact tests. Of 354 complete responses, 308 (87.0%) reported a family history of CM-I. Compared with sporadic cases, familial CM-I patients more often reported a family history of joint replacement or surgery (59.1% vs 39.5%, P = .0162), joint dislocation/injury (58.5% vs 16.7%, P < .0001), easy bruising (80.0% vs 57.1%, P = .0010), and CTDs (53.4% vs 18.9%, P < .0001), with EDS being the most common. Familial CM-I respondents were also more likely to report hyperflexibility (69.4% vs 47.7%, P = .0045) and systemic comorbidities, including postural orthostatic tachycardia syndrome (24.0% vs 13.0%) and mast cell activation disorder (9.4% vs 0%). Familial CM-I is strongly associated with CTDs, particularly EDS, and systemic comorbidities such as hypermobility, postural orthostatic tachycardia syndrome, and mast cell activation disorder. These findings support a heritable link between CM-I and CTDs and highlight the importance of detailed family history and connective tissue evaluation in CM-I patients. Comprehensive assessment and counseling of at-risk relatives may improve diagnosis, surgical planning, and long-term outcomes.

Dysautonomia, including postural orthostatic tachycardia syndrome (POTS) and related orthostatic disorders, is frequently associated with debilitating gastrointestinal (GI) symptoms in adolescents, including chronic nausea, early satiety, postprandial fullness, and functional dysmotility. Despite the significant disease burden, pharmacological options for GI dysmotility in this population remain poorly studied. To our knowledge, no prior case series has described metoclopramide as a targeted prokinetic bridge therapy specifically in adolescents with dysautonomia-associated GI dysmotility symptoms. We describe three adolescent females (ages 13, 16, and 16 years) with specialist-confirmed dysautonomia and refractory GI symptoms who were treated with a standardized short-course, low-dose metoclopramide bridge protocol (5 mg three times daily, tapered over approximately 12 weeks). All patients received concurrent multidisciplinary management including dietary modification, neuromodulators, integrative therapies, and behavioral support. All three demonstrated subjective improvement in nausea and GI symptoms, enabling engagement with broader rehabilitative and nutritional interventions. No extrapyramidal symptoms or serious adverse effects were observed. Cumulative metoclopramide doses across all three cases ranged from approximately 770 to 1050 mg-well below the threshold associated with tardive dyskinesia risk in contemporary real-world data. Short-course, low-dose metoclopramide, administered as part of a structured multidisciplinary protocol with explicit safety counseling and planned taper, may serve as a feasible bridge therapy for adolescents with dysautonomia-associated GI dysmotility symptoms. These observations are hypothesis-generating and should be interpreted with caution given the small sample size, concurrent multidisciplinary interventions, and absence of standardized outcome instruments. They support the need for prospective investigation of short-course, weight-dosed metoclopramide use in this specific population.

Long COVID Postural Orthostatic Tachycardia Syndrome (LCPOTS) is characterized by persistent orthostatic tachycardia and systemic symptoms following SARS-CoV-2 infection. Many features of LCPOTS suggest ongoing immune activation, but the mechanisms driving this response remain unclear. In this study, we show that patients with LCPOTS, compared with individuals who recovered from SARS-CoV-2 without POTS, exhibit increased monocyte mitochondrial content and superoxide production, along with downregulation of NRF2-dependent antioxidant enzymes. This is accompanied by a marked increase in the formation of isolevuglandins (IsoLGs) in monocytes, which modify self-proteins and act as neoantigens capable of activating T cells. Consistent with this, LCPOTS patients exhibit a 3-fold increase in circulating T cell-monocyte doublets with immunological synapse formation. T cells in these complexes display a proinflammatory effector-memory and TEMRA phenotype, producing IFN-γ and IL-17A, which correlated with symptom severity. Circulating cytokines, including IL-17A, IFN-γ, and TNF-α, are elevated in patients with LCPOTS. In a subset of patients, transcutaneous vagal nerve stimulation (t-VNS) reduced circulating CD3 CD14 doublets, IsoLG accumulation, and IL-6 expression in CD14 monocytes. Our findings suggest that reduced vagal tone in LCPOTS leads to monocyte oxidative stress, IsoLG neoantigen formation, and T cell activation, linking immune dysregulation to cardiovagal dysfunction. Targeting these pathways may offer novel therapeutic opportunities.

