Research Library

A randomized, double-blind, placebo-controlled crossover trial in 22 patients with hyperadrenergic POTS, about 95 percent women. Each patient took ivabradine for one month and placebo for one month. Ivabradine significantly lowered heart rate versus placebo and improved physical and social functioning on a quality-of-life survey, with a non-significant trend toward lower standing norepinephrine and without significant side effects such as an overly slow heart rate or low blood pressure.

Design: randomized crossover RCT. Limits: very small (n=22), single hyperadrenergic subtype, one month per arm, single center.

A sham-controlled, double-blind randomized trial in 26 women, 12 active and 14 sham, over two months. An ear clip delivered low-level stimulation to the tragus of the ear (active) or the earlobe (sham) for one hour daily. The active group had a smaller rise in heart rate on standing at two months, about 17.6 versus 31.7 beats per minute, along with lower antiadrenergic autoantibodies and inflammatory markers and better heart-rate variability, with no device-related side effects.

Design: sham-controlled randomized trial. Limits: small (n=26), single center, two-month window, all participants female.

A proof-of-concept study with no sham or control group, in 22 patients with hyperadrenergic POTS, assessed at baseline, after 14 days of stimulation, and within 24 months after stopping. After 14 days the study recorded reduced sympathetic nerve activity, improved vagal (rest-and-recovery) tone, and lower orthostatic symptom scores, with some benefits persisting after stimulation ended.

Design: uncontrolled, open-label proof-of-concept, not randomized. Limits: small (n=22), no control group, hyperadrenergic subtype only.

A retrospective case series of 7 patients with severe POTS that had not responded to standard treatment, given either subcutaneous immunoglobulin or plasmapheresis. All 7 improved on retrospective symptom and function scores, roughly a 50 percent drop in autonomic symptoms and a large rise in functional ability. Six of the 7 reduced or stopped oral POTS medications and 5 returned to work or school. The authors call for randomized controlled trials to test this.

Design: retrospective case series, no control group. Limits: very small (n=7), outcomes recalled retrospectively by patients, selected treatment-refractory cases.

The first randomized controlled trial of IVIG in presumed autoimmune POTS. Thirty patients received either IVIG or intravenous albumin, eight infusions over 12 weeks, with albumin used to control for the effect of added fluid volume and to keep the trial blinded. There was no statistically significant difference between the groups on the main autonomic symptom measure. Both groups improved, which may reflect added fluid volume or other effects, and side effects were common but usually mild and similar in both groups.

Design: single-site randomized controlled trial with active comparator. Limits: small (n=30), single site, improvement in both arms may hide a true difference between treatments.

A randomized, double-blind, placebo-controlled crossover trial in 30 adults with mastocytosis. Each person took rupatadine, a second-generation H1 antihistamine, for four weeks and placebo for four weeks. Compared with placebo, the antihistamine improved quality of life and reduced itch, wheal and flare, flushing, tachycardia, and headache. It did not improve gastrointestinal symptoms.

Design: randomized, double-blind, placebo-controlled crossover. Limits: small (n=30), four weeks per arm, and gastrointestinal symptoms did not respond.

A double-blind crossover study in five patients with systemic mastocytosis, given oral cromolyn sodium, which limits mast cell mediator release, or placebo over many months. On the drug, fifteen of eighteen trials brought marked relief of itching, whealing, flushing, diarrhea, abdominal pain, and difficulty with concentration; on placebo, none of nineteen trials improved. The drug is poorly absorbed from the gut yet still helped those symptoms.

Design: double-blind crossover. Limits: only five patients, published in 1979, but one of the few placebo-controlled looks at the gastrointestinal symptoms an antihistamine often misses.

Twenty-one patients with idiopathic MCAS who were not controlled on standard treatments had omalizumab, an anti-IgE antibody, added to their care. Over the following year, their symptom scores on a visual analog scale and their number of anaphylaxis episodes both fell significantly compared with before omalizumab and with the time of diagnosis.

