Treatment and prognosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder

INTRODUCTION — The hypermobile type of Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) are among a group of conditions characterized by joint hypermobility and other frequently shared clinical features (table 1). HSD includes those individuals with a hypermobility-related condition who do not fulfill either the more stringent criteria for hEDS or criteria for another of the hereditary disorders of connective tissue (HDCT) [1,2]. Many of the patients with hEDS and HSD were historically described as having joint hypermobility syndrome (JHS), a term no longer used to classify patients since a major revision of the criteria for JHS and the Ehlers-Danlos syndromes (EDS) in 2017 [3,4].

An overview of the management and prognosis of hEDS and HSD in adults and in younger persons is presented here. The epidemiology, pathogenesis, clinical manifestations, and diagnosis of these conditions are described separately. (See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)

Overviews of the clinical manifestations, diagnosis, and management of the other, rarer types of EDS, and diagnosis and treatment of other conditions with prominent joint hypermobility, including Marfan syndrome, Loeys-Dietz syndrome, osteogenesis imperfecta, and Stickler syndrome, are presented separately:

●Ehlers-Danlos syndromes (see "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes" and "Overview of the management of Ehlers-Danlos syndromes")

●Marfan syndrome and related disorders (see "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders")

●Osteogenesis imperfecta (see "Osteogenesis imperfecta: An overview")

●Stickler and Marshall syndromes (see "Syndromes with craniofacial abnormalities", section on 'Stickler and Marshall syndromes')

WHOM TO TREAT — Isolated joint hypermobility is common in the general population and can affect isolated joints or be more generalized. However, asymptomatic patients who do not experience any consequences of hypermobility do not require any treatment. These individuals would be considered to have a physical trait on the end of the normal spectrum, rather than a medical condition. By contrast, patients with hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) have symptoms that do require treatment. (See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder", section on 'Epidemiology'.)

TREATMENT

Approach to management — Treatment of patients with hypermobility spectrum disorder (HSD) or hypermobile Ehlers-Danlos syndrome (hEDS) should be individualized, based upon the patient's symptoms, clinical findings, and response to treatment interventions [5-8]. Patients can often be managed effectively by their primary care provider, who should coordinate the patient's individualized multidisciplinary care, including patient education regarding the condition, and referrals for physical and occupational therapy and to medical and surgical specialists, depending upon the patient's clinical manifestations. (See 'Patient education and self-management' below and 'Musculoskeletal manifestations and pain' below and 'Fatigue' below and 'Referral for associated manifestations' below.)

The major elements of management for both HSD and hEDS include [5-8]:

●All patients

•Patient education and instruction in self-management (see 'Patient education and self-management' below)

•Physical and occupation therapy, including exercise, therapy, splinting, and orthoses (see 'Physical and occupational therapy and exercise' below)

●Selected patients and patient groups – Certain patients may require additional interventions for the following:

•Chronic widespread pain – Multidisciplinary management with medication, exercise, and psychosocial measures (see 'Chronic widespread pain' below)

•Fatigue – Medical evaluation and medical and behavioral management of pain, sleep, and autonomic dysfunction, if present (see 'Fatigue' below)

•Comorbid anxiety and/or depression – Medical management, psychotherapy, and other behavioral measures (see 'Referral for associated manifestations' below)

•Specialty referrals may be required for additional management issues affecting different organs and systems, including neurologic, gastrointestinal, genitourinary, hematologic, and neuromuscular manifestations (see 'Referral for associated manifestations' below)

Patients for whom the diagnosis is uncertain, or for whom assistance is needed in overall management, should be referred to an expert in the management of such cases, such as clinical geneticist. (See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder", section on 'When to refer'.)

Patient education and self-management — All patients should receive education regarding the nature of the condition, and we advise interested patients to seek further education, self-help, and supportive advice through national organizations such as the Hypermobility Syndromes Association (HMSA), Ehlers-Danlos Support United Kingdom, and The Ehlers-Danlos Society. There are also a number of other national-based charities with helpful local/regional information on their websites.

