Ehlers-Danlos syndromes: Overview of the management

INTRODUCTION — 

Ehlers-Danlos syndrome (EDS) is the term used for a group of genetic disorders of connective tissue that are characterized by skin hyperextensibility, joint hypermobility, and/or tissue fragility (table 1). There are no medical treatments that can reverse or "cure" EDS. Therefore, management of EDS emphasizes patient and clinician education for the prevention and early recognition of injuries and complications. Patients with specific clinical manifestations may benefit from targeted interventions (eg, treatment of diffuse musculoskeletal pain). In addition, patients with certain forms of EDS require monitoring for potential complications (eg, arterial and valvular heart disease) [1]. Most interventions used in patients with EDS have not been evaluated in randomized trials.

This topic presents an overview of the approach to the management, monitoring, and prognosis of patients with EDS. This information can help primary care providers and other non-EDS specialists to support and educate patients with EDS and to coordinate care and referrals to appropriate specialists, depending upon the type and severity of EDS. Patients with EDS should be managed in collaboration with a relevant expert in clinical genetics or a provider with special expertise in EDS (ie, a "care team"). (See 'Creating a care team' below.)

The pathogenesis, clinical manifestations, diagnosis, and differential diagnosis of the major forms of EDS and a detailed discussion of the management of the hypermobile EDS (hEDS) and other pediatric hypermobility syndromes are presented separately:

●(See "Ehlers-Danlos syndromes: Clinical manifestations and diagnosis".)

●(See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)

●(See "Treatment and prognosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)

MANAGEMENT

Creating a care team — Creating a care team for patients with Ehlers Danlos syndrome (EDS) is a fundamental aspect of management. Care is coordinated by a primary care provider and must also involve a geneticist or EDS specialist. Referral to other subspecialists depends on the specific type of EDS and disease manifestations:

●Geneticist or EDS specialist referral for all patients – We refer all patients with EDS to a medical geneticist or other EDS specialist. These specialists can work collaboratively with the primary care provider to coordinate care with appropriate consultants. Additionally, the clinical geneticist and other EDS specialists have a role in educating the other members of the health care team, given the relative rarity of these disorders in most practice settings.

●Physical and occupational therapy referral for patients with hypermobility – We refer patients with joint hypermobility to physical and occupational therapy for evaluation and management. (See 'Joint protection' below.)

●Additional subspecialist referrals – Additional subspecialist evaluation and management may be required depending on the type of EDS and the specific clinical manifestations. Examples include the following:

•Recurrent joint subluxations or dislocations – Patients with recurrent joint issues related to hypermobility may benefit from evaluation with an orthopedic, sports medicine, and/or physical medicine and rehabilitation specialist. (See 'Joint protection' below.)

•Pes planus – Patients with pes planus may benefit from evaluation by a pedorthist or podiatrist to assess the need for arch supports or orthotics.

•Chronic musculoskeletal pain – Patients who develop chronic musculoskeletal pain may benefit from referral to rheumatologist to rule out alternative diagnoses as well as a pain medicine specialist and/or a multidisciplinary pain treatment program. (See 'Musculoskeletal pain' below.)

•Skin fragility and/or poor wound healing – Patients may benefit from a referral to dermatology and/or a wound care specialist when they have especially fragile skin and/or poor wound healing. (See 'Skin fragility, wound management, and easy bruising' below.)

•Concern for sleep disorders – Symptoms suggestive of a sleep disorder (eg, prominent fatigue and daytime sleepiness) should prompt further evaluation and potential referral to sleep medicine. (See 'Fatigue' below.)

•Anxiety and depression – We refer patients who have mental health disorders to a behavioral health specialist (eg, a psychiatrist, psychologist, or counselor). We also consider referring patients who need additional coping resources. (See 'Psychosocial support' below.)

•Concern for vascular manifestations of EDS – We refer patients to cardiology and/or vascular surgery when they have types of EDS that carry higher risks of vascular complications (ie, vascular EDS [vEDS], cardiac-valvular EDS [cvEDS]) and/or if they develop signs or symptoms suggestive of valvular issues (eg, orthopnea, paroxysmal nocturnal dyspnea). (See 'Cardiovascular complications' below.)

Conservative measures for all patients — Some major issues are common to several or most forms of EDS (eg, joint hypermobility and subsequent pain). The management of such issues is generally the same regardless of the EDS type and includes patient education, psychosocial support, and measures to promote joint protection.

Patient education — We counsel patients with EDS (and parents or caregivers where appropriate) on several aspects of management, including the following:

●The nature of the disorder and the absence of curative therapy.

●The mode of inheritance and risk of recurrence in the family (see "Ehlers-Danlos syndromes: Clinical manifestations and diagnosis", section on 'Genetics and pathogenesis'). The principles of genetic counseling are described separately. (See "Genetic testing".)