Design: real-world before-and-after study, no placebo or comparison group. Limits: small (n=21), and without a control arm it cannot separate the drug from natural fluctuation or other changes in care.

A randomized, placebo-controlled phase 2 trial in 212 patients with indolent systemic mastocytosis; 141 took avapritinib, a drug that blocks the mutated KIT protein that drives clonal mast cell disease, and 71 took placebo. At 24 weeks the drug group had larger reductions in skin lesion size and color, in the number of mast cells in the skin, and in skin symptoms including itching, flushing, and spots.

Design: randomized, double-blind, placebo-controlled phase 2 trial. Limits: this studied indolent systemic mastocytosis, a clonal mast cell disease, which is not the same as the non-clonal MCAS many people here live with; several authors are employed by the drug's maker.

A systematic review that searched for trials of H1 antihistamines, the usual first-line treatment, in primary MCAS. Across the whole literature it found only five small crossover trials, enrolling 71 patients in total, four of them from the 1980s and 1990s and all judged at moderate to high risk of bias. The single modern trial was the rupatadine study above. The authors concluded that good evidence is still missing and called for large, well-designed trials.

Design: systematic review of five small, mostly older trials. Limits: little high-quality evidence exists even for the most commonly used treatment, which is itself the finding worth knowing.

The team enrolled 21 adults with hEDS or HSD by 2017 criteria and multidirectional shoulder instability from a Belgian medical genetics center, then randomized them to one of two 6-month home-based exercise programs. Both arms received supervised initial instruction and progressed through scapular and rotator-cuff strengthening with proprioceptive components. The primary outcome was the Western Ontario Shoulder Index. Secondary outcomes included arm-shoulder-hand disability, fear of movement (Tampa Scale for Kinesiophobia), patient-specific function, global rating of change, and pain pressure thresholds. Western Ontario Shoulder Index scores improved by 240 points at 12 weeks and 325 points at 24 weeks across both arms. Disability scores improved 8.6 points by 24 weeks; patient-specific function 4.3 points; global rating of change 1.0 point. Fear of movement did not change significantly in either arm.

Design: randomized controlled trial. Limits: small sample (n=21), no non-exercise control (both arms exercised), single tertiary center, supervised initial instruction in both arms. The trial compares two exercise programs rather than testing exercise against no exercise. The authors note that shifting fear of movement may require multidisciplinary supervised care that a home program cannot supply.

The team studied 40 adults with benign joint hypermobility syndrome (the pre-2017 classification that maps onto much of today's HSD population) and 30 healthy controls. They first compared knee proprioceptive sensibility between the two groups and found it significantly impaired in the hypermobile group. They then randomized the hypermobile participants to an 8-week clinic-based knee proprioceptive exercise program (n=15) or no intervention (n=25). Outcomes were knee proprioceptive sensation, the Arthritis Impact Measurement Scale 2, and pain on a visual analog scale. The exercise arm had significantly lower pain scores and significantly better occupational function on the Arthritis Impact Measurement Scale 2 compared to the no-intervention arm at 8 weeks.

Design: randomized controlled trial. Limits: small sample with unequal arm sizes (n=15 vs n=25), no sham or active control (exercise vs nothing), no blinding, single Turkish center, benign joint hypermobility syndrome rather than hEDS by 2017 criteria. Older trial (2008); the basic positive finding for proprioception in hypermobility has not been replicated at larger scale since.

An Australian team developed a self-paced online pain management program (HOPE) for hEDS and HSD with patient-stakeholder input across 12 modules over 8 weeks, then ran a pilot randomized controlled trial. 72 adults were randomized; 36 completed the intervention, 34 continued usual care. Assessments occurred at baseline, post-treatment, and 3 months post-treatment. On feasibility, acceptability, and appropriateness, 62 to 91 percent of intervention participants rated the program favorably across measures. Of 8 clinical effectiveness outcomes, two reached statistical significance: worst pain intensity at 3-month follow-up (Cohen's d 0.63, moderate effect) and impact of hypermobility (d 0.32, small effect). Six of the eight clinical outcomes did not differ from usual care. The authors frame the result as supporting a fully powered effectiveness trial.

