Welcome back to Research Round-up where we feature some of the latest developments in Ehlers-Danlos syndrome (EDS) research. Hitch up your horse, gather ‘round the campfire, and see what we have in store for you today.

ICYMI: a possible blood test for hEDS?

Cardiology
“Longitudinal echocardiography in pediatric patients with hypermobile Ehlers-Danlos syndrome”
Published in the American Journal of Medical Genetics on August 16, 2024 | Link to full text article
Research by Hannah Lahey, Haewon Shin, Katherine Myers, and Kim L. McBride

Summary: This study investigates the prevalence and progression of aortic root dilation in pediatric patients diagnosed with hypermobile Ehlers-Danlos syndrome (hEDS). The study, conducted retrospectively (looking at medical care that has already occurred) at a single pediatric center, analyzed data from echocardiograms performed between 2010 and 2021. The authors found that while some patients initially presented with mild aortic root dilation, this tended to decrease with time, suggesting that the condition may be less serious than previously believed. The study also found no evidence of aortic dissection in first- or second-degree relatives, indicating a low risk of transmission of this cardiovascular complication within families. They recommend that echocardiograms may not be necessary for all pediatric patients with hEDS, particularly in the absence of other cardiac concerns. This could potentially reduce healthcare costs and anxiety for both patients and caregivers.

“Association Between Cardiac Size, Systolic Function, and Complications in Vascular Ehlers-Danlos Syndrome”
Published in the Canadian Association of Radiologist Journal on September 6, 2024 | Link to full text 
Research by Aly Fawzy, William Warnica, Kate Hanneman, Rachel M. Wald, Erwin Oechslin, Paaladinesh Thavendiranathan, and Gauri R. Karur

Summary: This research explores the association between cardiac size, systolic function (the ability of the heart to contract), and complications in individuals with vascular EDS (vEDS). The study retrospectively compared (looked at previously-given medical care) 26 individuals with vEDS to 26 individuals without vEDS using cardiac MRI. The study found that individuals with vEDS had lower ventricular ejection fractions (both left and right) and larger ventricular volumes, particularly in the left ventricle, compared to controls. Lower left ventricular ejection fraction was strongly associated with the presence of complications like dissections, aneurysms, and pneumothorax. The authors suggest that these findings could indicate issues with the heart muscle—making it difficult to pump blood—in vEDS, possibly related to the underlying collagen issues.

Connecting the Dots Between Conditions
“The Suggested Relationships Between Common GI Symptoms and Joint Hypermobility, POTS, and MCAS”
Published in Gastroenterology & Hepatology in August 2024 | Link to full text
Research by Eamonn M. M. Quigley, Oscar Noble, and Usman Ansari

Summary: The research examines the relationship between common gastrointestinal (GI) symptoms and three other disorders: hypermobility spectrum disorders (HSDs) or hypermobile EDS (hEDS), postural orthostatic tachycardia syndrome (POTS), and mast cell activation syndrome (MCAS). The study focuses on a group of young adult females who presented with debilitating GI symptoms like intractable nausea and vomiting, gastroesophageal reflux, and constipation, alongside a history of HSD/hEDS, POTS, and/or MCAS. The article discusses the potential mechanisms linking these systemic disorders to the observed GI symptoms, emphasizing the role of visceral hypersensitivity (increased sensitivity to pain in the internal organs), dysautonomia, and mast cell degranulation (the process during which mast cells release inflammatory substances). While the way these conditions change the body and cause disease is still under investigation, the authors suggest there is a potential “disease cluster” where these disorders frequently coexist and may even amplify the symptom severity of the others. They highlight the need for standardized diagnostic criteria and further research to better understand these conditions, particularly in the context of their shared GI symptoms.

“An overview of Ehlers-Danlos syndrome and the link between postural orthostatic tachycardia syndrome and gastrointestinal symptoms with a focus on gastroparesis”
Published in Frontiers in Neurology on August 28, 2024 | Link to full text
Research by William Wu and Vincent Ho

Summary: Gastroparesis, a condition characterized by delayed gastric emptying, is highlighted in this research as a significant concern for individuals with both EDS and postural orthostatic tachycardia syndrome (POTS). The authors discuss the potential role of dysautonomia in the development and progression of these interconnected conditions. The review concludes by highlighting the need for further research to better understand these complex relationships and develop more effective treatments for individuals with these often-debilitating disorders.

New: How do you tell the difference between POTS and anxiety?

