A review of respiratory manifestations and their management in Ehlers-Danlos syndromes and hypermobility spectrum disorders.

BACKGROUND: Ehlers-Danlos Syndromes (EDS) and Hypermobility Spectrum Disorders (HSD) are a heterogeneous group of heritable genetic connective tissue disorders with multiple characteristics including joint hypermobility, tissue fragility, and multiple organ dysfunction. Respiratory manifestations have been described in EDS patients, but have not been systematically characterized. A narrative review was undertaken to describe the respiratory presentations and management strategies of individuals with EDS and HSD. METHODS: A broad literature search of Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane CENTRAL was undertaken from inception to November 2020 of all study types, evaluating EDS/ HSD and pulmonary conditions. This narrative review was limited to adult patients and publications in English. RESULTS: Respiratory manifestations have generally been described in hypermobile EDS (hEDS), classical and vascular EDS subtypes. Depending on EDS subtype, they may include but are not limited to dyspnea, dysphonia, asthma, sleep apnea, and reduced respiratory muscle function, with hemothorax and pneumothorax often observed with vascular EDS. Respiratory manifestations in HSD have been less frequently characterized in the literature, but exertional dyspnea is the more common symptom described. Respiratory symptoms in EDS can have an adverse impact on quality of life. The respiratory management of EDS patients has followed standard approaches with thoracotomy tubes and pleurodesis for pleural manifestations, vocal cord strengthening exercises, continuous positive pressure support for sleep apnea, and exercise training. Reduced respiratory muscle function in hEDS patients responds to inspiratory muscle training. CONCLUSION: Respiratory symptoms and manifestations are described in EDS and HSD, and have generally been managed using conservative non-surgical strategies. Research into the prevalence, incidence and specific respiratory management strategies in EDS and HSD is needed to mitigate some of the associated morbidity.

Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers-Danlos syndrome clinic: A retrospective review.

The new 2017 diagnostic criteria for hypermobile Ehlers-Danlos Syndrome (hEDS) provide a framework for diagnosing hEDS but are more stringent than the previous Villefranche criteria. Our clinical experience at the GoodHope EDS clinic was that the 2017 criteria left many highly symptomatic patients without a diagnosis of hEDS. We conducted a retrospective cohort study to confirm our clinic experience and assess the accuracy of the 2017 diagnostic criteria for hEDS in patients who had a previous hEDS diagnosis based on the Villefranche criteria. Our study found that 15% (n = 20 of 131) of patients with a prior diagnosis of hEDS met the 2017 diagnostic criteria, and many of the traits used to distinguish hEDS were not significantly more frequent in patients who met 2017 criteria versus those who did not. In both groups objective systemic manifestations were found less frequently than subjective systemic manifestations. Beighton score (BS) as assessed by primary care practitioner was found to be higher than assessment by EDS practitioner in 81% (n = 74 of 91) of cases. Generalized joint hypermobility was confirmed in only 46% (n = 51 of 111) of patients who had a previous diagnosis of hEDS. Higher BS did not correlate with increased number of systemic manifestations in our cohort. Common comorbidities of hEDS were found with similar frequency in those who met 2017 criteria and those who did not. Based on our cohort, the 2017 hEDS diagnostic criteria require refinement to improve its diagnostic accuracy.

Management of childbearing with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: A scoping review and expert co-creation of evidence-based clinical guidelines.