●Strategies that may help to prevent or reduce symptoms of EDS, including musculoskeletal pain (table 2). (See 'Joint protection' below and 'Musculoskeletal pain' below.)

●Recognition of symptoms of potentially serious conditions that may require urgent medical attention. (See 'Symptoms requiring urgent evaluation' below.)

●For female patients, the risks of pregnancy and childbirth. (See 'Reproductive options and pregnancy' below.)

Depending upon their interest, some patients and families or caregivers may benefit from involvement with a resource such as the Ehlers-Danlos Society (or a similar organization) that provides information and support to those affected by EDS. Patients who are at risk of developing aortic disease may also benefit from connecting with the Marfan Foundation.

Patients with vascular EDS should be advised to obtain a medical alert device, such as a bracelet or necklace, which indicates their diagnosis and possible complications to facilitate appropriate emergency medical care. Other patients who are at increased risk of vascular and other acute events, including patients with the classical and kyphoscoliotic types (cEDS and kEDS), may also benefit from use of such a device. Patients in North America can enroll in MedicAlert by calling (800) 432-5372 or through the internet at www.medicalert.org (United States) and www.medicalert.ca (Canada).

Psychosocial support — We refer patients with comorbid mood disorders (eg, anxiety, depression) and those who experience difficulty coping with the physical limitations or pain posed by EDS for appropriate psychological counseling and support. Patients with joint hypermobility, including those with EDS, have higher rates of chronic pain, anxiety, and depression. Many patients may be adversely affected by the limitations posed by EDS (eg, when someone's work or recreational activities require heavy lifting). Patients who have pursued activities enhanced by their hypermobility (eg, professional ballerinas, competitive dancers, gymnasts, college athletes dependent upon sports scholarships) may be in particular need of psychosocial support.

Joint protection — An important objective for many patients with EDS is to "preserve and protect" joint function, with the goal of preventing recurrent joint dislocations, chronic joint pain, and early onset of osteoarthritis. This is particularly critical for those with cEDS and hypermobile EDS (hEDS). Prevention is of particular value because orthopedic procedures and other surgeries may take longer than expected to heal, and many patients undergo repeated orthopedic procedures as their connective tissues increase in laxity [2]. (See 'Prognosis' below.)

Components of joint protection include the following:

●Patient education – We educate patients about precautions and modifications to their daily activities that can help protect their joints, including measures to optimize function, relieve symptoms, and prevent injury (table 2). These measures should be individualized according to the patient's clinical manifestations. Additionally, patients with substantial joint laxity and/or recurrent dislocations should avoid carrying heavy items.

●Selection of safe exercise options – We generally encourage activities that are joint sparing (eg, swimming, walking, noncompetitive outdoor or indoor recumbent biking), with particular emphasis on low-impact, low-resistance exercise for joint stability and strengthening of core and extremity muscles. Due to the risk of joint strain and injury, we discourage contact sports and repetitive or isotonic exercises that stress the joints (eg, running and weightlifting), especially if such exercise worsens symptoms. Patients may be attracted to activities in which their flexibility is a particular advantage, such as gymnastics; however, these activities increase the risk of joint injury and earlier development of arthritis. Children with EDS who have hypotonia should perform non-weightbearing exercise. These measures are useful in the authors' clinical experience but have not been evaluated in clinical trials.

●Physical and occupational therapy evaluation – We refer all patients with joint hypermobility for physical and occupational therapy evaluation and management (see 'Creating a care team' above). A low-impact muscle-strengthening program for joint protection and appropriate use of assistive devices (eg, a cane or lightweight collapsible walking stick, lightweight orthoses such as braces or splints) can be of particular benefit. More detailed information on the use of physical and occupational therapy for patients with EDS is described separately. (See "Treatment and prognosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder", section on 'Physical and occupational therapy and exercise'.)

More information on the principles of joint protection and programs for specific parts of the body is provided separately:

●(See "Overview of joint protection".)

●(See "Joint protection program for the neck".)

●(See "Joint protection program for the upper limb".)

●(See "Joint protection program for the lower limb".)

Management of specific clinical manifestations — There are some common management strategies for certain clinical manifestations that are seen across multiple types of EDS, including musculoskeletal pain, fatigue, and skin fragility. However, these management strategies should still be tailored to the type of EDS and individual manifestations. (See 'Management of specific Ehlers-Danlos syndrome subtypes' below.)

Musculoskeletal pain — Patients with EDS may develop several types of musculoskeletal pain related to hypermobile joints, ranging from acute nociceptive pain from injuries to chronic nociplastic pain (table 3). It is important to distinguish the underlying cause so that it can be appropriately targeted.