Prior to the COVID-19 pandemic, the etiology of postural orthostatic tachycardia syndrome (POTS) remained elusive. Since the pandemic, a newly recognized disorder, termed Long COVID, has emerged with a significant subset of patients developing dysautonomia and a multitude of comorbidities consistent with POTS. The aim of this study was to determine if pre-pandemic POTS and Long COVID POTS share a common inflammatory-associated biomarker profile. Volunteers were recruited for four study groups; patients diagnosed with POTS prior to the pandemic, Long COVID-associated POTS, SARS-CoV-2-recovered controls, and naïve controls. All participants completed a COMPASS-31 survey and a medical history questionnaire. Plasma biomarkers of the innate and adaptive immune system were quantified using a custom multiplex bead assay and ELISAs. Both POTS cohorts demonstrated indistinguishable and significant elevations in 14 of the 15 measured biomarkers including markers of the NLRP3 axis (Caspase-1p20, interleukins IL-1β, IL-18), regulatory cytokine IL-10, and immune activation markers (sCD40L, sCD40, sCD30) compared to controls. Multivariate PERMANOVA analysis revealed no significant difference in global cytokine profiles between the two POTS cohorts. Random Forest classification accurately distinguished POTS from controls, with IL-18 emerging as the most important feature. These associative findings suggest that pre-pandemic POTS and Long COVID-associated POTS share a distinct inflammatory profile among measured cytokines. The identification of IL-18 as a key biomarker, alongside Caspase-1p20 and other inflammatory cytokines, are compatible with inflammasome-related signaling. Further investigation is necessary to characterize the role of the inflammasome, platelet activation, and immune dysregulation in POTS and Long COVID.

Ehlers-Danlos syndromes (EDSs) are heritable connective tissue disorders caused by defects in collagen and related extracellular matrix proteins. Because the vocal fold (VF) lamina propria is a collagen-dependent structure, the voice might be expected to be affected, yet voice and laryngeal involvement has received comparatively little attention. This scoping review, conducted according to the Joanna Briggs Institute framework and reported following the PRISMA extension for Scoping Reviews (PRISMA-ScR), mapped the available evidence on voice and laryngeal manifestations in adults with EDS. PubMed, Scopus, and Web of Science were searched to 11 March 2026, and thirteen studies were included: four questionnaire-based and nine clinical or instrumental. Self-reported voice complaints were common across EDS and hypermobility spectrum disorder populations, ranging from mild-to-moderate handicap in large cohorts to frequent, fluctuating difficulties in professional singers, although their prevalence varied with population and assessment method. Direct laryngeal examination revealed a recurring substrate of cricoarytenoid joint subluxation or fixation, arytenoid prolapse, and hyolaryngeal instability, together with microvascular and mucosal fragility, characteristically accompanied by preserved VF mobility. Muscle tension dysphonia was the most frequent diagnosis in high-vocal-demand cohorts. Reflux, vocal load, and autonomic comorbidities such as postural orthostatic tachycardia syndrome were frequently reported and may modulate the clinical picture. The evidence indicates that voice and laryngeal involvement is a plausible, multi-level manifestation of EDS that remains under-recognised. The current literature is limited by small, heterogeneous, and largely uncontrolled studies; prospective research using standardised multimodal assessment is needed to clarify its prevalence, mechanisms, and management.

Safety data on human papillomavirus (HPV) vaccination in the Japanese population remain limited owing to the lack of healthcare databases available for vaccine safety assessment. In this study, we assessed the risk of adverse events of special interest (AESIs) following HPV vaccination among females aged 12-26 y using medical claims data linked to routine or catch-up vaccination records provided by municipalities. We conducted a population-based cohort study and self-controlled case series (SCCS) from April 2015 to March 2023 for bivalent/quadrivalent vaccines and from April 2023 to March 2024 for the 9-valent vaccine. All females eligible for the vaccination program were included in the cohort study, whereas only those who experienced AESIs were included in the SCCS. The observation period was classified according to vaccination status as unvaccinated and post-vaccination risk periods following the first, second, and third doses. Adjusted rate ratios with 95% confidence intervals were estimated for the cohort and SCCS. In the bivalent/quadrivalent vaccines analysis cohort (25131 females), 1763, 1492, and 975 received the first, second, and third doses, respectively. In the 9-valent vaccine analysis cohort (38970 females), 3931, 2389, and 934 received the first, second, and third doses, respectively. Rates of 54 AESIs were calculated during unvaccinated periods. AESIs with feasible quantitative analyses for either the bivalent/quadrivalent or 9-valent vaccines included migraine, hypotension, asthma, polycystic ovary syndrome, postural orthostatic tachycardia syndrome, hypothyroidism, hyperthyroidism, and epilepsy. No statistically significant increased risk following HPV vaccination was observed for these AESIs. Larger datasets are needed to assess rarer AESIs.