“Long COVID and hypermobility spectrum disorders have shared pathophysiology”
Published in Frontiers in Neurology on September 4, 2024 | Link to full text
Research by Ravindra Ganesh and Bala Munipalli

Summary: This paper explores the connection between hypermobility spectrum disorders (HSD) (including hEDS) and long COVID, arguing that they share underlying sources and causes. Joint hypermobility is frequently associated with conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia, and postural orthostatic tachycardia syndrome (POTS). HSD and long COVID also share symptoms as well, such as musculoskeletal pain, dysautonomia, and fatigue. The paper explores potential reasons for this, including mast cell activation (when a mast cell is triggered by an allergen), mitochondrial dysfunction, and genetic MTHFR mutations, which may contribute to both conditions. Screening and managing individuals with HSD and long COVID will require a multidisciplinary approach that addresses the unique needs of each patient.

Bonus article: more big news about how everything is related when it comes to EDS.

“Decoding the Genetic Basis of Mast Cell Hypersensitivity and Infection Risk in Hypermobile Ehlers-Danlos Syndrome”
Published in Current Issues in Molecular Biology on October 17, 2024 | Link to full text
Research by Purusha Shirvani and Michael F. Holick  

Summary:  This study explores the connection between hypermobile Ehlers-Danlos syndrome (hEDS) and mast cell activation syndrome (MCAS). The authors posit that these conditions are linked at a genetic level, impacting how well the immune system works and how susceptible someone with hEDS is to getting infections. They used whole-genome sequencing to identify specific genetic variants in individuals with hEDS, focusing on those associated with mast cell dysregulation. The study looked at a number of genes, including MT-CYB, HTT, MUC3A, HLA-B, and HLA-DRB1, and found variations that are more common in people with hEDS compared to the control group, which was made up of seven first-degree relatives of the participants. These findings suggest a genetic cause for mast cell hypersensitivity and infection risk in hEDS patients. The authors believe these findings could be utilized to develop potential therapies for treating MCAS

Related: Need more mast cell content? EDS Awareness has a patient guide for you!

Hematology
“Low vitamin C status and hypermobility-related disorders in patients with bleeding disorder of unknown cause”
Published in Haemophilia on September 23, 2024 | Link to full text
Research by Eva Leinøe, Halla Fridriksdottir, Andreas Ørslev Rasmussen, Eva Funding, Anne Louise Tølbøll Sørensen, Peter Kampmann, Jens Lykkesfeldt, and Maria Rossing

Summary: This study investigated the link between bleeding disorders of unknown cause (BDUC), hypermobility disorders (like hypermobility EDS and hypermobility spectrum disorder), and vitamin C status. The study found that about half of the patient participants with BDUC had a positive Beighton score; one was officially diagnosed with hEDS. The control group of patients only had one person with a positive Beighton score. The patients with BDUC were also shown to have normal vitamin C levels, but they were “lower normal” than the patients without BDUC. The researchers suggest that the association between BDUC and lower vitamin C levels might be due to increased vitamin C consumption in hEDS, as it plays a crucial role in collagen synthesis. The study also highlighted the need for further research to explore the potential benefits of vitamin C supplementation in patients with BDUC and hEDS to reduce bleeding.

Joint Surgery
“Functional benefit of joint surgery in patients with non-vascular Ehlers-Danlos syndrome: results of a retrospective study”
Published on September 23, 2024 in Orphanet Journal of Rare Diseases | Link to full text
Research by Sharon Abihssira, Karelle Benistan, and Geoffroy Nourissat

Summary: This is a retrospective study (meaning they looked at medical care that already happened) examining the benefits, success rates, and complications of joint surgery in patients with non-vascular Ehlers-Danlos. The study looked at the surgical management of patients with EDS (55 with hypermobile EDS and 14 with other non-vascular subtypes) in order to determine the role of joint surgery in treatment of EDS. (The joints studied were shoulder, elbow, wrist, knee, and ankle.) The researchers evaluated the results of surgery, including the rates at which patients needed intervention after surgery (such as an infection, a failure of the hardware, or other issues requiring medical attention). The researchers found that surgery for joint instability is more likely to succeed when performed on patients with a known diagnosis of EDS before surgery and that knee surgeries are particularly beneficial. The majority of patients were satisfied with their surgery (greater than 70%), and the rate of re-operation was low; however, there was a high rate of dislocations (almost 75%). This suggests the need for further research and improved surgical techniques rather than completely shying away from surgery as has been recommended for EDS patients in the past.

Bonus article: The United States and New Zealand are the only countries in the world that allow direct-to-consumer marketing of pharmaceutical drugs. Find out more about this phenomenon in this bonus article fron Out-of-Pocket.