●Acute pain from a joint sprain or dislocation – Patients with joint hypermobility, including those with EDS, are at risk for recurrent joint sprains or dislocations that can cause acute episodes of pain. The approach to treating discrete episodes of musculoskeletal pain from injuries is described separately. (See "Approach to the management of acute pain in adults".)

●Chronic, widespread pain – Many patients with EDS develop more chronic, widespread pain, similar to that experienced with fibromyalgia or chronic neuropathic pain. In our experience, patients benefit from reassurance that this type of chronic pain is "real" and not "all in their head." The approach to chronic, widespread pain in all types of EDS is the same as that for hEDS, which is described in detail elsewhere. (See "Treatment and prognosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder", section on 'Chronic widespread pain'.)

Fatigue — Several factors may contribute to fatigue in patients with EDS, including chronic musculoskeletal pain. In addition, fatigue may be related to sleep-disordered breathing [3] and obstructive sleep apnea, which are more common in patients with EDS [4,5]. We evaluate patients with EDS who report fatigue for potential sleep disorders and, when appropriate, refer to a sleep specialist. (See "Evaluation of suspected obstructive sleep apnea in children" and "Approach to the adult patient with fatigue".)

Skin fragility, wound management, and easy bruising — Special precautions may be required to prevent skin trauma and to optimize wound healing in patients with skin fragility, as can be seen with cEDS and vEDS:

●Avoidance of skin lacerations – Individuals with significant skin fragility, particularly children, may decrease the risk of developing skin lacerations by the use of protective bandages or pads over especially exposed areas, such as the knees, shins, and, in young children learning to walk, the forehead.

●Avoidance of bruising – We advise patients with easy bruising to avoid heavy exercise, contact sports, and medications that may decrease platelet function, such as aspirin and most nonsteroidal antiinflammatory drugs (NSAIDs).

●Promotion of wound healing – Since many patients with EDS have abnormal wound healing with an increased risk of dehiscence, experts generally close skin wounds in two layers when possible, with generous suturing of deep wounds to aid in wound healing. Sutures usually remain in for twice as long as is typical for a given procedure. Taping can help prevent stretching of the scar.

●Vitamin C supplementation – For patients with easy bruising or skin fragility, the use of vitamin C (in doses ranging from 1 to 4 grams daily in adults) has been advocated by some experts in an effort to decrease bruising and improve wound healing. This approach may be especially helpful in patients with the kyphoscoliotic and vascular types of EDS [1,6,7]. Some experts also suggest a lower dose of vitamin C (500 mg daily in adults) in patients with hEDS [8]. We do not routinely prescribe vitamin C in our practice; however, if patients are interested in this approach, we typically start with 500 mg of vitamin C by mouth twice a day and, if needed, increase up to 2 g/day. Vitamin C supplementation has not been formally tested in patients with EDS.

While these measures have not been evaluated in randomized trials, they may be useful according to experts and in our experience [1,9].

Gastrointestinal symptoms — Esophagitis, gastroesophageal reflux, stomach upset, and irritable bowel syndrome (IBS) are common in patients with multiple forms of EDS and are treated in the same manner as in patients without EDS. When endoscopy is required, it should be done cautiously given increased tissue fragility. The evaluation and management of these symptoms are described in the respective symptom-related topics.

Postural tachycardia syndrome and dysautonomia — Postural tachycardia syndrome (POTS) and dysautonomia can affect patients with EDS, especially those with cEDS and hEDS. The approaches to the evaluation and management of POTS and other dysautonomic syndromes are described separately:

●(See "Postural tachycardia syndrome".)

●(See "Mechanisms, causes, and evaluation of orthostatic hypotension".)

●(See "Treatment of orthostatic and postprandial hypotension".)

Management of specific Ehlers-Danlos syndrome subtypes — The management strategies required in patients with EDS differ to some degree between EDS types and should be individualized depending upon the severity of disease and the specific manifestations caused by the underlying genetic disorder (table 1).

Classical Ehlers-Danlos syndrome — The following concerns require particular attention in the management of cEDS [7]:

●Musculoskeletal preventive care (eg, physical therapy) and symptom management. (See 'Musculoskeletal pain' above.)

●Measures for the prevention and management of skin fragility, wound healing, and easy bruising. (See 'Skin fragility, wound management, and easy bruising' above.)

●Appropriate evaluation and management of gastrointestinal symptoms (eg, gastroesophageal reflux, IBS) and dysautonomic symptoms (eg, in those rare patients with cEDS who have symptoms related to POTS). (See 'Gastrointestinal symptoms' above and 'Postural tachycardia syndrome and dysautonomia' above.)

●Emergency evaluation of patients with sudden onset of pain or bleeding. (See 'Symptoms requiring urgent evaluation' below.)

