Ehlers-Danlos Syndrome (EDS) is an umbrella term for a heterogeneous group of inherited connective tissue disorders characterized by symptoms including, but not limited to, skin hyperextensibility, joint hypermobility, and vascular fragility.1 It is a result of genetic mutations that cause defects in the formation of types I, III, and/or V collagen, which can manifest with pathologies in collagen-rich tissues like skin, tendons, ligaments, joints, and blood vessels.1 The variety of genes that can be involved leads to a variety of phenotypic presentations. Although the classification of these phenotypes has changed over time, there are generally six main subtypes of EDS: Classical, Hypermobile, Vascular, Kyphoscoliosis, Arthrochalasia, and Dermatosparaxis.2 As of 2017, there are also seven further, rarer subtypes officially recognized.3
In addition to skin hyperextensibility and joint hypermobility, patients with EDS can present with easy bleeding/bruising, atrophic scarring, aortic root dilation, mitral valve prolapse, gastrointestinal complications, scoliosis, and chronic joint pain, among other concerns.1 Since EDS patients can present with such a variety of symptoms, the combination of which can vary depending on their specific subtype, EDS is likely underdiagnosed in the clinical setting. This can present a problem both for EDS patients and the physicians treating them.
Most patients will not outrightly present complaining of skin or joint hyperextensibility; for someone who has lived with these issues their whole life, an EDS patient is not likely to recognize these things as abnormal. However, thorough history taking with these patients is likely to elicit past or current issues with joint dislocations, joint subluxations, easy bruising, easy bleeding, and atrophic scarring. Depending on the spectrum of their EDS, they may also attest to dizziness upon standing or palpitations and/or gastrointestinal concerns. Patients with histories significant for these findings should subsequently be further examined for EDS.
Basic visual findings on physical exam that can further corroborate suspected EDS include scoliosis, pes planus, and/or blue sclerae.1 Examination of the skin can reveal dystrophic scars, striae, or soft consistency, which may have not directly been elicited from the patient’s history. Skin hyperextensibility can be tested by pulling until there is resistance on the volar surface of the forearm.4 Cardiovascular examination can reveal any underlying mitral valve prolapse or aortic root dilation that may have previously been asymptomatic. If there is a high clinical suspicion of EDS, a patient should be assessed via the Beighton Scoring System.5 A score of 4 out of the nine total criteria would define a patient as ‘hypermobile’, while a score of 5+ is generally considered to be clinically diagnostic of EDS and warrants additional workup.1 A patient with a score of 4/9 with a significant history of joint instability, skin elasticity, any of the aforementioned concomitant symptoms can also strongly be considered for additional workup. As of 2017, further question sets have been developed that dive deeper into personal and family history of EDS symptoms. These can be used for patients with high clinical suspicion of hypermobile EDS who are unable to provide a Beighton Score or have inconclusive Beighton Score results. The full “hEDS Diagnostic Checklist” can be found on the Ehlers-Danlos Society website.6 Genetic testing is used for definitive diagnosis of EDS, but it is not currently applicable to the hypermobility subtype.1,2
In all fields of medicine, but especially the fields of physical medicine and rehabilitation, cardiology and immunology, recognition of EDS can be an important consideration in addressing pathologies and developing a treatment regimen. Chronic, life-long joint hypermobility likely with compounded subluxations and dislocations will almost assuredly lead to issues like arthritis, cartilage tears, tendinopathies, etc., and studies have shown that up to 100% of EDS patients eventually report some form of chronic joint or back pain.7,8 Early recognition of EDS in these patients can lead to the use of prophylactic braces or pads to enhance joint stability and potentially minimize long-term joint damage.1 It can also help guide exercise regimens aimed at enhancing strength and joint stability. Typically, an emphasis should be placed on low-impact exercises (eg: pool exercise) over high-impact exercises that may serve to further increase joint stress.1
