What is the best initial approach to assess and manage a patient with Ehlers-Danlos syndrome and potential orthostatic intolerance or autonomic dysfunction, considering cardiovascular risks?

Initial Assessment and Management of Ehlers-Danlos Syndrome with Suspected Autonomic Dysfunction

Your proposed diagnostic approach is appropriate: echocardiogram should be performed first to assess the mitral valve and rule out coarctation of the aorta, followed by 48-hour Holter monitoring, before considering tilt table testing. 1

Immediate Cardiovascular Evaluation

Echocardiography is the essential first test in all patients with Ehlers-Danlos syndrome, as aortic root dilation occurs in 25-33% of hypermobile and classic EDS cases. 2 This imaging must specifically assess:

• Mitral valve structure and function (prolapse is common in EDS) 2
• Aortic root diameter at multiple levels 2
• Exclusion of coarctation of the aorta 2

If the aortic root is normal, repeat echocardiography every 2-3 years; if dilated (>4.5 cm) or growing >0.5 cm/year, increase monitoring to every 6 months. 2

Autonomic Function Assessment

Before proceeding to tilt table testing, perform bedside orthostatic vital signs with an active stand test. 1 This requires:

• Measuring heart rate and blood pressure supine after 5 minutes of rest 1
• Having the patient stand quietly for 10 minutes 1
• Recording heart rate and blood pressure at 1,3,5, and 10 minutes 1

POTS is diagnosed if heart rate increases ≥30 beats/min in adults (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing, without orthostatic hypotension (systolic BP drop ≥20 mmHg or diastolic BP drop ≥10 mmHg). 1

Tilt table testing should be reserved for patients with negative bedside orthostatic testing but persistent symptoms, or when more detailed autonomic assessment is needed. 1 The active stand test has comparable diagnostic yield for POTS and is more practical in the outpatient setting. 1

Holter Monitoring Strategy

A 48-hour Holter monitor is appropriate to assess baseline heart rate patterns and exclude arrhythmias. 1 This duration is sufficient for most patients with daily symptoms. 1 However, if the patient reports episodic palpitations occurring less frequently than every 48 hours, consider extended Holter monitoring (7-14 days) or event monitoring instead. 1

The Holter should specifically evaluate:

• Resting heart rate trends and whether they are persistently elevated 1
• Heart rate response to activity 1
• Presence of arrhythmias (atrial or ventricular) 1
• Heart rate variability patterns 1

Pharmacologic Management Considerations

Midodrine

Midodrine is a reasonable option for orthostatic intolerance in EDS patients, but only after non-pharmacologic interventions have been optimized. 3 Before initiating midodrine:

• Ensure adequate fluid intake (2-3 liters daily) 4
• Increase salt intake (6-10 grams daily unless contraindicated) 4
• Recommend compression garments (waist-high, 30-40 mmHg) 4
• Implement physical counter-pressure maneuvers 4

Midodrine dosing starts at 2.5-5 mg three times daily, with the last dose taken 3-4 hours before bedtime to minimize supine hypertension. 3 The dose can be titrated up to 10 mg three times daily based on response. 3

Critical midodrine precautions in EDS patients:

• Monitor for supine hypertension (have patient sleep with head of bed elevated) 3
• Avoid if patient has urinary retention, as midodrine acts on bladder neck alpha-receptors 3
• Use cautiously with fludrocortisone due to increased risk of supine hypertension 3
• Assess renal function before initiation, as the active metabolite is renally cleared 3

Fludrocortisone (Florinef)

Fludrocortisone can be considered as an alternative or adjunct to midodrine, particularly in patients with hypovolemic POTS phenotype. 5 However, it carries risks of:

• Fluid retention and peripheral edema 5
• Supine hypertension (especially when combined with midodrine) 3
• Increased intraocular pressure (concerning in EDS patients who may have ocular complications) 3

If using fludrocortisone with midodrine, reduce the fludrocortisone dose or decrease salt intake to minimize supine hypertension risk. 3

Additional Testing to Consider

Mast Cell Activation Syndrome Screening

Do NOT routinely test for MCAS in all EDS patients with isolated orthostatic symptoms. 1 However, if the patient reports episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing, abdominal cramping, neuropsychiatric symptoms), obtain baseline serum tryptase. 1, 2

If MCAS is suspected, collect serum tryptase both at baseline and 1-4 hours after a symptom flare; an increase of 20% above baseline plus 2 ng/mL confirms mast cell activation. 1, 2 If positive, refer to an allergy specialist or mast cell disease research center. 1

Gastrointestinal Evaluation

Given that 98% of hypermobile EDS patients experience GI symptoms 1, 2, and those with comorbid POTS have higher rates of dysmotility 1:

• Consider celiac disease serological testing earlier than you would in the general population, even without classic diarrhea symptoms. 1, 2
• If chronic upper GI symptoms are present with POTS, consider gastric emptying studies (abnormal in up to 30% of hEDS patients). 4
• If reporting incomplete evacuation, consider anorectal manometry or defecography (pelvic floor dysfunction affects up to 50% of hEDS patients). 4

Common Pitfalls to Avoid

Do not proceed directly to tilt table testing without first performing bedside orthostatic vital signs. 1 The active stand test is diagnostic in most cases and avoids unnecessary testing. 1

Do not start pharmacologic therapy before optimizing non-pharmacologic interventions (hydration, salt, compression, exercise training). 4, 5 These foundational measures are often sufficient and avoid medication side effects. 4

Do not prescribe opioids for chronic pain management in EDS patients. 1, 2, 4 Instead, consider neuromodulators (tricyclic antidepressants, SNRIs, gabapentin, pregabalin) for pain control. 4

Do not perform invasive vascular procedures unnecessarily in EDS patients, particularly if vascular EDS is suspected, as these carry risk of fatal complications. 2

Monitor supine blood pressure carefully if initiating midodrine, especially in patients also taking fludrocortisone or with baseline hypertension. 3 Supine systolic pressures ≥200 mmHg occurred in 22% of patients on midodrine 10 mg in clinical trials. 3