What is the recommended treatment approach for Ehlers‑Danlos syndrome?

Treatment of Ehlers-Danlos Syndrome

The treatment of Ehlers-Danlos syndrome requires a multidisciplinary team approach with subtype-specific management: celiprolol and aggressive blood pressure control for vascular EDS, and symptom-directed therapy with physical rehabilitation, gastrointestinal management, and cardiovascular surveillance for hypermobile EDS. 1

Immediate Subtype Determination

• Vascular EDS (Type IV) requires urgent identification because it carries life-threatening arterial rupture risk with median survival of 48 years; immediate COL3A1 genetic testing is mandatory. 2
• Hypermobile EDS (80-90% of cases) has no genetic test available and is diagnosed clinically using the 2017 criteria requiring Beighton score ≥5/9, soft/velvety skin without fragility, and exclusion of alternative diagnoses. 2, 3

Vascular EDS Management

Pharmacologic Therapy

• Celiprolol is the first-line medication for vascular EDS, demonstrating reduction in arterial rupture in retrospective studies and an open randomized trial, though it lacks FDA approval in the United States. 1, 3
• Aggressive blood pressure control is essential to reduce rupture and arterial dissection risk. 1

Surveillance Protocol

• Baseline imaging with Doppler ultrasound, low-radiation angiography, or cardiovascular MRI from head to pelvis is required to evaluate the entire aorta and branching vessels, including renal arteries. 1, 3
• Annual surveillance imaging is mandatory for any dilated or dissected segments. 3

Critical Surgical Precautions

• Avoid all invasive vascular procedures due to fatal complication risk; use exclusively non-invasive imaging. 3
• When surgery is unavoidable, meticulous surgical technique with careful tissue handling and suturing with pledgets for anastomoses is required. 1

Hypermobile EDS Management

Cardiovascular Surveillance

• Echocardiogram every 2-3 years until adult height is reached, and repeat if cardiovascular symptoms develop or significant physical activity increases are planned. 1, 3
• For aortic root >4.5 cm or growth rate >0.5 cm/year, perform echocardiography every 6 months. 1, 3
• Aortic root dilation occurs in 25-33% of hypermobile EDS cases, making this surveillance critical. 2, 3

Musculoskeletal Management

• Low-resistance exercise and physical therapy are the cornerstone of musculoskeletal management. 1, 3
• Occupational therapy and bracing showed the highest efficacy with 70% of patients reporting improvement in one retrospective cohort. 4
• Avoid high-impact activities that increase joint dislocation risk. 5

Gastrointestinal Management

Up to 98% of hypermobile EDS patients experience GI manifestations. 2, 3

• For reflux and gastritis: proton pump inhibitors, H2-blockers, or sucralfate. 3
• For delayed gastric emptying: promotility agents after excluding anatomical/structural disease with gastric emptying studies. 1
• For nausea, vomiting, and abdominal pain: antiemetics, prokinetics, and neuromodulators. 1
• For constipation: laxatives, chloride channel activators (lubiprostone), and guanylate cyclase-C receptor agonists (linaclotide). 1
• For diarrhea: antidiarrheal agents, bile acid sequestrants, and mixed opioid receptor agonists/antagonists. 1
• Consider celiac disease testing in all hEDS patients with any GI symptoms (not just diarrhea) due to elevated risk. 1

Autonomic Dysfunction (POTS)

• Measure postural vital signs with active stand test: heart rate increase ≥30 beats/min in adults (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension confirms POTS. 2, 1
• Tilt-table testing is indicated for borderline cases to phenotype POTS subtypes (hypovolemic, neuropathic, or hyperadrenergic). 2
• Refer to autonomic specialists if lifestyle modifications fail. 2

Chronic Pain Management

Approximately 90% of EDS patients suffer from chronic pain. 6

• Cognitive-behavioral therapy is recommended for anxiety, stress vulnerability, and pain management. 1, 7
• Neuropathic modulators (gabapentin, pregabalin) can be used but are poorly tolerated with 47% reporting adverse effects. 4
• Avoid opioid dependence for chronic pain management, particularly problematic in patients with gastrointestinal manifestations. 2, 3
• Pain self-management sessions including graded exercises, coping, and relaxation strategies showed significant improvement in two case reports. 6

Mast Cell Activation Syndrome Screening

• Obtain baseline serum tryptase ONLY if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing). 2, 1
• Do not perform routine MCAS testing in all hEDS patients with isolated GI symptoms. 2
• Diagnostic threshold: tryptase increase of 20% above baseline plus 2 ng/mL during symptom flares. 2

Critical Pitfalls to Avoid

• Do not diagnose hEDS without genetic testing to exclude alternative diagnoses—26.4% of clinically diagnosed cases had alternative genetic conditions requiring different management. 1, 3
• Do not escalate to invasive nutrition support in hEDS with pain-predominant presentation; most hEDS patients have visceral hypersensitivity rather than true dysmotility. 3
• Avoid invasive diagnostic procedures in vascular EDS—fatal complications have been reported. 2, 3
• Review and possibly reduce stimulant medications (methylphenidate) when POTS symptoms worsen, as they aggravate autonomic instability. 2
• Do not overlook associated conditions—screen for POTS, mast cell activation disorder, chronic urinary retention, and pelvic floor dysfunction. 2, 3

Multidisciplinary Team Composition

The core team should include: cardiologists, vascular surgeons (for vascular EDS), gastroenterologists, geneticists, physical medicine and rehabilitation specialists, clinical psychologists, physical therapists, and occupational therapists. 1, 6