What is the differential diagnosis for a patient with mood disturbance, gastrointestinal symptoms, peripheral neuropathy, musculoskeletal pain, tachycardia, and orthostatic symptoms, who has shown improvement in mood and gastrointestinal symptoms with Effexor (venlafaxine)?

Differential Diagnosis

This patient's constellation of symptoms—peripheral neuropathy, tachycardia with orthostatic intolerance, gastrointestinal dysfunction, musculoskeletal pain, and mood disturbance—is highly suggestive of hypermobile Ehlers-Danlos Syndrome (hEDS) with associated Postural Orthostatic Tachycardia Syndrome (POTS) and possible autonomic neuropathy.

Primary Diagnostic Considerations

Hypermobile Ehlers-Danlos Syndrome (hEDS) with POTS

hEDS should be at the top of the differential given the clustering of peripheral neuropathy, orthostatic tachycardia, gastrointestinal symptoms, and musculoskeletal pain. 1

• hEDS is characterized by chronic pain due to both peripheral and central sensitization, overlapping with anxiety and dysregulated autonomic nervous system including POTS 1
• The core features include musculoskeletal pain (neck and upper back pain in this patient), autonomic dysfunction (tachycardia and orthostatic symptoms), and gastrointestinal manifestations 1
• In a survey of 616 hEDS patients, 37.5% reported a diagnosis of POTS 1
• Patients with hEDS and concomitant POTS are more likely to have fibromyalgia, irritable bowel syndrome, gastroesophageal reflux disease, or dysmotility 1
• The peripheral neuropathy (burning, tingling in hands and feet) fits with the small fiber neuropathy commonly seen in hEDS 1
• Symptoms worsening after chiropractic manipulation and dry needling is consistent with the connective tissue fragility in hEDS 1

Postural Orthostatic Tachycardia Syndrome (POTS)

• POTS is defined as a sustained increase in heart rate of ≥30 bpm within 10 minutes of standing from a recumbent position 1
• This patient's elevated heart rate consistently above baseline with significant increase upon standing or walking fits this definition 1
• POTS is a form of dysautonomia characterized by impaired autonomic responses leading to orthostatic intolerance 1
• Different POTS phenotypes include hypovolemic, neuropathic, and primary hyperadrenergic POTS 1
• The association between hEDS and POTS may be explained by vascular laxity and/or peripheral neuropathy, with newer evidence implicating possible autoimmune etiologies 1

Autonomic Neuropathy (Diabetic or Idiopathic)

• Autonomic neuropathy presents with cardiovascular manifestations (resting tachycardia >100 bpm, orthostatic hypotension), gastrointestinal symptoms, and peripheral neuropathy 1, 2
• Resting tachycardia is often an early sign of cardiovascular autonomic neuropathy 2
• Orthostatic symptoms (significant heart rate increase upon standing) are hallmark features of advanced autonomic neuropathy 2
• Gastrointestinal neuropathies may involve any portion of the GI tract with manifestations including dysmotility 1
• Peripheral neuropathy symptoms (burning, tingling in hands and feet) are consistent with small fiber involvement 1, 2
• However, this diagnosis would typically require evidence of diabetes or other systemic causes 1

Small Fiber Neuropathy

• Small fiber neuropathy often presents with burning pain affecting the extremities, with allodynia, involving concurrent involvement of autonomic and somatic C fibers 2
• The peripheral nerve pain, burning, and tingling in hands and feet with variable daily intensity fits this pattern 2
• Autonomic symptoms (tachycardia, orthostatic intolerance, GI symptoms) can accompany small fiber neuropathy 2
• Sudomotor dysfunction testing (Sudoscan) is particularly valuable in documenting small fiber neuropathy 2