●Monitoring for the development of cardiac valvular disease and for aortic dilatation. (See 'Cardiovascular complications' below.)

●Pregnancy management. (See 'Reproductive options and pregnancy' below.)

●Monitoring of bone density. (See 'Other complications' below.)

Hypermobile Ehlers-Danlos syndrome — The management of hEDS is discussed in detail separately. (See "Treatment and prognosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)

Vascular Ehlers-Danlos syndrome — Patients with vEDS have an increased risk of arterial and internal organ rupture (eg, colon, uterus). We educate patients about these risks and implement monitoring and preventive strategies as follows, which are supported by the authors' experience and expert opinion [10-13]:

●Urgent evaluation of sudden onset of pain or bleeding – Patients with any sudden onset of pain or bleeding should be evaluated urgently, given the potentially catastrophic nature of organ or vascular rupture. (See 'Symptoms requiring urgent evaluation' below.)

●Managing the risk of vascular rupture

•Cardiovascular monitoring – We refer all patients with vEDS to an expert in cardiovascular disease for evaluation; some patients may benefit from ongoing comanagement with cardiology for monitoring. At the time of diagnosis, baseline echocardiography and computed tomography angiography (CTA) or magnetic resonance angiogram (MRA) of the vasculature (head, neck, chest, abdomen, and pelvis) are performed [14]. Some experts recommend vascular surveillance using noninvasive measures (ie, ultrasound, CT with or without contrast, or MR imaging [MRI]) for the detection of asymptomatic aneurysms and dissections [10]. (See 'Cardiovascular complications' below.)

•Pharmacologic management – Some experts recommend the use of drugs such as beta blockers and/or an angiotensin receptor blocker to control blood pressure [10]; these medications are usually managed by cardiology or the primary care provider.

In addition, there are limited data to suggest that celiprolol, a long-acting beta-1 adrenoreceptor antagonist and partial beta-2 agonist, may reduce the occurrence of major arterial rupture or dissection in vEDS [15]. One study showed a 4.7 percent risk of a significant vascular event in treated individuals compared with 12 percent in controls [16]. Celiprolol is not approved by the US Food and Drug Administration (FDA) for use in the United States.

•Avoidance of vascular trauma – Patients should generally avoid arterial and, when feasible, intramuscular punctures. Given the high complication rate and risk of mortality, they should also avoid arteriography unless it is required preoperatively to identify a source of bleeding [10,12,13]. When feasible, endovascular procedures may have lower risks compared with open surgery; however, data are limited to small case series, and estimates of mortality risk in patients requiring such procedures are variable [12,13,17].

●Managing the risk of organ rupture

•Prevention of bowel rupture – We and other experts do not ask patients to undergo baseline gastrointestinal evaluation because specific predictive factors for bowel rupture have not been identified [10]. In addition, we avoid routine and virtual colonoscopies because of the risks of colonic perforation from instrumentation and/or insufflation. Instead, we advocate for the use of alternative, noninvasive measures for colon cancer screening [10]. (See "Screening for colorectal cancer: Strategies in patients at average risk".)

Patients may also benefit from conservative measures to avoid constipation, such as hydration, high-fiber foods, and, if needed, stool softeners. (See "Management of chronic constipation in adults", section on 'Initial measures for all patients'.)

•Reproductive counseling – We counsel female patients with vEDS who are in their childbearing years about the high risk for uterine and vascular ruptures during pregnancy. In addition, we counsel patients that there is a 50 percent chance for each child of an affected individual to inherit the pathogenic variant and be affected by vEDS. (See 'Reproductive options and pregnancy' below.)

Kyphoscoliotic Ehlers-Danlos syndrome — Patients with kEDS should be seen in consultation by an expert in orthopedic management of spine disease and may benefit from joint follow-up with the consultant. The following concerns require particular attention in the management of kEDS [18]:

●Management of kyphoscoliosis. Patients should undergo orthopedic spine consultation and follow-up for care of the scoliosis, in part to prevent development of restrictive lung disease. (See 'Scoliosis/spinal disease' below.)

●Musculoskeletal preventive care and symptom management, including physical therapy for strengthening of large muscle groups, especially the shoulder region, and bracing of unstable joints. (See 'Musculoskeletal pain' above.)

●Measures for the prevention and management of skin fragility, wound healing, and easy bruising. (See 'Skin fragility, wound management, and easy bruising' above.)

●Cardiovascular evaluation and follow-up [18] (see 'Cardiovascular complications' below). A high level of suspicion should be maintained for spontaneous arterial dissection in patients in whom symptoms are present that could be compatible with this condition. (See 'Symptoms requiring urgent evaluation' below.)