OBJECTIVE: To co-create expert guidelines for the management of pregnancy, birth, and postpartum recovery in the context of hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). DESIGN: Scoping Review and Expert Co-creation. SETTING: United Kingdom, United States of America, Canada, France, Sweden, Luxembourg, Germany, Italy, and the Netherlands. SAMPLE: Co-creators (n = 15) included expertise from patients and clinicians from the International Consortium on the Ehlers-Danlos syndromes and Hypermobility Spectrum Disorders, facilitated by the Ehlers-Danlos Society. METHODS: A scoping review using Embase, Medline, the Cochrane Central Register of Controlled Trials and CINHAL was conducted from May 2022 to September 2023. Articles were included if they reported primary research findings in relation to childbearing with hEDS/HSD, including case reports. No language limitations were placed on our search, and our team had the ability to translate and screen articles retrieved in English, French, Spanish, Italian, Russian, Swedish, Norwegian, Dutch, Danish, German, and Portuguese. The Mixed Methods Appraisal Tool was used to assess bias and quality appraise articles selected. The co-creation of guidelines was based on descriptive evidence synthesis along with practical and clinical experience supported by patient and public involvement activities. RESULTS: Primary research studies (n = 14) and case studies (n = 21) including a total of 1,260,317 participants informed the co-creation of guidelines in four overarching categories: 1) Preconceptual: conception and screening, 2) Antenatal: risk assessment, management of miscarriage and termination of pregnancy, gastrointestinal issues and mobility, 3) Intrapartum: risk assessment, birth choices (mode of birth and intended place of birth), mobility in labor and anesthesia, and 4) Postpartum: wound healing, pelvic health, care of the newborn and infant feeding. Guidelines were also included in relation to pain management, mental health, nutrition and the common co-morbidities of postural orthostatic tachycardia syndrome, other forms of dysautonomia, and mast cell diseases. CONCLUSIONS: There is limited high quality evidence available. Individualized strategies are proposed for the management of childbearing people with hEDS/HSD throughout pregnancy, birth, and the postpartum period. A multidisciplinary approach is advised to address frequently seen issues in this population such as tissue fragility, joint hypermobility, and pain, as well as common comorbidities, including dysautonomia and mast cell diseases.

Evaluation and Management of Dyspnea in Hypermobile Ehlers-Danlos Syndrome and Generalized Hypermobility Spectrum Disorder: Protocol for a Pilot and Feasibility Randomized Controlled Trial.

BACKGROUND: Dyspnea is a prevalent symptom in individuals with hypermobile Ehlers-Danlos Syndrome (hEDS) and generalized hypermobility spectrum disorder (G-HSD), yet its contributors have not been identified. One known contributor to dyspnea is respiratory muscle weakness. The feasibility and effectiveness of inspiratory muscle training (IMT) in combination with standard-of-care rehabilitation (aerobic, resistance, neuromuscular stabilization, and balance and proprioception exercises) in improving respiratory muscle strength and patient-reported outcomes in patients with hEDS or G-HSD have not been evaluated. OBJECTIVE: This study aims to evaluate dyspnea, respiratory muscle strength, and patient-reported outcome measures (PROMs) in hEDS or G-HSD compared with healthy controls and to assess the feasibility of a randomized controlled trial of IMT and standard-of-care rehabilitation for improving respiratory muscle strength, exercise capacity, and PROMs compared with standard-of-care rehabilitation in hEDS and G-HSD. METHODS: The study will include 34 participants with hEDS or G-HSD and 17 healthy, age- and sex-matched controls to compare respiratory muscle structure and function and PROMs. After baseline assessments, participants with hEDS or G-HSD will be randomized into the intervention group and provided IMT combined with Ehlers-Danlos Syndrome standard-of-care rehabilitation or into the usual care group, and provided only standard-of-care rehabilitation for 8 weeks. The intervention group will be prescribed IMT in their home environment using the POWERbreathe K5 IMT device (POWERbreathe International Ltd). IMT will comprise 2 daily sessions of 30 breaths for 5 days per week, with IMT progressing from 20% to 60% of the baseline maximal inspiratory pressure (MIP) over an 8-week period. Feasibility will be assessed through rates of recruitment, attrition, adherence, adverse events, and participant satisfaction. The primary pilot outcome is MIP change over an 8-week period in hEDS or G-HSD. Secondary outcomes will include the evaluation of dyspnea using Medical Research Council Scale and 18-point qualitative dyspnea descriptors; diaphragmatic thickening fraction using ultrasound; respiratory muscle endurance; pulmonary function; prefrontal cortical activity using functional near-infrared spectroscopy; aerobic capacity during cardiopulmonary exercise testing; quality of life using Short Form-36; and scores from the Depression, Anxiety, and Stress scale-21. These measures will also be performed once in healthy controls to compare normative values. Multivariable regression will be used to assess the contributors to dyspnea. Paired 2-tailed t tests will be used to assess the changes in MIP and secondary measures after 8 weeks of IMT. RESULTS: Study recruitment began in August 2021 and, with several disruptions owing to COVID-19, is expected to be completed by December 2023. CONCLUSIONS: This study will provide a better understanding of the factors associated with dyspnea and the feasibility and effectiveness of IMT combined with standard-of-care rehabilitation. IMT may be a novel therapeutic strategy for improving respiratory muscle function and patient-reported outcomes in individuals with hEDS or G-HSD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04972565; https://clinicaltrials.gov/ct2/show/NCT04972565. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44832.