Musculoskeletal manifestations and pain

Physical and occupational therapy and exercise — We advise all patients to undergo physical therapy for management of the musculoskeletal issues, including use of appropriate exercises, splints, and adaptive devices [9,10]. We refer patients to a physical therapist, when available, who has expertise in the care of hypermobility disorders and related conditions. Patients with significant upper extremity involvement or anatomic abnormalities affecting the feet should be further evaluated and treated by an occupational therapist or podiatrist, respectively.

School-age children with handwriting difficulties should be assessed by an occupational therapist, and those with pronated feet and lower limb pain should be assessed by a podiatrist. Custom made in shoe orthotics can reduce activity-related lower limb pain [11].

●Therapy and exercise – Patients should participate in physical and occupational therapy and exercise adapted for individuals with joint hypermobility to improve joint stability, strength, proprioception, and motor control, with the goals of preventing injury and overcoming physical concerns [9,10]. The approach should be global, with a focus on joint protection, muscular rebalancing, strengthening, and joint stabilization, rather than an isolated view of one joint or body region. Physical therapies should take account of the individual's normal range of joint movement, joint instability, risk of soft tissue injury, and poor proprioception. Therapies that may be of benefit include physiotherapy, occupational therapy, and exercise programs such as Pilates and tai chi. Clinicians should individualize recommendations for exercise and activities depending on the patient's presentation. Patients should receive a regimen to continue at home after completing physical therapy and may need periodic repeat evaluation by a therapist for new or worsening symptoms.  

●Splints and orthoses – We use orthotics and splints for improving joint alignment and providing stability in conjunction with physical and occupational therapy and podiatry evaluation. Patients with excessively pronated feet and lower limb pain may benefit from the provision of custom-made supportive in-shoe orthosis. Orthoses can:

•Protect an acutely injured joint by encouraging rest

•Reduce pain

•Provide intermittent support for chronically injured joints to improve function and ease of daily activities

•Provide temporary additional support during exercise or physical therapy to improve overall ability and compliance with therapies

Chronic widespread pain — Patients with longstanding (over three months), debilitating, and/or widespread musculoskeletal pain symptoms may benefit from individual pain management using a multidisciplinary approach of the type advocated for patients with fibromyalgia or chronic neuropathic pain [7,12]. (See "Approach to the management of chronic non-cancer pain in adults" and "Treatment of fibromyalgia in adults", section on 'When to refer'.)

Pharmacologic treatments may include simple analgesics, such as acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs); and patients may benefit from the use of selected antidepressants, antiseizure medications, and muscle relaxants that are of benefit in the management of chronic pain. Patients may benefit from physiotherapy, psychological therapies such as cognitive behavioral therapy, and multidisciplinary pain management programs. These treatments are described in detail separately. (See "Treatment of fibromyalgia in adults", section on 'When to refer'.)

Patients who do not respond adequately to initial measures for pain management in an outpatient setting should be referred to a specialist team for complex pain management. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Pharmacologic therapy for neuropathic pain, or nociplastic or centralized pain'.)

Treatments for pain appear similarly effective in HSD and hEDS compared with other chronic pain syndromes, both in our experience and that of other experts. There are no randomized trials that have evaluated any differences in outcomes from multidisciplinary pain interventions in complex pain populations with HSD or hEDS compared with those without.

Fatigue — The potential causes of fatigue in each patient should be identified and individually addressed [13]. Underlying metabolic or hematologic causes should be managed accordingly. Otherwise, in HSD and hEDS the management of fatigue is primarily rehabilitative, with a focus on treatment of comorbid conditions that contribute to fatigue including pain, sleep disorders (eg, sleep apnea), autonomic dysfunction, migraine, and anxiety and depression [8]. Individually tailored rehabilitation programs including pacing, lifestyle interventions, activity modification, and supervised and tailored exercise prescriptions are of value in patients of all ages. (see 'Musculoskeletal manifestations and pain' above and "Approach to the adult patient with fatigue" and 'Referral for associated manifestations' below).

Patients with fatigue who are suspected of an endocrine/metabolic disorder (eg, hypothyroidism, hypoadrenalism) as a potential cause for such symptoms may require referral to an expert in endocrinology.