●Avoidance of vascular surgical trauma. Similar precautions to those employed for vEDS are suggested by experts, although published clinical experience is lacking [18]. (See 'Vascular Ehlers-Danlos syndrome' above.)

●Ophthalmologic care. Patients should be followed by an ophthalmologist for ongoing ophthalmologic care with particular attention to high myopia and/or astigmatism as well as early detection of glaucoma, retinal detachment, microcornea, and scleral fragility. (See "Refractive errors in children" and "Visual impairment in adults: Refractive disorders and presbyopia" and "Retinal detachment".)

●Audiology. Patients with kEDS type 2 should be screened for hearing loss. (See "Hearing loss in children: Screening and evaluation" and "Evaluation of hearing loss in adults".)

Management of certain clinical scenarios

Anesthetic and perioperative management — Patients with EDS who undergo surgical procedures should receive care from providers and facilities with knowledge of EDS. Management will differ by type of EDS and the severity of disease, but several general principles apply including the following [19]:

●Careful preoperative evaluation and determination of the EDS type, which is critical for proper care.

●Assessment of bleeding history, cardiovascular history, and difficulties with intubation and wound healing.

●Use of noninvasive monitoring whenever possible.

●Careful attention to patient positioning for the procedure, with appropriate padding and caution when using tourniquets in those with tissue fragility.

●Careful fluid monitoring and blood pressure control throughout the pre-, intra-, and postoperative periods.

●Attention to difficulties with airway management, which are more frequent than in the general population, including potential bleeding, tissue damage, and joint dislocation.

●Careful assessment of patients with temporomandibular dysfunction and cervical spine instability.

●Management of bleeding, which should be individualized. Some patients benefit from use of desmopressin.

●Local anesthesia may be less effective in some patients [20].

Reproductive options and pregnancy

Counseling and genetic testing — We provide all patients with appropriate education, counseling, support, and medical consultation to help facilitate individualized decision-making regarding pregnancy and family planning. Patients should also receive genetic counseling regarding the risk to their potential children of EDS and additional testing which may facilitate decision-making. (See "Genetic testing".)

In those in whom the genetic mutation is known, preimplantation genetic testing (PGT) or prenatal diagnosis may be performed. In general, first-trimester deoxyribonucleic acid (DNA) testing is by chorionic villus sampling (CVS), and second trimester testing is by amniocentesis. Caution should be taken with these invasive procedures in patients with EDS given the risk of serious maternal and fetal complications such as bleeding, separation, and rupture of membranes [21,22]. Intrauterine treatment or prevention of EDS is not available for the fetus. (See "Chorionic villus sampling" and "Diagnostic amniocentesis".)

Pregnancy, delivery, and postpartum care — Patients with EDS should be considered at high risk and followed by a maternal-fetal-medicine specialist [23-25]. Considerations for patients with EDS during specific time points include the following:

●Pregnancy – Ligamentous laxity and tendon rupture can complicate the third trimester in patients with most types of EDS. (See "Maternal adaptations to pregnancy: Musculoskeletal changes and pain", section on 'Pelvic girdle pain'.)

●Labor and delivery – Premature delivery due to cervical insufficiency or premature rupture of membranes is common. Labor and delivery may progress rapidly in patients with hEDS, but there is no clear advantage to either vaginal or Cesarean delivery [8]. Uterine rupture can occur in several types of EDS, most commonly in vEDS [26,27]. Patients with vEDS may benefit from performing a scheduled cesarean delivery [26]. (See "Uterine rupture of the unscarred uterus: Risk factors, clinical manifestations, management, and outcome".)

●Postpartum – After delivery, postpartum hemorrhage, extension of episiotomies, and uterine and bladder prolapse can occur; patients with the classical and vascular forms of EDS are at greatest risk [26,27]. (See "Overview of postpartum hemorrhage" and "Effect of pregnancy and childbirth on urinary incontinence and pelvic organ prolapse".)

Patients with chronic postpartum dyspareunia should be evaluated for occult prolonged diastasis of the pubic symphysis, as painful postpartum separation of the pubic symphysis may require surgical repair. (See "Approach to acute abdominal/pelvic pain in pregnant and postpartum patients", section on 'Pubic symphysis separation'.)

Additional considerations during pregnancy for patients with specific types of EDS include the following:

●cEDS – Although all pregnant patients are counseled about signs and symptoms of preterm labor and prelabor rupture of membranes, this is especially important in patients with cEDS given their probable increased risk of these complications [7]. (See "Preterm prelabor rupture of membranes: Clinical manifestations and diagnosis".)