Management of acute pain and pathologies in the EDS patient can be non-surgical, surgical, or both. Pharmacologic management is an important first-line treatment for acute pain in this patient population. NSAIDs are a common first-line approach for mild to moderate pain, but studies have shown poor NSAID tolerance in many EDS patients due to comorbid gastrointestinal issues.9,10 Corticosteroids and opiates have shown to be efficacious in the management of acute pain for EDS patients, but each is a questionable long term option.9 Chronic corticosteroid use has a plethora of side effects,11,12 which especially contraindicates use in EDS patients who are already predisposed to cardiovascular, gastrointestinal, and musculoskeletal complications. In addition to the increased risk of dependence for any patient treated on long-term opioid therapy, chronic opioid therapy has been shown to potentially lead to central pain sensitization in the EDS patient.10
In addition to pharmacologic considerations, non-surgical management can consist of physical and interventional modalities. As mentioned above, management with braces or pads can enhance joint stabilization, minimize chronic damage, and reduce long-term disability in EDS patients. Additionally, studies have shown that the use of braces, splints, or massage therapy can reduce the perception of acute and chronic pain in the EDS patient.10,13,14 A common interventional therapy that has proven effective for acute or chronic musculoskeletal pain in the non-EDS patient is local injection with corticosteroids and short-acting anesthetics such as lidocaine and or bupivacaine,15,16 or dextrose prolotherapy. Early research suggests that low-dose Naltrexone may be of benefit.
First, studies have shown that EDS patients, especially those with Hypermobile EDS, do not respond adequately to local anesthesia.17-19 Second, as mentioned above, while short-term corticosteroid therapy can be effective in EDS patients, they are likely to be at increased risk of chronic corticosteroid-related side effects that could occur with multiple injections. However, while there is still minimal research, the newest trend in EDS management largely revolves around regenerative therapies. Among these, prolotherapy and sclerosant therapy have shown to be a promising treatment for reducing pain and improving function.20,21 Still, in total, there has been minimal research in this area. Further extensive clinical trials are still needed to demonstrate proven benefits, though this may be complicated by the lack of awareness of and clinical under-recognition of EDS.
Surgical interventions will inevitably be indicated for severe joint traumas or due to pain or pathologies refractory to non-surgical management. However, there is currently mixed evidence on the efficacy of surgery in the treatment of moderate to severe joint pain in EDS patients.9,23,24 Surgical interventions may also present problems for EDS patients due to the aforementioned issues that cause an increased risk of cardiac complications, increased bleeding risk, lack of anesthetic response, and atrophic scarring, among other general surgical risks present with all patients.1,24 Furthermore, EDS patients are at increased risk of subluxation and dislocation injuries associated with operating room positioning and movement.25 In total, EDS patients have shown to have an increased rate of surgical complications as compared to the general population.26,27
Other clinical considerations for EDS patients largely revolve around psychological concerns and lifestyle management. Practitioners should be keen to look out for psychiatric symptoms, sleep disorders, and fatigue symptoms, which have an increased incidence in the EDS patient population.9,28 Due to the increased risk of cardiovascular pathologies, patients should be counseled on the avoidance of smoking and weight control. Athletic participation should be carefully considered against the current magnitude of EDS-related symptoms and future potential for complications in EDS patients. Extensive cardiac workup should be conducted before clearance to play, and protective pads and braces should be highly encouraged, especially in patients that already present with joint pathologies.
In summary, EDS is a chronic, inherited connective tissue disorder that can present with a wide variety of clinical features, the most common of which revolve around joint pain and hypermobility. All clinicians, but especially those who work in the field of musculoskeletal medicine, should be careful to note possible signs and symptoms of EDS through thorough history taking and complete physical examination. Patients with high suspicion of EDS should be assessed via the Beighton Scoring System, with further evaluation via the hEDS checklist or genetic testing as indicated. EDS patients should be counseled on the importance of bracing, muscle strengthening, and low-impact exercise to enhance joint stability and minimize long-term damage. Differences in response to traditional pharmacologic and interventional therapies between EDS and non-EDS patients should be considered when developing a management plan for EDS patients. Future research into therapies for EDS patients, especially in the field of musculoskeletal regenerative medicine, should be at the forefront.
Guest Post by Chris Duncan, MD, Tulane University School of Medicine