Design: pilot randomized controlled trial. Limits: pilot scale, online self-selection, six of eight clinical effectiveness outcomes did not reach significance. Co-author Alan Hakim is affiliated with the Ehlers-Danlos Society, which has institutional interests in patient-education programming.

The team conducted a PRISMA systematic review and meta-analysis of total hip arthroplasty and total knee arthroplasty outcomes in EDS. Eight studies pooled 1,769 EDS patients (1,011 hip replacements, 758 knee replacements) and compared outcomes against non-EDS controls. After hip arthroplasty, EDS patients had 2.40 times the odds of all-cause revision, 3.22 times the odds of instability or dislocation, and 3.76 times the odds of aseptic loosening (all p<0.001). After knee arthroplasty, all-cause revision odds were 1.54 (p=0.006), instability 2.96 (p<0.001), periprosthetic fracture 2.91 (p=0.009), and wound complications 2.91 (p<0.001). Rates of periprosthetic joint infection and readmission did not differ between groups. Patient-reported outcome scores improved from baseline in both cohorts and reached similar absolute scores at follow-up.

Design: systematic review and meta-analysis of case series and cohort studies. Limits: includes all EDS subtypes (vascular, classical, hypermobile, and others) without subtype-level breakouts, so the elevated complication rates reflect mixed connective-tissue tissue biology and cannot be cleanly attributed to hEDS alone. Underlying studies are mostly retrospective; selection and surveillance bias possible.

A Belgian team searched six databases through April 2020 for randomized trials of physiotherapy in hEDS, in both children and adults. From 1,045 retrieved references, 6 randomized controlled trials met inclusion criteria with sample sizes ranging from 20 to 57. Interventions varied widely: generalized physiotherapy, targeted physiotherapy, inspiratory muscle training, proprioception programs, and other techniques, with durations of 4 to 8 weeks. Despite the heterogeneity, the review found that pain or proprioception improved significantly in the intervention arms regardless of which technique was tested, inspiratory muscle training added functional exercise capacity, and quality of life improved in every trial included. The authors conclude that physiotherapy benefits proprioception and pain in hEDS even though robust randomized controlled studies remain missing.

Design: systematic review. Limits: only 6 included randomized controlled trials, small samples across them (n=20 to 57), heterogeneous protocols and short durations (4 to 8 weeks), no meta-analysis possible. The honest closer: physiotherapy is the most widely recommended treatment for hEDS and the evidence base supporting it remains thin.

A double-blind crossover trial in 31 women with fibromyalgia, each taking low-dose naltrexone (a small fraction of the dose used for opioid or alcohol dependence) and placebo in turn. Daily pain fell more on the drug than on placebo, about a 29 percent reduction versus 18 percent, and life satisfaction and mood improved, though sleep and fatigue did not. Roughly a third of participants responded on the drug, against about one in nine on placebo.

Design: small randomized double-blind crossover. Limits: only 31 patients, all women, single center; the authors call it preliminary and ask for larger parallel-group trials.

A systematic review that pooled seven randomized trials of low-dose naltrexone across a range of chronic pain conditions, 406 patients in total. Taken together, the trials did not show that low-dose naltrexone reliably reduced chronic pain or improved quality of life. The authors call for larger trials with consistent methods before any firm conclusion is drawn.

Design: systematic review of seven small randomized trials. Limits: the conditions and methods varied across trials, which the authors flag as a reason the pooled result is not the last word; it sits in direct tension with the smaller fibromyalgia-specific trial above.

An overview gathering 21 Cochrane reviews, 87 trials, and 17,631 patients. Three drugs, duloxetine, milnacipran, and pregabalin, had reasonable evidence of meaningful pain relief, at least halving pain, in about one in ten adults with moderate to severe fibromyalgia pain over four to twelve weeks, with no evidence of benefit beyond six months. Results for amitriptyline and SSRIs were shaped by publication bias, mirtazapine showed moderate evidence of no effect, and seven other drugs had no usable trials at all.