Referral for associated manifestations — Additional referrals depend upon the clinical manifestation. There is a lack of evidence to support a difference in response to treatment for these associated conditions in patients with hEDS or HSD, and therefore, our approach is to use best-evidence pathways for each in patients without hEDS or HSD. The management of these disorders is described in detail separately.

Conditions that may require further referral may include:

●Comorbid anxiety and depression – Patients with diagnosed mood disorders, such as anxiety and/or depression, should be evaluated and managed by experts in the treatment of these conditions. Where possible, such management should be incorporated into multidisciplinary pain management programs [14,15]. (See "Generalized anxiety disorder in adults: Management" and "Unipolar major depression in adults: Choosing initial treatment" and "Pharmacologic management of chronic non-cancer pain in adults", section on 'Pharmacologic therapy for neuropathic pain, or nociplastic or centralized pain'.)

●Orthostatic intolerance and other symptoms of possible autonomic dysfunction – Patients with orthostasis or other symptoms suggesting cardiovascular disease or autonomic dysfunction should be referred to a specialist in these areas (see "Mechanisms, causes, and evaluation of orthostatic hypotension" and "Treatment of orthostatic and postprandial hypotension" and "Postural tachycardia syndrome"). Patients suspected of a cardiac structural anomaly should also be referred to an expert in cardiovascular disease [16].

●Gastrointestinal symptoms – Patients with symptoms of bowel dysmotility or other gastrointestinal disturbance, including rectal prolapse, should be referred to an expert in gastroenterology for evaluation and assistance in management. Irritable bowel syndrome is managed as described separately [17]. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults" and "Treatment of irritable bowel syndrome in adults" and "Overview of rectal procidentia (rectal prolapse)".)

●Genitourinary symptoms – Patients with bladder dysfunction or interstitial cystitis should be referred to an expert in urology or urogynecology. The management of these disorders is described in detail separately. (See "Interstitial cystitis/bladder pain syndrome: Clinical features and diagnosis" and "Evaluation and diagnosis of bladder dysfunction in children" and "Interstitial cystitis/bladder pain syndrome: Management" and "Pelvic organ prolapse in females: Epidemiology, risk factors, clinical manifestations, and management".)

●Symptoms or findings of abnormal hemostasis – Patients with easy bruising or those in whom there is a question of whether a coagulation disorder is also present should be referred to a hematologist with expertise in the evaluation and treatment of bleeding disorders. (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder".)

●Muscle weakness and/or suspected myopathy – Patients with muscle weakness or pain suspected of a myopathy should be referred to an expert in muscle disease, such as a neurologist or rheumatologist. (See "Approach to the patient with muscle weakness" and "Approach to the patient with myalgia".)

●Symptomatic spinal instability – Patients with symptomatic spinal instability should be evaluated by an expert in the treatment of such disorders, such as a neurosurgeon. The major symptoms indicating a need for consultation are the reproducible exacerbation or precipitation of autonomic and/or neurologic symptoms, such as autonomic dysfunction or pain, when the cervical spine is moved in certain directions [18]. For example, intermittent cervical cord compression can be suggested by symptoms that occur with extension or hyperextension of the cervical spine. The evaluation of such patients may include magnetic resonance imaging (MRI) of the cervical spine and base of the skull with the neck in extension to determine whether cord compression and low-grade Chiari-1 malformations are present. Dynamic upright MRI of the cervical spine with flexion/extension views may reveal significant craniocervical instability responsible for inducing transient dysfunction of the cervical cord and extensive autonomic nervous system dysfunction [18,19].

Management in pregnancy and childbirth — People with hEDS and HSD may be at higher risk for certain symptoms and complications during pregnancy and childbirth (see "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder", section on 'Symptoms during pregnancy and childbirth'). Alongside midwifery and medical obstetric care, patients may benefit from early referral to therapy services depending on their symptoms, such as physiotherapy (including pelvic floor therapy), occupational therapy, and podiatry. The indications for elective cesarean section in a person with HSD or hEDS are not different than those for the general population. However, the risk of a vaginal delivery exacerbating symptoms related to laxity in the pelvic girdle and pelvic floor musculature should be considered when evaluating a possible elective cesarean section [20-22].

