What is the recommended management approach for a patient with livedo reticularis, dysautonomia with Postural Orthostatic Tachycardia Syndrome (POTS), small fiber neuropathy, hypermobility, endometriosis, and recurrent Clostridioides difficile (C. difficile) infection?

Management of Complex Multisystem Disease with hEDS/HSD, POTS, MCAS, and Recurrent C. difficile

This patient requires an integrated multidisciplinary approach prioritizing treatment of the immune-mediated vascular process (given dramatic response to IV dexamethasone), aggressive management of recurrent C. difficile infection, and systematic evaluation and treatment of POTS and suspected MCAS according to the 2025 AGA guidelines for hEDS/HSD with autonomic and immune dysfunction. 1

Immediate Priorities

1. Address the Immune-Mediated Vascular Process

• The complete resolution of livedo reticularis with IV dexamethasone strongly indicates an immune-mediated vascular process requiring immunosuppressive therapy. This is not typical of primary POTS or hEDS alone. 2, 3
• Dermatological manifestations including livedo reticularis are well-documented in POTS but typically do not resolve completely with corticosteroids unless there is an underlying autoimmune or inflammatory component. 2, 3
• Consider evaluation for antiphospholipid syndrome, vasculitis, or other autoimmune conditions that can present with livedo reticularis and multisystem involvement. 4

2. Manage Recurrent C. difficile Infection Aggressively

• For recurrent C. difficile infection after multiple episodes, fidaxomicin 200 mg twice daily for 10 days is the preferred treatment, or vancomycin in a tapered and pulsed regimen. 5
• Fecal microbiota transplantation (FMT) should be strongly considered after at least 2 recurrences of CDI, which this patient clearly meets. 6, 5
• The tapered vancomycin regimen consists of 125 mg 4 times daily for 10-14 days, then twice daily for 7 days, then once daily for 7 days, then every 2-3 days for 2-8 weeks. 5
• Bezlotoxumab (monoclonal antibody against C. difficile toxin B) should be considered as adjunctive therapy, particularly given her immunocompromised status and severe presentation. 5

3. Confirm and Treat POTS

• Testing for POTS should be performed through postural vital signs with a symptomatic increase in heart rate of 30 beats/min or more with 10 minutes of standing during an active stand or head-up tilt table test in the absence of orthostasis. 1
• Treatment includes increasing fluid intake (2-3 liters daily) and salt intake (10-12 grams daily), exercise training (particularly recumbent exercise initially), and compression garments. 1
• Pharmacological treatments for volume expansion (fludrocortisone), heart rate control (beta-blockers), and vasoconstriction (midodrine) should be considered if conservative measures fail. 1
• Integrated care from cardiology or neurology is essential for refractory cases. 1

4. Evaluate and Treat Suspected MCAS

• Testing for MCAS should be performed given her multisystem symptoms involving at least 2 organ systems (cutaneous with livedo reticularis, GI symptoms, dysautonomia, neurological with small fiber neuropathy). 1
• Serum tryptase levels should be collected at baseline and 1-4 hours following symptom flares; increases of 20% above baseline plus 2 ng/mL are necessary to demonstrate mast cell activation. 1
• If MCAS is confirmed, refer to an allergy specialist or mast cell disease research center for additional testing (urinary N-methylhistamine, leukotriene E4, 11β-prostaglandin F2). 1
• Treatment includes histamine receptor antagonists (H1 and H2 blockers) and mast cell stabilizers (cromolyn sodium), plus avoidance of triggers including certain foods, alcohol, temperature changes, mechanical stimuli, emotional distress, and specific medications (opioids, NSAIDs). 1