Measuring Outcomes
“Defining a core outcome set for hypermobility spectrum disorders and hypermobile Ehlers-Danlos syndrome: A Delphi consensus study”
Published in Clinical Rheumatology on October 9, 2024 | Link to full text
Research by Natalie L. Clark, Melissa Johnson, Amar Rangan, Lucksy Kottam, Andrea Hogarth, Sarah Scott, and Katherine Swainston

Summary: This study aims to develop a standardized set of outcomes, called a core outcome set (COS), for individuals with hypermobility spectrum disorder (HSD) and hypermobile EDS (hEDS). Due to provider unawareness and the various presentations of hEDS and HSD, it often goes undiagnosed or misdiagnosed. Using a three-round Delphi consensus study, the authors engaged patients, family members, and healthcare professionals to determine the most important symptoms that should be measured in research and clinical practice. Note: these are not diagnostic criteria. These are areas for providers to examine, check on, ask about, and measure when treating a person with hEDS and HSD. Not all symptoms show up when a patient is diagnosed with HSD or hEDS, so these are the things for providers to check on and ask about. It can be helpful in diagnosis, but it is separate from the diagnostic criteria. The study found the required >70% consensus on 30 symptoms across eight specialties:

• Musculoskeletal and Orthopedics
  • Joint hypermobility, instability, flexibility, or feeling loose
  • Muscle spasms or weaknesses
  • Physical discomfort or fatigue, feeling “heavy”
  • Joint dislocation or subluxation (partial dislocation)
  • Joint or tendon inflammation
  • Nerve compression (symptoms include nerve pain, pins and needles, and numbness)
  • Stiffness
  • Sprains (recurrent)
•  Social Aspects
  • Impact on exercise
  • Negative healthcare experiences
  • Impaired quality of life
  • Modified or restricted behaviors
  • Physical or daily activity limitations
  • Unable to participate in activities (social functioning and abandoning of hobbies)
  • Loss of independence
  • Work-life imbalance or lack of financial independence (professional difficulties)
• Areas of Pain
  • Neck and/or back
  • Pelvis or hip
  • Lower limb (legs, knees, ankles, feet)
  • Upper limb (elbow, hands, fingers, shoulders, wrists)
  • Neuropathic (nerves)
• Gynecology and Urology
  • Urinary urgency
  • Incontinence or difficulty emptying the bladder
  • Pain, cramps, and/or spasms
  • Increased symptoms of HSD/hEDS around menstrual cycle
• Negative Affect
  • Medical gaslighting
  • Made to feel fraudulent, burdensome, stigmatized, or misunderstood
• Neurological
  • Dizziness or lightheadedness
  • Cognitive fogs (including poor concentration and feeling confused)
• Gastrointestinal
  • Difficulty with bowel movements (including pain, blood in stool, and urgency)
• Other
  • Sleep (including daytime sleepiness, disturbances, or quality)
  • Fatigue or exhaustion

The authors conclude that this COS will be used to develop appropriate measurement instruments and ultimately improve the assessment of interventions, management, and care pathways for individuals with HSD/hEDS.

Related: EDS Awareness has a series of articles to help with medical gaslighting and feeling misunderstood by doctors. Did you know that feeling has a name?

Neurology
“Revision Chiari surgery in adults: surgical evaluation algorithm and outcomes in a continuity-of-care practice”
Published in the Journal of Neurosurgery on August 1, 2024 | Link to full text 
Research by Rita H. Nguyen, John K. Chae, Kyle E. Zappi, Grant Luhmann, Alexa Kisselbach, Amanda Cruz, and Jeffrey P. Greenfield

Summary: This research discusses the challenges of doing a second surgery on adult patients with Chiari malformation (CM). The authors analyzed a cohort of 40 adult patients who had undergone CM surgery in childhood or young adulthood and presented with recurrent symptoms. They found that while revision surgery can be favorable, careful evaluation and patient selection can make the difference between a successful surgery and an unsuccessful one. They looked at three different surgical procedures that were used for the revision (second) surgery: fossa decompression with or without duraplasty (PFD/D), occipitocervical fusion without ventral decompression (OCF), and ventral decompression in the form of endoscopic endonasal odontoidectomy (VD).  Rate of improvement after the revision surgery were 60.0% with PFD/D, 85.6% with OCF, and 85.7% with VD, but “the difference in these rates is not statistically significant.” A retroflexed odontoid was significantly more common in the VD group, and, interestingly, the PFD/D group had fewer diagnosed cases of craniocervical instability (CCI), EDS, and dysautonomia than the other groups. The paper also emphasizes the importance of transitional care for CM patients as they age, highlighting the need for multidisciplinary teams to address complex cases and ensure continuity of care. The authors propose an algorithm for evaluating and managing recurrent CM, which incorporates considerations specific to both pediatric and adult patients.