PROGNOSIS — The long-term prognoses for patients with hypermobility spectrum disorder (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS; and of joint hypermobility syndrome [JHS] by prior criteria) have not been systematically examined, but several features have been associated with an adverse prognosis in our clinical experience. These include pain, dislocations and recurring injury, chronic fatigue, anxiety and depression, and persistent symptoms of autonomic dysfunction.

A three-year follow-up study of pediatric and adolescent patients identified three subgroups, with the group who deteriorated presenting with higher baseline levels of pain and fatigue and with autonomic symptoms [23]. The strongest predictor of functional decline was the number of multisystemic complaints at baseline (skin, eye, cardiovascular, and genitourinary/gastrointestinal); thus, both an extended phenotype and the presence of autonomic symptoms predicted poor outcomes.

Joint hypermobility does decrease with age in many cases. Also, there have been no longitudinal studies exploring the association between joint hypermobility and possible complications such as early-onset or progressive osteoarthritis.

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

SUMMARY AND RECOMMENDATIONS

●Asymptomatic joint hypermobility – Most people with joint hypermobility alone, which may affect 10 to 20 percent of the general population to some degree and affect isolated joints or be more generalized, do not experience any problems from the condition; hence, they will not require any treatment. (See 'Approach to management' above.)

●Approach to management – Treatment for patients with hypermobility spectrum disorder (HSD) or hypermobile Ehlers-Danlos syndrome (hEDS) should be individualized based upon the patient's symptoms, clinical findings, and response to treatment interventions. Patients can often be managed effectively by their primary care provider, who should coordinate the patient's individualized multidisciplinary care, including patient education regarding the condition and referrals for physical and occupational therapy and to medical and surgical specialists, depending upon the patient's clinical manifestations. (See 'Approach to management' above.)

●Patient education and self-management – All patients should receive education regarding the nature of the condition, and we advise interested patients to seek further education, self-help, and supportive advice through national organizations. (See 'Patient education and self-management' above.)

●Musculoskeletal manifestations and pain

•Physical and occupational therapy and exercise – We suggest that all patients with HSD and hEDS undergo physical therapy rather than providing education or self-management strategies alone (Grade 2C). Whenever available, the physical therapist should have expertise in the care of joint hypermobility and related conditions. The therapist can provide assistance in the management of the musculoskeletal issues, including use of appropriate exercises, splints, and adaptive devices. Patients with significant upper extremity involvement or anatomic abnormalities affecting the feet should be further evaluated and treated by an occupational therapist or podiatrist, respectively. (See 'Physical and occupational therapy and exercise' above.)

•Chronic widespread pain – Patients with longstanding (over three months), debilitating, and/or widespread musculoskeletal pain symptoms may benefit from individual pain management using a multidisciplinary approach of the type advocated for patients with fibromyalgia or chronic neuropathic pain. (See 'Chronic widespread pain' above.)

●Fatigue – Fatigue is common for patients with HSD and hEDS and is usually multifactorial. Management is primarily rehabilitative, with a focus on treatment of comorbid conditions that contribute to fatigue including pain, sleep disorders (eg, sleep apnea), autonomic dysfunction, migraine, anxiety and depression, and mast cell activation. Individually tailored rehabilitation programs including pacing, lifestyle interventions, activity modification, and supervised and tailored exercise prescriptions are of value in patients of all ages. (See 'Fatigue' above.)

●Referral for associated manifestations – The management of symptoms and conditions associated with HSD and hEDS is generally the same or very similar to usual management for these conditions in patients who do not have these diagnoses. Conditions that may require further referral include bowel dysmotility or other gastrointestinal disturbance, orthostasis or other symptoms suggesting cardiovascular disease or autonomic dysfunction, bladder dysfunction or interstitial cystitis, easy bruising or other findings suggesting coagulation disorder, muscle weakness or pain suggestive of a myopathy, and symptomatic spinal instability. (See 'Referral for associated manifestations' above.)

●Prognosis – While studies describing prognosis are limited, patients with hEDS and HSD may experience chronic pain, joint dislocations and recurring injuries, chronic fatigue, anxiety and depression, and persistent symptoms of autonomic dysfunction. (See 'Prognosis' above.)