Gastrointestinal Management

Diagnostic Evaluation

• Testing for celiac disease should be considered earlier in patients with hEDS/HSD who report a variety of GI symptoms, not only those with diarrhea. 1
• Diagnostic testing for functional defecation disorders with anorectal manometry, balloon expulsion test, or defecography should be considered given the high prevalence of pelvic floor dysfunction in hEDS/HSD. 1
• Timely diagnostic testing of gastric motor functions (gastric emptying study and/or accommodation testing) should be considered after exclusion of structural disease, as abnormal gastric emptying is more common in hEDS/HSD with POTS than in the general population. 1
• There is insufficient evidence to support routine testing for disaccharidase deficiencies or other diet-mediated mechanisms in hEDS/HSD. 1

Treatment Approach

• Medical management should focus on treating the most prominent GI symptoms and abnormal GI function test results, in addition to treating symptoms attributable to POTS and/or MCAS. 1
• Consider a gastroparesis diet (small particle diet) and various elimination diets (low fermentable carbohydrates, gluten-free, dairy-free, low-histamine diets) with appropriate nutritional counseling to avoid restrictive eating. 1
• Avoid opioid medications for chronic pain; if already prescribed, manage through a careful multidisciplinary approach with facilitation of opioid cessation where possible. 1

Addressing the hEDS/TNXB Variant

Genetic and Clinical Evaluation

• The Beighton score should be used to assess joint hypermobility, and if positive, apply the 2017 diagnostic criteria for hEDS or refer to a specialist. 1
• The TNXB variant of uncertain significance raises the possibility of classical-like EDS overlap, which may have implications for surgical risk and tissue fragility. 1
• While endoscopy-related complications such as perforation do not appear increased in adults with hEDS/HSD (except vascular EDS), age- and indication-appropriate endoscopic evaluation should still be performed with awareness of potential tissue fragility. 1

Orthostatic Rehabilitation

• Orthostatic rehabilitation should be considered for patients who have been bedbound or have developed symptoms of orthostatic intolerance, particularly those with pre-existing POTS and hypermobility syndromes. 1
• The rehabilitation program should address both skeletal muscle deconditioning and autonomic postural response deconditioning. 1

Critical Pitfalls to Avoid

Medical Gaslighting and Functional Diagnoses

• This case exemplifies the psychological impact of medical gaslighting in complex multisystem disease, where objective findings (livedo reticularis resolution with steroids, confirmed endometriosis, genetic variant) were initially dismissed as functional. 1
• The dramatic response to IV dexamethasone is objective evidence of an immune-mediated process and should not be dismissed. 2
• Small fiber neuropathy is an objective finding that can be confirmed with skin biopsy showing reduced intraepidermal nerve fiber density. 7

Infection Risk

• Given her history of severe postsurgical infectious complications and recurrent C. difficile, any immunosuppressive therapy for the immune-mediated vascular process must be carefully balanced against infection risk. 6
• Strict handwashing with soap and water (alcohol does not inactivate C. difficile spores) and isolation precautions should be implemented during active CDI. 6
• Discontinue unnecessary antibiotics if possible, as they worsen CDI and increase recurrence risk. 6

Medication Considerations

• Avoid antimotility agents such as loperamide and opiates, especially during acute CDI, as they may worsen outcomes. 6, 8
• When treating comorbid primary headache, use caution with drugs that potentially lower CSF pressure (topiramate, indomethacin) or reduce blood pressure (candesartan, beta-blockers), as they may exacerbate POTS symptoms. 1

Multidisciplinary Coordination

This patient requires coordinated care involving:

• Gastroenterology for GI symptoms, endometriosis, and CDI management 1
• Cardiology or neurology for POTS evaluation and treatment 1
• Allergy/immunology for MCAS evaluation and treatment 1
• Rheumatology or immunology for immune-mediated vascular process 4
• Genetics for TNXB variant interpretation and EDS subtype clarification 1
• Infectious disease for recurrent CDI and consideration of FMT 6, 5
• Physical therapy for orthostatic rehabilitation 1
• Psychology/psychiatry for addressing the psychological impact of medical gaslighting and chronic illness 1

Explicit recognition of the validity of her symptoms and the complexity of her condition is essential for therapeutic alliance and optimal outcomes. 1