“Differentiating the Structural and Functional Instability of the Craniocervical Junction”
Published in Healthcare on October 7, 2024 | Link to full text
Research by Piotr Godeek and Wojciech Rucinski

Summary: This paper focuses on the complex issue of instability in the craniocervical junction (CCJ), the connection between the skull and the first cervical vertebra. The authors delve into the anatomical and biomechanical aspects of CCJ instability, exploring both its structural and functional forms. They emphasize that structural instability arises from ligamentous or bony damage, often requiring surgical intervention. CCJ functional instability stems from dysfunction in the cervical proprioceptive system (CPS). The CPS gets information from muscle spindles, joint receptors, Gogli tendon organs, and skin receptors. This information allows it to coordinate movement, balance, posture, and motor coordination as well as perceiving where the head and trunk are oriented. When the CPS is disrupted (possibly by a loose CCJ or Chiari malformation), it can lead to symptoms like dizziness and balance issues. The paper highlights the importance of careful diagnosis and treatment of both forms of instability to improve patients’ quality of life, as both can significantly impact physical function, mental well-being, and overall health. The authors present diagnostic criteria for both forms of instability, discuss relevant clinical tests and imaging techniques, and outline appropriate management approaches. More awareness is needed among medical professionals about functional CCJ instability and the need for a multidisciplinary approach to its diagnosis and treatment.

Related: EDS Awareness has a great patient guide for Cervical Spine Instability

Skin & Wound Healing
“Investigation of dermal collagen nanostructures in Ehlers-Danlos Syndrome (EDS) patients”
Published in PLoS One on August 22, 2024 | Link to full text
Research by Mehrnoosh Neshatian, Nimish Mittal, Sophia Huang, Aiman Ali, Emilie Khattignavong, and Laurent Bozec

Summary: This research article explores the structural and mechanical properties of skin collagen in individuals with EDS. The authors investigate the nanoscale (one-billionth of a meter) characteristics of collagen in skin biopsies from patients with classical EDS (cEDS), hypermobile EDS (hEDS), and hEDS with Scleroderma, comparing them to a patient without EDS. Using advanced techniques such as atomic force microscopy (AFM) and Picrosirius Red staining (a technique used to highlight collagen structure), the study reveals significant differences in collagen structure and mechanics between individuals with EDS and healthy individuals. The results demonstrate three things: 1) EDS-affected collagen displays disrupted fibril (fiber) organization; 2) EDS-affected collagen has a higher prevalence of collagen that is undefined in shape; and 3) EDS-affected collagen has a lower compressive elastic modulus (which is the ratio of mechanical stress to strain when an elastic substance is compressed). The study also suggests that AFM image analysis, even by non-specialists, could potentially serve as a diagnostic tool for EDS, especially for hEDS, which is currently awaiting a definitive way to make a diagnosis. This study has some neat images of collagen fibers at nanoscale. Be sure to check them out!

“Modulating the extracellular matrix to treat wound healing defects in Ehlers-Danlos syndrome”
Published in iScience on September 20, 2024 | Link to full text
Research by Kindra M. Kelly-Scumpia, Maani M. Archang, Prabhat K. Purbey, Tomohiro Yokota, Rimao Wu, Jackie McCourt, Shen Li, Rachelle H. Crosbie, Phillip O. Scumpia, and Arjun Deb

Summary: This research article focuses on understanding and treating wound healing defects in classical Ehlers-Danlos syndrome (cEDS) and could be applied to other types of EDS with skin healing issues. The authors created a mouse model of cEDS by specifically deleting the Col5a1 gene in skin fibroblasts at the time of wounding. The Col5a1 gene has the instructions for making for type V collagen (Col5=type V [five] collagen), so deleting it deletes the body’s ability to make type V collagen. Researchers found that this change accurately mimics the wound healing defects seen in human cEDS. It displayed delayed wound closure, abnormal extracellular matrix (ECM) organization, and persistent inflammation. The study shows that blocking some of the signaling on integrin, a protein on the surface of cells that helps cells stick to each other and the ECM, or injecting fibroblasts from mice who do not have EDS into the wounds of cEDS mice made the wounds heal much faster. This suggests that these methods could be used to treat patients.

Bonus article: Nikhil Krishnan from Out-of-Pocket discusses the troubles with healthcare in the US. Don’t worry—he adds plenty of jokes and fun along the way.