Secondary Considerations

Venlafaxine-Related Effects

• Venlafaxine is associated with mean increases in pulse rate of approximately 3 beats per minute compared to placebo 3
• Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients 3
• While venlafaxine can occasionally induce orthostatic hypotension (particularly in geriatric patients), this patient's presentation is more consistent with orthostatic tachycardia rather than hypotension 4
• The improvement in mood and GI symptoms with Effexor suggests therapeutic benefit rather than causation of the other symptoms 3
• Venlafaxine has evidence for treating neuropathic pain, with 56% of participants achieving at least 50% reduction in pain intensity at doses of 150-225 mg 5, 6

Mast Cell Activation Syndrome (MCAS)

• MCAS is characterized by mast cell activation caused by triggers such as food, heat, emotion, and mechanical stimuli 1
• Symptoms typically occur in 2 or more body systems (GI tract, skin, cardiac, nervous system) 1
• In one study of 139 patients with MCAS and refractory GI symptoms, 23.7% had EDS and 25.2% had POTS 1
• However, MCAS diagnosis requires specific testing and this patient lacks the typical skin manifestations 1

Fibromyalgia

• Fibromyalgia commonly overlaps with hEDS and chronic fatigue, with chronic pain as a core feature 1
• The musculoskeletal pain (neck and upper back pain) could be consistent with fibromyalgia 1
• However, fibromyalgia alone would not explain the autonomic dysfunction and peripheral neuropathy 1

Diagnostic Approach

Initial Evaluation

• Confirm POTS diagnosis with orthostatic vital signs: measure blood pressure and heart rate after 5 minutes supine, then at 1 and 3 minutes after standing 7
• Look for sustained heart rate increase of ≥30 bpm within 10 minutes of standing 1
• Assess for orthostatic hypotension (drop in systolic BP ≥20 mmHg or diastolic BP ≥10 mmHg) 1, 7

Specific Testing for hEDS

• Apply 2017 diagnostic criteria for hEDS, which include generalized joint hypermobility, systemic manifestations of connective tissue disorder, and exclusion of other heritable connective tissue disorders 1
• Examine for skin hyperextensibility, atrophic scarring, and joint hypermobility using Beighton score 1
• Document musculoskeletal manifestations including chronic pain and joint instability 1

Autonomic Testing

• Cardiovascular autonomic reflex tests (CARTs) to assess autonomic function 2
• Heart rate variability testing with deep breathing to detect early autonomic dysfunction 2
• Sudomotor function testing (Sudoscan) to document small fiber neuropathy 2

Peripheral Neuropathy Workup

• Blood glucose and HbA1c to exclude diabetes 1, 8
• Serum B12 with metabolites (methylmalonic acid with or without homocysteine) 8
• Serum protein electrophoresis with immunofixation to exclude monoclonal gammopathies 8
• Consider skin biopsy for intraepidermal nerve fiber density if small fiber neuropathy is suspected 2

Additional Testing if Indicated

• Testing for POTS/MCAS should be targeted to patients presenting with clinical manifestations, but universal testing in all patients with hEDS is not supported by current evidence 1
• Tilt table testing if office orthostatic vital signs are inconclusive 1
• Exclude other causes of tachycardia including hyperthyroidism, anemia, and cardiac arrhythmias 1

Critical Clinical Pitfalls

• Do not dismiss the symptom cluster as anxiety or panic disorder alone—67% of patients with unrecognized SVT fulfilled criteria for panic disorder, and physicians attributed symptoms to panic in 54% of cases 1
• Avoid confusing POTS with heightened awareness of sinus tachycardia or panic disorder—the sustained orthostatic tachycardia and associated symptoms distinguish POTS 1
• Do not attribute all symptoms to venlafaxine—while venlafaxine can cause mild tachycardia, the constellation of symptoms predates or is independent of medication effects 3
• Recognize that symptoms worsening after physical therapy and chiropractic manipulation suggests underlying connective tissue disorder rather than simple musculoskeletal injury 1
• Avoid parenteral nutrition in hEDS patients with GI symptoms—management should focus on multidisciplinary biopsychosocial and rehabilitative approaches rather than invasive interventions 1
• Be aware that hEDS diagnosis is often missed or delayed—the 2017 criteria should be systematically applied when this symptom cluster is present 1