How should a patient with hypermobile Ehlers-Danlos syndrome (hEDS) and chronic fatigue, presenting with persistent tachycardia, be evaluated and managed?

Evaluation of hEDS Patient with Chronic Fatigue and Persistent Tachycardia

Yes, the presence of persistent tachycardia in an hEDS patient with chronic fatigue fundamentally changes the evaluation protocol—you must systematically screen for postural orthostatic tachycardia syndrome (POTS), cardiovascular autonomic dysfunction, and small fiber neuropathy, as these conditions affect 33-90% of hEDS patients and directly contribute to both tachycardia and fatigue. 1, 2

Initial Cardiovascular Assessment

The observed elevated heart rates require immediate structured evaluation:

• Measure postural vital signs with active stand test: Document heart rate increase ≥30 beats/min within 10 minutes of standing without orthostatic hypotension to diagnose POTS, which affects 33% of hEDS patients 1, 2
• Obtain 12-lead ECG: Look specifically for short PR interval, prolonged QT interval, prominent Q waves in leads I, aVL, V5-V6, and QRS widening ≥120 ms—all characteristic findings in hEDS 3
• Perform 24-hour ambulatory ECG monitoring: This detects conduction abnormalities, diminished heart rate variability indicating sympathetic predominance, and ventricular arrhythmias that occur in proportion to autonomic dysfunction severity 4, 3
• Order transthoracic echocardiography: Screen for aortic root dilation (occurs in 25-33% of hEDS), mitral valve prolapse (7.5% prevalence), and tricuspid/mitral valve insufficiency 1, 5

Autonomic Function Testing

Given the high prevalence of autonomic dysfunction in hEDS:

• Refer for formal tilt table testing if postural vital signs confirm POTS or if symptoms persist despite initial management 1, 6
• Request expanded autonomic testing including Valsalva maneuver, deep breathing response, and sudomotor assessment—90% of hEDS patients demonstrate widespread but mild autonomic failure on comprehensive testing 2
• Measure orthostatic cerebral blood flow velocity if available, as 79% of hEDS patients show reduced orthostatic CBFv correlating with dizziness and fatigue 2

Comprehensive Fatigue Evaluation

The chronic fatigue requires systematic exclusion of treatable causes:

Laboratory Testing

• Complete blood count: Rule out anemia contributing to fatigue 7
• Thyroid-stimulating hormone: Exclude hypothyroidism 7
• Fasting glucose and hemoglobin A1c: Screen for diabetes 4
• Comprehensive metabolic panel: Assess renal and hepatic function 4
• Iron studies including ferritin: Screen for iron deficiency even without anemia, as supplementation improves fatigue in similar conditions 8
• Vitamin B12 and folate levels: Identify nutritional deficiencies 7

Screening for Common Comorbidities

• Baseline serum tryptase level: Obtain ONLY if patient presents with episodic multisystem symptoms (flushing, urticaria, wheezing) involving ≥2 physiological systems to screen for mast cell activation syndrome 1, 6
• Celiac disease serological testing: Perform earlier in hEDS patients with any GI symptoms, as risk is elevated 1
• Sleep study referral: Evaluate for sleep disorders contributing to fatigue 7

Skin Biopsy for Small Fiber Neuropathy

This is a critical but often overlooked evaluation:

• Order distal leg skin biopsy: Small fiber neuropathy occurs in 64% using structural criteria and 82% using combined structural/functional criteria in hEDS patients, directly contributing to fatigue and autonomic symptoms 2

Cardiovascular Surveillance Protocol

The presence of tachycardia mandates ongoing monitoring:

• Annual echocardiography if aortic root is normal at baseline 1
• Every 6-month echocardiography if aortic diameter >4.5 cm or growth rate >0.5 cm/year 1
• Consider MR angiography if there are any features suggesting vascular complications, though this is rare in hypermobile type 1

Critical Pitfalls to Avoid

• Do not dismiss tachycardia as anxiety: The overlap between hEDS and chronic fatigue syndrome is substantial, with orthostatic intolerance present in essentially all cases when systematically evaluated 9, 7
• Do not perform routine genetic testing for hEDS: No causative genes have been identified, making such testing clinically useless 1
• Do not universally test for MCAS: Reserve testing for patients with episodic multisystem symptoms, not isolated fatigue or tachycardia 1, 6
• Do not attribute all symptoms to deconditioning: While deconditioning contributes, the underlying autonomic dysfunction and small fiber neuropathy require specific identification and treatment 7, 2

Specialist Referrals Based on Findings

If POTS Confirmed

• Refer to cardiology or neurology with autonomic expertise for management including fluid/salt expansion (2-3 L fluid, 10 g sodium daily), compression garments, fludrocortisone for volume expansion, low-dose propranolol for heart rate control, and midodrine for significant orthostatic hypotension 6

If Small Fiber Neuropathy Confirmed

• Refer to neurology for neuropathic pain management and consideration of immunomodulatory therapy if inflammatory markers are elevated 2

If Refractory Symptoms

• Refer to medical genetics for comprehensive phenotyping and exclusion of other EDS subtypes, particularly if there are any vascular features 1, 6

Treatment Considerations for Fatigue

While addressing the underlying autonomic dysfunction:

• Initiate supervised exercise training starting at very low intensity and gradually increasing based on tolerance—this is the most evidence-based intervention for improving functional capacity and preventing deconditioning 8, 7
• Consider physical therapy for biomechanical problems common in hEDS that contribute to fatigue 7
• Avoid opioids for chronic pain management 1
• Treat specific symptoms such as headache, menstrual dysfunction, or myalgia with targeted medications 7

The key distinction from standard fatigue evaluation is the mandatory systematic screening for autonomic dysfunction and small fiber neuropathy, which are present in the vast majority of hEDS patients and directly explain both the tachycardia and fatigue symptoms.