In an adult with hypermobile Ehlers‑Danlos syndrome presenting with persistent fatigue and brain fog, what is the most efficient diagnostic and treatment pathway?

Diagnostic and Treatment Protocol for Fatigue and Cognitive Impairment in hEDS

Initial Screening and Diagnostic Workup

Begin with postural vital signs using an active stand test—measure heart rate increase ≥30 beats/min within 10 minutes of standing without orthostatic hypotension to diagnose POTS, which affects up to 37.5% of hEDS patients and is a primary driver of fatigue and brain fog. 1, 2

Essential Laboratory Testing

• Order celiac disease serological testing immediately, as the risk is elevated up to 20% in hEDS patients and can cause profound fatigue and cognitive symptoms 1
• Measure thyroid-stimulating hormone (TSH) and free T4 to exclude hypothyroidism 3
• Obtain complete blood count (CBC) to rule out anemia 3
• Check vitamin B12 and vitamin D levels, as deficiencies are common contributors to fatigue 3
• Measure baseline serum tryptase only if the patient has episodic multisystem symptoms (flushing, urticaria, wheezing) involving ≥2 physiological systems, suggesting mast cell activation syndrome 4, 1

Autonomic and Neurological Assessment

• Refer for tilt table testing and expanded autonomic function testing if postural vital signs confirm POTS or if symptoms persist despite initial management 1, 2
• Recent evidence shows 79% of hEDS patients have reduced orthostatic cerebral blood flow velocity, which correlates directly with orthostatic dizziness and cognitive impairment 2
• Small fiber neuropathy affects 64-82% of hEDS patients using combined structural and functional criteria, contributing significantly to fatigue 2
• Widespread but mild autonomic failure is present in 90% of hEDS patients and explains many fatigue symptoms 2

Sleep and Pain Evaluation

• Screen systematically for sleep disorders, as sleep disturbances are one of the five primary determinants of fatigue severity in hEDS 3, 5
• Assess chronic pain severity using validated scales, as pain is a major independent contributor to fatigue 5
• Evaluate for concentration problems and psychological distress, which are strongly associated with severe fatigue 5

Treatment Algorithm

First-Line POTS Management (if diagnosed)

• Increase fluid intake to 2-3 liters daily and salt intake to 6-10 grams daily 1
• Prescribe compression garments (30-40 mmHg) for lower extremities to reduce venous pooling 1
• Initiate structured exercise training program starting with recumbent exercises 1

Pharmacological Management for POTS (if conservative measures fail)

• Start fludrocortisone 0.1-0.2 mg daily for blood volume expansion 1
• Add low-dose propranolol (10-20 mg three times daily) for heart rate control 1
• Consider midodrine 5-10 mg three times daily if significant orthostatic hypotension develops 1

Pain and Neuropathic Symptom Management

• Initiate gabapentin first, titrating to 2400 mg daily in divided doses for neuropathic pain components 1
• Alternatively, use pregabalin 75-300 mg every 12 hours 1
• Consider tricyclic antidepressants (amitriptyline starting at 10-25 mg at bedtime, titrating to 75-100 mg) for both pain and sleep 1
• Never prescribe NSAIDs, as they worsen gastrointestinal symptoms in hEDS 1
• Acetaminophen is safe for pain management 1
• Avoid opioids completely for chronic pain management 1

MCAS Treatment (if diagnosed)

• Start histamine H1 receptor antagonists (cetirizine 10 mg daily or fexofenadine 180 mg daily) 1
• Add histamine H2 receptor antagonists (famotidine 20-40 mg twice daily) 1
• Consider mast cell stabilizers (cromolyn sodium 200 mg four times daily) 1
• Advise avoidance of triggers: certain foods, alcohol, strong smells, temperature changes, specific medications 4

Physical Therapy and Exercise Protocol

• Refer to physical therapy with myofascial release techniques before initiating exercise programs 1
• Prescribe low-resistance exercise to improve joint stability through increased muscle tone 1
• Start with recumbent exercises to avoid orthostatic stress, then gradually progress 1
• Focus on preventing deconditioning, which is a major contributor to fatigue 3

Cognitive Behavioral Therapy

• Refer for CBT specifically targeting chronic pain and fatigue management, as this promotes patient acceptance and development of adaptive behaviors with response rates up to 70% 1
• Address psychological distress, which is significantly higher in severely fatigued hEDS patients 5
• Target self-efficacy concerning fatigue, as this is one of five key determinants of fatigue severity 5

Nutritional Support

• Ensure adequate calcium and vitamin D supplementation 1
• Consider gastroparesis diet if upper GI symptoms are present 1
• Provide nutritional counseling to avoid restrictive eating patterns 1

Critical Pitfalls to Avoid

• Do not perform routine MCAS testing in all hEDS patients with isolated fatigue—only test those with episodic multisystem symptoms 4, 1
• Do not delay celiac testing, as this is frequently missed and highly treatable 1
• Avoid attributing all symptoms to hEDS without excluding treatable causes like hypothyroidism, anemia, or celiac disease 3
• Do not prescribe opioids for chronic pain, as this worsens outcomes 1
• Avoid high-impact or high-resistance exercise initially, as this can worsen joint instability 1

Specialist Referrals

• Refer to cardiology or neurology with autonomic expertise for refractory POTS after lifestyle modifications 1, 6
• Refer to allergy/immunology or mast cell disease research center if MCAS is confirmed through clinical and laboratory features 4, 1
• Consider gastroenterology referral for refractory GI symptoms, as 98% of hEDS patients have GI manifestations 6
• Refer to pain management specialist for complex chronic pain requiring multimodal therapy 1

Monitoring and Follow-up

• Reassess postural vital signs at each visit to monitor POTS treatment response 1
• Monitor for new symptoms suggesting autonomic dysfunction progression 2
• Repeat serum tryptase 1-4 hours following symptomatic flares if MCAS is suspected, looking for 20% increase above baseline plus 2 ng/mL 1
• Track functional status and quality of life measures to guide treatment adjustments 3