Exercise and Rehabilitation in People With Ehlers-Danlos Syndrome: A Systematic Review.

Objective: To conduct a systematic review examining the effect of exercise and rehabilitation in people with Ehlers-Danlos syndrome (EDS). Data Sources: The following databases were systematically searched: MEDLINE, MEDLINE In-Process/ePubs, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and Cumulative Index to Nursing and Allied Health. The final time point captured by the search is November 27, 2020. Study Selection: Eligible study designs included case-control, case-series, prospective cohort, retrospective cohort, and intervention studies of structured exercise or rehabilitation interventions. Eligible populations included adults (18 years or older) with EDS (all subtypes) and hypermobility spectrum disorders. The search was restricted to articles published in English. Data Extraction: Data were extracted by 2 independent reviewers. Risk of bias was assessed using the Physiotherapy Evidence Database (PEDro) scale for randomized controlled trials (RCTs) and Risk Of Bias In Nonrandomized Studies of Interventions (ROBINS-I) for non-RCTs. Reporting quality of RCTs was assessed using the Consolidated Standards for Reporting of Trials statement with the harms extension. Reporting was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Data Synthesis: The search yielded 10 eligible studies including 330 participants. The study designs included 5 RCTs, 1 cohort, 2 single-arm interventions, 1 retrospective, and 1 feasibility study. All studies showed some improvement in a physical and/or psychological outcome after the intervention period. One adverse event (nonserious) potentially related to the intervention was reported. Of the 5 RCTs, 2 were rated as high quality with low risk of bias using PEDro, and the majority of non-RCTs were rated as critical risk of bias by ROBINS-I. Conclusions: The results suggest that exercise and rehabilitation may be beneficial for various physical and psychological outcomes. Adequately powered and rigorous RCTs of exercise and rehabilitation interventions for people with EDS are needed.

The GoodHope Exercise and Rehabilitation (GEAR) Program for People With Ehlers-Danlos Syndromes and Generalized Hypermobility Spectrum Disorders.

Introduction: The Ehlers-Danlos Syndromes (EDS) and Generalized Hypermobility Spectrum Disorders (G-HSD) comprise a heterogeneous group of genetic disorders of abnormal synthesis and/or maturation of collagen and other matricellular proteins. EDS is commonly characterized by manifestations such as multi joint hypermobility that can lead to musculoskeletal pains, subluxations and dislocations, fragile skin, organ dysfunction, and chronic significant diffuse pain with fatigue, deconditioning eventuating to poor quality of life. Evidence suggests exercise and rehabilitation interventions may ameliorate symptoms of unstable joints, recurrent subluxations/dislocations, and chronic widespread musculoskeletal pain. To date, there have only been a few reports describing exercise and rehabilitation care strategies for people with EDS. Methods: In this manuscript, we describe the GoodHope Exercise and Rehabilitation (GEAR) program, its overarching principles, as well as the program development and delivery model. The GEAR program aims to decrease functional impairment, reduce pain, increase confidence in symptom self-management, and provide a community of support for people with EDS/G-HSD. To achieve these goals, we detail the model of care that includes exercise and rehabilitation therapy, education for self-management, and support accessing relevant community resources. Strengths and Limitations of the Study: GEAR represents a novel exercise and rehabilitation care model for people with G-HSD and various clinical EDS subtypes, beyond the commonly included hEDS subtype. Systematic collection of data via validated measurements is ongoing and will guide the refinement of GEAR and support the development of emerging exercise and rehabilitation programs for people with EDS.