Hypermobile Ehlers-Danlos syndrome (hEDS), frequently presents with pain and autonomic symptoms suggestive of small fiber neuropathy (SFN). However, systematic comparisons between hEDS and idiopathic SFN (iSFN) using combined clinical, functional, and morphological approaches are lacking. We prospectively studied a population of SFN patients who also fulfilled the 2017 criteria for hEDS (hEDS/SFN) and compared them with a group of iSFN patients of similar age. All underwent SFN-Symptoms Inventory Questionnaire (SFN-SIQ), Douleur Neuropathique 4 (DN4), and the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaires, quantitative sensory testing (QST), autonomic testing (cardiovascular reflexes, sympathetic skin response, dynamic sweat test), and skin biopsy from leg, thigh, and fingertip. Clinical, morphological and functional data were compared with our normative dataset and between the two patient groups. 35 hEDS/SFN and 38 iSFN patients were included in the study. hEDS/SFN patients had earlier symptom onset (19.5 ± 5.9 years vs. 35.2 ± 8.7 years, p < 0.001), more generalized distribution, and higher COMPASS-31 scores (54.3 ± 16.9 vs. 33.9 ± 19.4 p < 0.01), particularly in orthostatic intolerance, gastrointestinal, and urinary domains. Postural Orthostatic Tachycardia Syndrome (POTS) was present in half of hEDS/SFN patients while it was not found in iSFN (51.5% vs. 0.0%). Skin biopsy revealed similar intraepidermal nerve fiber loss in both groups, but hEDS had greater autonomic fiber loss (p < 0.05). Small fiber involvement in hEDS is characterized by earlier onset, more generalized pain and severe autonomic symptoms, and higher autonomic morpho-functional impairment compared with iSFN. Systematic autonomic assessment and targeted management should be considered in this population.

Postural orthostatic tachycardia syndrome (POTS) is widely treated as a cardiovascular-autonomic syndrome, but cognitive dysfunction is a disabling and poorly treated clinical phenomenon. This scoping review discusses why brain fog, impaired attention, slowed processing speed, memory difficulties, word-finding issues, and executive dysfunction may persist despite conventional pharmacological and non-pharmacological POTS treatments. The study uses a structured scoping review design to synthesize 18 peer-reviewed sources that meet the inclusion criteria, with publication dates between 2013 and 2025, across the domains of mechanistic, clinical, treatment, rehabilitation, and interventional studies. The evidence can be grouped into three principal mechanistic pathways: cerebral hypoperfusion and hemodynamic dysfunction; autonomic dysregulation and sympathetic overactivation; and neuroinflammation, autoimmune responses, mast cell activation, and microclot formation. The review found that abnormal cerebral blood flow (CBF) was reported in 61% of 56 POTS patients with cognitive dysfunction, and that sustained cognitive stress induced a greater reduction in CBF velocity in POTS patients than in controls, at approximately 7.8% and 1.8%, respectively. Current therapies, including beta-blockers, ivabradine, midodrine, exercise, salt and fluid loading, compression garments, cognitive behavioral therapy (CBT), and sleep management, rarely use cognition as a primary endpoint. Findings suggest that persistent cognitive dysfunction in POTS may reflect incomplete alignment between neurological mechanisms and cardiovascular-centered care, requiring validated cognitive outcomes and multimodal trials combining biological, autonomic, and rehabilitative interventions.

Postural orthostatic tachycardia syndrome (POTS) is associated with autonomic dysregulation, but ambulatory markers that capture autonomic phenotype remain incompletely defined. To compare Holter-derived heart rate variability (HRV) metrics between adolescents with POTS and healthy controls and to derive candidate discriminatory thresholds. Retrospective case-control analysis of an existing Holter dataset (POTS n = 19, controls n = 44). Heart rate variability was processed in Kubios HRV Premium. Between-group comparisons used Welch's t-test with Benjamini-Hochberg false discovery rate adjustment. Nonparametric sensitivity analyses yielded similar results. Discrimination was assessed using receiver operating characteristic analysis; optimal thresholds were defined by the Youden index. An exploratory penalized logistic regression model (L1 regularization) was fit with standardized candidate HRV predictors and internal cross-validation. Among 19 POTS patients and 44 control subjects, POTS demonstrated lower time- and frequency-based HRV, higher rate-related and sympathetic composite indices, and lower parasympathetic composite measures. The strongest univariate discriminator was PNSi (Parasympathetic Nervous System index; AUROC 0.874; threshold ≤ -1.10; sensitivity 77.8%; specificity 88.6%). Other high-performing discriminators included SNSi, mean RR, mean heart rate, and SDNNi. Holter-derived HRV metrics demonstrate a reproducible pattern consistent with reduced parasympathetic modulation and relative sympathetic predominance in POTS. Several variables yield candidate discriminatory thresholds that may support physiologic phenotyping and warrant validation in independent cohorts.