●vEDS – Patients with vEDS are at high risk for uterine and vascular ruptures. Maternal mortality for vEDS is estimated at 5.7 percent per pregnancy [23,26]; in a systematic review including six studies with a total of 412 pregnancies, the maternal mortality rate was 5.7 percent (22 of 386 patients), and deaths were attributed to vascular rupture or dissection (12 patients), uterine rupture (7 patients), and rupture of other organs (1 patient) [26]. There were no deaths in the group of 28 patients who underwent a scheduled cesarean delivery, although the mode of delivery was only specified for 30 percent of patients. In addition, among the 203 patients with available data, 23 (11 percent) developed obstetric anal sphincter injury (OASI). In another study, survival data indicated that pregnancy did not appear to affect overall mortality compared with nulliparous females with vEDS [28].

The 2018 European Society of Cardiology (ESC) guidelines for the management of cardiovascular diseases during pregnancy describe pregnancy for patients with vEDS as a "very high-risk undertaking" that is not advised, recommending shared decision-making for those females with vascular EDS who contemplate pregnancy [29]. The ESC also suggests use of the beta blocker celiprolol throughout pregnancy in females with thoracic aortic disease associated with vEDS; this medication is notably not approved by the FDA for use in the United States. (See 'Vascular Ehlers-Danlos syndrome' above.)

It is uncertain which mode of delivery might have any less or greater risk in patients with vEDS. Some have recommended scheduling a cesarean delivery at 37 weeks of gestation to minimize morbidity and mortality in the peripartum period [26]. For those undergoing a trial of labor, it is unclear whether prophylactic mediolateral episiotomy may be beneficial given the increased risk of OASI. We counsel patients about potential risks related to spinal or epidural anesthesia; some providers avoid these forms of anesthesia [19], although data to support this approach are limited.

Avoidance of fluoroquinolones — We avoid using fluoroquinolone antibiotics for patients with all types of EDS, particularly those who have an elevated risk of vascular complications. Based on observational studies in the general population, these medications have been associated with an increased risk for aortic dissections, tendonitis, and, for levofloxacin, tendon rupture [30-33]. While data in patients with EDS are very limited, their underlying defect in connective tissue may further increase such risks. (See "Fluoroquinolones", section on 'Aortic aneurysm and dissection'.)

MONITORING — 

Patients with Ehlers-Danlos syndrome (EDS) require monitoring for symptoms that should prompt urgent evaluation (eg, for suspected vascular or organ rupture) and for conditions that may be asymptomatic (eg, aneurysms). Patients with EDS should have baseline ophthalmologic and cardiovascular evaluations, including echocardiography, for detection of cardiac involvement, including valvular disease. The frequency of subsequent monitoring depends upon the type of EDS and presence or absence of clinical findings. Patients with EDS who develop scoliosis, peripheral neuropathy, or new neck pain should be evaluated and monitored as needed by an expert in spine care.

Symptoms requiring urgent evaluation — Certain symptoms should prompt suspicion for potentially serious complications of EDS. These include:

●Sudden onset of pain or bleeding – Patients with EDS who experience sudden, unexplained onset of pain or bleeding should immediately undergo emergency evaluation, given their increased risk for and the catastrophic consequences of organ or vascular rupture. Such events are most commonly seen in patients with vascular EDS (vEDS) or kyphoscoliotic EDS (kEDS) and may affect any part of the vascular tree, especially midsized arteries in the thorax and abdomen, as well as hollow or solid organs, most often the sigmoid colon, liver, spleen, and gravid uterus [12]. Vascular events can rarely occur in patients with classical EDS (cEDS) and other rare types of EDS [34].

Acute chest pain may be a sign of an acute vascular or cardiac event. In addition, costochondritis and rib-sternal subluxations due to EDS can each be confused with the chest pain of an acute myocardial infarction or other cardiovascular event. (See "Clinical evaluation of musculoskeletal chest pain", section on 'Ribs and chest wall examination' and "Major causes of musculoskeletal chest pain in adults".)

●Sudden onset of dyspnea – Patients with a sudden onset of dyspnea should be evaluated for the possibility of a pneumothorax. (See "Pneumothorax in adults: Epidemiology and etiology" and "Spontaneous pneumothorax in children".)

●Orthostatic intolerance – Patients with sudden onset of orthostatic symptoms should be evaluated urgently to determine if hypovolemia from an acute vascular event is present or whether symptoms may represent autonomic dysfunction. (See 'Postural tachycardia syndrome and dysautonomia' above.)

●Visual loss – Patients who experience sudden onset of visual "blind spots" or silvery flashes should be evaluated for retinal detachment (see "Retinal detachment"). Carotid-cavernous fistulas can also cause sudden vision loss, diplopia, and conjunctival injection. (See "Carotid-cavernous fistulas".)