Design: overview of systematic reviews, graded for quality. Limits: the honest headline is the size of the effect, real for roughly one person in ten and unproven past six months, not a promise for any single reader.

A network meta-analysis of 36 trials and 11,930 patients comparing off-label amitriptyline with the three approved drugs. Duloxetine ranked highest for pain and depression, though the effect was small; amitriptyline ranked highest for sleep, fatigue, and overall quality of life. Every approved drug led to more people quitting from side effects than placebo did, while amitriptyline did not. The authors' takeaway was to match the drug to a person's most troubling symptom.

Design: network meta-analysis ranking treatments indirectly. Limits: indirect comparisons are weaker than head-to-head trials, and several authors report pharmaceutical-industry employment, including Merck and AbbVie.

A Cochrane review of 13 randomized trials, 839 people, comparing aerobic exercise with no exercise. Exercise probably improved quality of life and was completed about as often as the no-exercise condition, and it may have slightly reduced pain and improved physical function, with little difference in fatigue or stiffness. Most of the benefit faded over the longer term. The evidence was rated low to moderate quality, downgraded for small trials and bias.

Design: systematic review of randomized trials, GRADE-assessed. Limits: most trials did not measure harms, so the review itself is uncertain about safety, and these are fibromyalgia trials that do not capture people whose illness overlaps with ME/CFS, for whom exertion can trigger a crash. Pacing, and any increase in activity, is a conversation for a clinician who knows that risk.

The PACE trial was a large UK randomized trial that had reported cognitive behavioral therapy (CBT) and graded exercise therapy (GET) to be moderately effective for chronic fatigue syndrome, with recovery in over a fifth of patients. Wilshire and colleagues re-analyzed PACE's results using the outcome procedures originally specified in PACE's published protocol, which they obtained through a Freedom of Information request. Under the original procedures, the CBT and GET groups did not significantly outperform the control group on the trial's primary outcome (overall improvement rates) after correcting for the protocol's specified multiple comparisons. Recovery rates were consistently low and not significantly different across groups. Significant effects on secondary measures were confined to self-report and did not endure beyond two years. The authors concluded that the modest effects observed could be reasonably accounted for by participant reporting biases. The PACE investigators published a response defending the original trial's conclusions (Sharpe et al, 2019, BMC Psychology); the field has not resolved this disagreement.

Design: a re-analysis of trial data accessed under freedom-of-information request, not the full PACE dataset. Limits: the original PACE trial's design choices (open-label, self-report primary outcomes) underlie much of the methodological argument on both sides.

The UK's National Institute for Health and Care Excellence published an updated clinical guideline for ME/CFS in October 2021, replacing its 2007 guideline. The new guideline recognizes post-exertional malaise as a defining feature of the condition, recommends against graded exercise therapy as defined by fixed incremental increases in physical activity (the form tested in the PACE trial), and downgrades cognitive behavioral therapy to a supportive treatment for managing symptoms rather than a curative approach. It recommends an energy management or pacing-based approach as the foundation of activity guidance. Reception has been polarized. Patient organizations welcomed the changes. The Royal College of Physicians and the Royal College of General Practitioners issued objections, and a group of 51 international specialists, including original PACE investigators, published a critique enumerating eight specific anomalies they identified in NICE's review process, arguing the change deviated from standard evidence-synthesis practice (White et al, 2023, Journal of Neurology, Neurosurgery & Psychiatry).

Design: a clinical practice guideline reflects committee judgment over a body of evidence, not a primary research study. Limits: the disagreement around this guideline is substantive and ongoing.