The GoodHope Ehlers Danlos Syndrome Clinic: development and implementation of the first interdisciplinary program for multi-system issues in connective tissue disorders at the Toronto General Hospital.

Ehlers-Danlos Syndrome (EDS) are a heterogeneous group of genetic connective tissue disorders, and typically manifests as weak joints that subluxate/dislocate, stretchy and/or fragile skin, organ/systems dysfunction, and significant widespread pain. Historically, this syndrome has been poorly understood and often overlooked. As a result, people living with EDS had difficulty obtaining an accurate diagnosis and appropriate treatment, leading to untold personal suffering as well as ineffective health care utilization. The GoodHope EDS clinic addresses systemic gaps in the diagnosis and treatment of EDS. This paper describes a leap forward-from lack of awareness, diagnosis, and treatment-to expert care that is tailored to meet the specific needs of patients with EDS. The GoodHope EDS clinic consists of experts from various medical specialties who work together to provide comprehensive care that addresses the multi-systemic nature of the syndrome. In addition, EDS-specific self-management programs have been developed that draw on exercise science, rehabilitation, and health psychology to improve physical and psychosocial wellbeing and overall quality of life. Embedded into the program are research initiatives to shed light on the clinical presentation, underlying mechanisms of pathophysiology, and syndrome management. We also lead regular educational activities for community health care providers to increase awareness and competence in the interprofessional management of EDS beyond our doors and throughout the province and country.

Modified EBMT Pretransplant Risk Score Can Identify Favorable-risk Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for AML, Not Identified by the HCT-CI Score.

INTRODUCTION: Risk scores have been developed for allogeneic hematopoietic cell transplantation (HCT) outcomes, such as the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) and the modified European Group for Blood and Marrow Transplantation risk score (mEBMT) for acute leukemia. We investigated the influence of these scores for 350 patients who underwent transplantation for acute myeloid leukemia (AML). PATIENTS AND METHODS: The HCT-CI scores were grouped as 0 to 2 and ≥ 3 (231 and 119 patients, respectively) and the mEBMT scores as 0 to 2 and ≥ 3 (166 and 184 patients, respectively). RESULTS: Univariate analysis showed a significant association between the HCT-CI score and overall survival (OS) (P = .01), as did the mEBMT score (P = .002). The 5-year OS rate was 50% and 34% for a mEBMT score of 0 to 2 and ≥ 3, respectively. A subgroup of patients with a mEBMT score of 0 to 1 (n = 32) demonstrated a favorable OS of 75% at 5 years. This subgroup was younger (median age, 31 years), in first remission at transplantation, and had related donors. For the HCT-CI, the 5-year OS was 46% and 34% for a score of 0 to 2 and ≥ 3, respectively. Patients with an HCT-CI score of 0 (n = 94) had a 5-year OS of 44%. Multivariable analysis confirmed both the HCT-CI score and the mEBMT score, as previously grouped, as independent prognostic variables for both OS (P = .02 and P = .001, respectively) and nonrelapse mortality (NRM) (P = .01 and P = .003, respectively). CONCLUSION: The results of the present study have demonstrated that the HCT-CI and mEBMT are both prognostic for OS and NRM in our cohort. However, the mEBMT score can identify a favorable-risk subgroup of patients not identifiable using the HCT-CI.