Cardiovascular complications — Patients with EDS should undergo cardiovascular evaluation, including echocardiography, for detection of cardiovascular complications such as cardiac valvular and vascular disease as well as aortic dilatation. There are no standardized protocols for such evaluation and monitoring in EDS. We and other EDS experts generally obtain baseline screening echocardiography in all pediatric and adult patients. Further evaluation depends upon the findings, type, and severity of EDS, as well as the preferences of the consulting cardiovascular disease specialist [8,10,35], but may include the following for patients with certain EDS subtypes:

●cEDS and hEDS – In patients with cEDS and hypermobile EDS (hEDS) who have an initially normal echocardiogram, we generally perform a follow-up examination in approximately two to five years. For those whose second echocardiogram is also normal and who do not have any symptoms suggestive of cardiac complications, the frequency of examinations can usually be decreased to every five years [8,35]. In adults with cEDS and hEDS who are over age 25 who have had a normal baseline and follow-up examination, no further testing is usually needed unless symptoms arise.

●vEDS and kEDS – Depending on the severity of EDS manifestations, closer monitoring may be required in patients with vEDS and kEDS given the higher risk of cardiovascular diseases. As examples, in patients in whom the aortic diameter is at the upper limit of normal on initial echocardiographic assessment, we perform a repeat study in one year, while those with an increasing aortic root diameter should be reevaluated by the cardiovascular disease consultant.

More information on the symptoms and diagnosis of valvular disease and aortic aneurysms is provided elsewhere:

●(See "Echocardiographic evaluation of the aortic valve".)

●(See "Mitral valve prolapse: Clinical manifestations and diagnosis".)

●(See "Clinical manifestations and diagnosis of thoracic aortic aneurysm".)

In patients with abnormal findings, consultation with an expert in cardiovascular disease should be obtained for further evaluation and follow-up, and to determine whether medication such as beta blockers (eg, celiprolol) or angiotensin receptor blockers are indicated to help prevent further aortic dilation. The management of aortic aneurysms and of aortic and mitral valvular disease is described separately:

●(See "Management of thoracic aortic aneurysm in adults".)

●(See "Natural history and management of chronic aortic regurgitation in adults".)

●(See "Mitral valve prolapse: Overview of complications and their management".)

●(See "Chronic primary mitral regurgitation: General management".)

Ophthalmologic complications — Regular ophthalmologic examinations should be performed in all patients with EDS. They are typically done on an annual basis and sometimes more frequently in patients with abnormal findings. Such examinations help to detect early retinal or scleral fragility, myopia, and glaucoma [36]. Patients with kEDS are at the higher risk of scleral fragility, rupture of the ocular globe, keratoconus, retinal detachment, and glaucoma compared with other forms of EDS [36]. (See "Ehlers-Danlos syndromes: Clinical manifestations and diagnosis", section on 'Kyphoscoliotic EDS'.)

Scoliosis/spinal disease — Patients with EDS who develop scoliosis, peripheral neuropathy, or new neck pain should be evaluated and monitored as needed by an expert in spine care. Evaluation for cervical spine instability with cervical spine flexion/extension films and MRI may be indicated.

Patients with kEDS are at particular risk of developing clinically significant scoliosis in childhood and may require intermittent use of braces or even surgical fusion [2,37,38]. However, scoliosis can be seen in other forms of EDS, including cEDS, hEDS, and arthrochalasia EDS (aEDS). Complications are higher in surgical treatment of EDS patients with scoliosis and careful monitoring of blood pressure and bleeding is critical. (See 'Anesthetic and perioperative management' above.)

More information about the evaluation and management of scoliosis and cervical spine instability is provided separately:

●(See "Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis".)

●(See "Adolescent idiopathic scoliosis: Management and prognosis".)

●(See "Scoliosis in the adult".)

●(See "Overview of musculoskeletal neck injuries in the child or adolescent athlete".)

●(See "Evaluation of the adult patient with neck pain".)

Other complications — Patients may benefit from screening for other conditions that are associated with EDS, including the following:

●Mental health disorders – We routinely screen patients for anxiety and other neuropsychological conditions, as the incidence of these appears to be increased in patients with EDS, such as in hEDS [39]. The approach to screening for such conditions in adults and children is discussed separately:

•(See "Overview of preventive care in adults", section on 'Psychosocial health concerns'.)

•(See "Screening tests in children and adolescents", section on 'Depression and suicide risk screening'.)

•(See "Screening tests in children and adolescents", section on 'Anxiety screening'.)

●Osteopenia and osteoporosis – Decreased bone density has been noted in patients with rarer subtypes of EDS (eg, classical-like [clEDS], kEDS) [40], although it is not clear whether it is intrinsic to EDS or to other factors such as decreased physical activity [41]. While there are no specific recommendations for screening such patients, we consider referring them to endocrinology. The general approach to screening for osteoporosis is discussed separately. (See "Overview of preventive care in adults", section on 'Osteoporosis'.)