80 people with ME/CFS (Canadian Clinical Criteria) and 64 healthy non-exercising controls underwent two maximal cardiopulmonary exercise tests separated by 24 hours, a protocol that has previously documented reduced anaerobic threshold on the second day in people with ME/CFS. The study quantified how long it took participants to recover to their pre-exercise functional and symptom state, tracked across ten days using a nine-symptom severity scale. Mean recovery time was 12.7 days for ME/CFS participants and 2.1 days for controls. The range in ME/CFS spanned 1 to 64 days, with one participant not recovered after a year (excluded from the average). Less than 10% of ME/CFS participants took more than three weeks. The authors note that this quantification supports more informed consent before exercise testing in this population and may help guide pacing decisions.

Design: an observational quantification using an objective exertional challenge. Limits: not a treatment study; the symptom-severity outcome is patient-reported; controls were sedentary and healthy, not an illness-matched comparison.

151 patients with ME/CFS (Canadian consensus criteria, illness duration 2 to 15 years) were randomized to receive rituximab (a monoclonal antibody that depletes B-lymphocytes) or placebo, with infusions across 12 months and follow-up to 24 months. Response rates, defined as a sustained reduction in fatigue score, were 35.1% in the placebo group and 26.0% in the rituximab group, a non-significant difference (p=0.22). The two groups did not differ on fatigue scores over 24 months or on any secondary outcome (self-reported function, SF-36 components, physical activity level). Serious adverse events occurred in 26.0% of the rituximab group and 18.9% of the placebo group. The authors concluded that B-cell depletion with rituximab was not associated with clinical improvement in ME/CFS. The trial was designed to test a positive phase II finding from the same research group (Fluge et al, 2011, PLoS One; 67% response in rituximab vs 13% in placebo, p=0.003, n=30); the phase III did not replicate it.

Design: a multi-center randomized, double-blind, placebo-controlled trial across five Norwegian hospitals. Limits: primary outcomes were self-reported; the negative result does not rule out benefit in a subgroup the trial was not designed to identify, but it does not support a general autoimmune-modulation strategy in unselected ME/CFS.

A retrospective review of 59 patients at Stanford who were prescribed low-dose naltrexone (LDN) off-label for post-acute sequelae of COVID-19. LDN is naltrexone administered at doses much lower than its FDA-approved use for opioid and alcohol dependence and has been proposed to act as an anti-inflammatory and immunomodulator. Patients on LDN had fewer symptoms after starting treatment and reported improvements in fatigue, post-exertional malaise, unrefreshing sleep, abnormal sleep patterns, and overall functional status. The authors describe the findings as warranting testing in rigorous randomized placebo-controlled trials. (LDN is also discussed in this library's Chronic Pain & Sensitization category, where its evidence base is in fibromyalgia.)

Design: a retrospective single-site cohort with no control arm, no placebo, and no randomization. Limits: improvements may reflect treatment effects, regression to the mean, placebo response, or selection bias toward responders; the Stanford research team is actively investigating LDN in long COVID, and their stated interpretation is in the direction of further investigation rather than neutral readout.

A 29-member multidisciplinary group, neurologists, neuroradiologists, anaesthetists, neurosurgeons, and patient representatives, drafted consensus recommendations using a modified Delphi process, backed by a systematic literature review and by surveys of patients and clinicians. Their first-line treatment recommendation is a non-targeted epidural blood patch, performed as early as possible, with the more invasive imaging used to locate a leak reserved for cases that do not respond. The document also covers when to consider surgery, how to manage symptoms, and how to handle complications.

Design: multidisciplinary consensus guideline using modified Delphi, supported by systematic review. Limits: a consensus document, not a trial; the strength of each recommendation reflects how thin or thick the underlying evidence is, which the authors are explicit about throughout.

A systematic review and meta-analysis pooling 144 studies on SIH, with study sizes averaging 53 patients. For treatment, conservative measures alone helped about 28 percent of patients, a single epidural blood patch worked in 64 percent, and a larger patch using more than 20 mL of blood reached 77 percent. The same review also pulled together the diagnostic picture: orthostatic headache in 92 percent, characteristic brain MRI findings in 73 percent though missing in 19 percent, and lumbar puncture pressure low or normal in nearly all patients.

Design: systematic review and meta-analysis using random-effects models. Limits: highly heterogeneous studies and no controlled interventional trials, which the authors flag as the central limitation; the pooled rates are averages across very different centers, techniques, and patient mixes.

A systematic review and meta-analysis of seven studies comparing two approaches to the epidural blood patch: targeted, where the leak is identified by imaging first, and non-targeted, where the patch is placed without locating the leak. The pooled results showed no significant difference between the two on overall outcome, success on the first attempt, or relapse rates. The authors conclude that a non-targeted patch is a reasonable initial approach, particularly when the imaging needed to localize a leak is invasive or hard to access.

Design: systematic review and meta-analysis of seven non-randomized comparative studies. Limits: a small number of included studies, patient selection and technique varied across centers, and the analysis pools observational data rather than randomized comparisons.

A systematic review and meta-analysis comparing two treatments for cerebrospinal fluid-venous fistula, a type of leak only widely recognized in the last decade. Across 15 studies and 321 patients, both transvenous embolization, an endovascular approach reaching the fistula through nearby veins, and surgical ligation reached over 90 percent partial or complete headache response, with no significant difference between them. Complete symptom resolution was also comparable, around 59 percent for embolization and 71 percent for surgery, and roughly 14 percent of patients across both groups needed retreatment.

Design: systematic review and meta-analysis using random-effects models. Limits: 15 mostly small case series with no randomized trials and no head-to-head comparisons, which the authors flag as raising the risk of selection and confounding bias because patients were not assigned to a treatment at random.

A systematic review structured as an evidence map of 139 studies on SIH treatment, designed to surface what is well-studied and what is not. The findings put numbers on a problem many SIH papers acknowledge in passing: 92 percent of studies were retrospective cohort or case series, no study reached level 1 evidence, and only about 11 percent compared treatments head to head. More than a third of studies did not clearly meet the formal diagnostic criteria for SIH, the type of CSF leak was unclear in three-quarters of them, and outcomes were rarely measured at the same time points across studies.

Design: systematic review presented as an evidence map. Limits: the review predates the larger transvenous-embolization literature for CSF-venous fistulas, which it explicitly excluded, so the entry just above this one fills that gap; the authors call for prospective studies, head-to-head trials, formal diagnostic criteria, and outcome measures collected at uniform time points.

An international group of physical therapy clinicians and one hypermobility-specialist rheumatologist developed expert consensus recommendations for screening, assessing, and managing upper cervical instability (which includes atlanto-occipital and atlantoaxial instability) in symptomatic generalized joint hypermobility, including hypermobile EDS and hypermobility spectrum disorder. The recommendations describe how to recognize presenting signs, how to grade severity, what conservative interventions to consider (postural retraining, manual therapy guidance, exercise progression, environmental modifications), and when to escalate to imaging or specialist referral. The authors acknowledge throughout that no validated diagnostic tests or prediction rules exist for upper cervical instability in this population, and frame their consensus as a starting point intended to stimulate further research.

Design: expert consensus, not a clinical trial. Limits: no patient outcome data; consensus rather than evidence-based recommendations; co-author Alan Hakim is affiliated with the Ehlers-Danlos Society, which has institutional interests in hypermobility care pathways; several other authors run specialty physical therapy clinics serving hypermobile patients, with direct financial interest in the conservative-care approach the consensus recommends. None of this disqualifies the consensus as informative, but it should be read as expert opinion shaped by clinical experience, not as evidence that conservative management produces specific outcomes.