PROGNOSIS — 

Ehlers-Danlos syndrome (EDS) generally results in slowly progressive changes in affected areas (eg, hypermobile joints, fragile skin). The prognosis depends upon the type of EDS and the severity with which the individual patient is affected. Patients who frequently engage in activities that stress hypermobile joints often experience more frequent joint dislocations and more musculoskeletal pain.

Survival can vary based upon the type of EDS and associated morbidities:

●Patients with classical EDS (cEDS) and hypermobile EDS (hEDS) are thought to have a normal lifespan.

●In vascular EDS (vEDS), 80 percent of individuals experience a major event by age 40 years [11], and there is a shortened lifespan with a median age of death of 51 years [42].

●The lifespan of patients with kyphoscoliotic EDS (kEDS) is also thought to be decreased, due to the vascular involvement and potential for restrictive lung disease.

The complication rate and surgical outcomes for patients with EDS undergoing orthopedic procedures appear to be worse than for non-EDS patients. In one study, a complication rate of 91 percent, including continued pain (including that associated with hardware), joint subluxations and dislocations, and increased infections has been reported [43].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ehlers-Danlos syndromes and joint hypermobility".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Ehlers-Danlos syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Creating a care team – We refer all patients with Ehlers Danlos syndrome (EDS) to a geneticist or other EDS specialist and those with joint hypermobility to physical and occupational therapy. Additional subspecialist evaluation and management may be required depending on the type of EDS and the specific clinical manifestations. (See 'Creating a care team' above.)

●Conservative measures for all patients – The management of several common issues that affect patients with EDS (eg, joint hypermobility and subsequent pain) is similar regardless of the subtype of EDS and includes patient education (eg, strategies to prevent or reduce symptoms (table 2)), psychosocial support, and joint protection. (See 'Conservative measures for all patients' above.)

●Management of specific clinical manifestations – Musculoskeletal pain in EDS is common and should be treated according to the underlying cause (eg, acute nociceptive pain from an injury, chronic nociplastic pain from repetitive trauma). We evaluate patients who report fatigue for potential sleep disorders and, when appropriate, refer to a sleep specialist. Special precautions may be required to prevent skin trauma and to optimize wound healing in patients with skin fragility. (See 'Management of specific clinical manifestations' above.)

●Management of specific EDS subtypes – Management strategies must be adapted for the subtype of EDS and individualized depending upon the patient’s disease severity and specific clinical manifestations (table 1). As examples, we refer patients with kyphoscoliotic EDS (kEDS) to an expert in orthopedic management of spine disease, and those with vascular EDS (vEDS) to cardiology for regular monitoring and blood pressure control. (See 'Management of specific Ehlers-Danlos syndrome subtypes' above.)

●Management of certain clinical scenarios

•Anesthetic and perioperative management – Patients with EDS who undergo surgical procedures should receive care from providers and facilities with knowledge of EDS. (See 'Anesthetic and perioperative management' above.)

•Reproductive options and pregnancy – We provide female patients with appropriate education, genetic counseling, and medical consultation to facilitate individualized decision-making regarding pregnancy and family planning. (See 'Reproductive options and pregnancy' above.)

•Avoidance of fluoroquinolones – For all patients with EDS who require antibiotic therapy, we suggest avoiding fluoroquinolones (Grade 2C). In the general population, observational studies suggest that these medications may be associated with an increased risk of aortic dissections and tendonitis. (See 'Avoidance of fluoroquinolones' above.)

●Monitoring

•Symptoms requiring urgent evaluation – Certain symptoms should prompt suspicion for potentially serious complications of EDS, including the sudden, unexplained onset of pain or bleeding, orthostatic intolerance, dyspnea, and/or visual loss. (See 'Symptoms requiring urgent evaluation' above.)

•Cardiovascular and ophthalmologic complications – Patients with EDS should have baseline ophthalmologic and cardiovascular evaluations, including echocardiography. (See 'Cardiovascular complications' above and 'Ophthalmologic complications' above.)

•Scoliosis/spinal disease – Patients with EDS who develop scoliosis, peripheral neuropathy, and/or new neck pain should be evaluated by an expert in spine care. (See 'Scoliosis/spinal disease' above.)

●Prognosis – EDS generally causes slowly progressive changes in affected areas (eg, hypermobile joints, fragile skin). The prognosis depends upon the type of EDS and the disease severity. While the lifespan is shortened in patients with vEDS and kEDS, it is thought to be normal in those with cEDS and hEDS. (See 'Prognosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Susan Pauker, MD, FACMG, who contributed to earlier versions of this topic review.