A University of Toronto neurosurgery team conducted a PRISMA systematic review of the published literature on CCI diagnosis and surgery in EDS. Searches across Ovid Medline, Embase, Cochrane, and PubMed yielded 16 articles that met inclusion criteria, pooling 78 surgical patients across all included studies. Ten different radiographic parameters had been used in the literature to indicate CCI; four were used most often for surgical decision-making (the clivo-axial angle, the Harris measurement, the Grabb-Mapstone-Oakes measurement, and the angular displacement of C1 on C2). The authors recommend those four parameters as the most reasonable basis for evaluating suspected CCI until better evidence emerges, and specify that surgical fixation should only be performed when radiographic instability and concordant symptoms are both clearly present.

Design: systematic review. Limits: only 16 included studies, total of 78 surgical patients across the entire pooled literature, evidence level III to V across included studies (the Newcastle-Ottawa Quality Assessment Scale ranged from 4 to 8 out of 9 stars), no prospective or controlled trials available, no consensus-based clinical pathway. The review's central finding is the smallness of the evidence base it had to work with.

A Johns Hopkins neurosurgery team published a critical narrative review of the diagnostic and surgical evidence for CCI in EDS. The review acknowledges that some EDS patients develop clinical instability of the craniocervical junction warranting consideration of occipitocervical fixation, then critically examines the radiographic parameters proposed for diagnosis (the clivo-axial angle, the basion-axial interval, the pB-C2 measurement, among others) and the published outcomes after surgery. The authors state directly that there remains a paucity of data supporting proposed radiographic parameters for spinal instability among EDS patients, and that there is a lack of high-quality evidence concerning the efficacy of surgical treatments for chronic debilitating pain prevalent in this population. They call for more standardized clinical measures and more rigorous study methodology before further surgical recommendations are made.

Design: narrative review by an academic spine surgery program. Limits: not a systematic review; reflects the authors' interpretation of the literature. The review functions as a counterweight: it cites the same literature that specialty centers cite and reaches a more cautious conclusion about what the literature supports.

A retrospective cohort from the Chiari EDS Center of Mount Sinai South Nassau described 717 patients referred to the center for connective tissue disorder evaluation and possible neurosurgical management between 2014 and 2023. Of the cohort, 460 (64%) had a diagnosis of hEDS; 426 (59%) carried a Chiari I malformation diagnosis. Among the 460 hEDS patients, 404 elected surgical intervention, and of those, 73% required craniocervical fusion for CCI. The paper documents the frequency at which the center diagnoses and operates on these conditions in the population referred to it, and reports comorbid mast cell activation disorder and POTS at elevated rates in the hEDS subgroup.

Design: retrospective single-center cohort, no outcome measures, no control group, no comparison to non-specialty referral patterns. Significant conflict of interest: co-author Paolo Bolognese is a CCI surgeon whose diagnostic and surgical practice patterns are themselves the controversy surveyed by Lohkamp 2022 and critiqued by Mao 2022; the center's referral and self-evaluation pipeline operates on the radiographic thresholds Mao 2022 specifically names as not yet supported by independent evidence. The paper is informative about what one high-volume specialty center sees and operates on, not about whether those surgeries help across a broader population. Mainstream academic spine surgery does not share these surgical thresholds. Read this cohort alongside Lohkamp 2022 and Mao 2022, not in isolation.

A Barcelona anesthesiology group published a review of perioperative analgesia approaches for hEDS and joint hypermobility syndrome patients with CCI undergoing occipito-cervical fixation. The paper documents that this population frequently presents with chronic neuroinflammation, opioid-induced hyperalgesia, and central sensitization, which together make standard opioid-based perioperative pain management both less effective and more harmful than in non-hEDS surgical populations. The authors propose a perioperative protocol built on total intravenous opioid-free anesthesia, multimodal analgesia, and post-operative combination of lidocaine, ketamine, and dexmedetomidine for an opioid-sparing effect. The protocol is presented as an update to the group's earlier case series.

Design: narrative review and protocol proposal, not a randomized trial. Limits: single-group experience from one anesthesiology service; no comparative outcome data against standard perioperative protocols. Relevant for patients facing surgery on this region who want to know that the central sensitization and opioid-response patterns common in hEDS are anesthesia-relevant and worth raising with the surgical team before the operation.