What is the differential diagnosis and workup plan for a 32-year-old male with chronic ventricular trigeminy and recurrent erythema nodosum-like lesions, with a normal 2-dimensional (2D) echocardiogram (echo)?

Differential Diagnosis and Workup for Chronic Ventricular Trigeminy with Erythema Nodosum-Like Lesions

The combination of chronic ventricular trigeminy and recurrent erythema nodosum-like lesions in a young adult with normal echocardiography should prompt immediate evaluation for cardiac sarcoidosis, as this represents the most critical diagnosis that could explain both manifestations and has significant implications for mortality. 1, 2

Primary Differential Diagnosis

High-Priority Considerations

• Cardiac Sarcoidosis: This is the most concerning diagnosis given the combination of ventricular arrhythmias and erythema nodosum-like lesions, as sarcoidosis is a well-established cause of both manifestations and can present with normal 2D echocardiography in early stages 1, 2

• Behçet's Disease: This systemic vasculitis can cause both cardiac arrhythmias and erythema nodosum-like lesions, representing another important inflammatory etiology 1, 2

• Inflammatory Bowel Disease (IBD): Both Crohn's disease and ulcerative colitis are associated with erythema nodosum and can have cardiac manifestations including arrhythmias 1, 2

Secondary Considerations

• Drug-induced phenomenon: Certain medications can cause both cutaneous reactions and cardiac arrhythmias, particularly clofazimine (if treating leprosy), which has documented cardiotoxicity with ventricular arrhythmias and skin manifestations 3

• Infectious etiologies: Post-streptococcal reactions, tuberculosis, or Mycoplasma infections can cause erythema nodosum, though isolated ventricular trigeminy would be less typical 1, 2

Recommended Workup Algorithm

Immediate Cardiac Evaluation

• Cardiac MRI with late gadolinium enhancement: This is superior to 2D echocardiography for detecting myocardial inflammation, fibrosis, and infiltrative processes characteristic of cardiac sarcoidosis 4

• 24-hour Holter monitoring: Document arrhythmia burden and assess for more concerning ventricular arrhythmias beyond trigeminy 5

• Exercise stress testing: Evaluate for exercise-induced arrhythmias or ischemia that may not be apparent at rest 5, 6

Systemic Inflammatory Workup

• Chest CT scan: Essential for detecting hilar lymphadenopathy and pulmonary parenchymal changes suggestive of sarcoidosis 1, 2

• Serum angiotensin-converting enzyme (ACE) level: Elevated in approximately 60% of active sarcoidosis cases 1

• Complete blood count with differential, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP): Secondary erythema nodosum cases typically show higher inflammatory markers than idiopathic cases 2

Infectious Disease Screening

• Anti-streptolysin O (ASO) titers: Post-streptococcal infection is the most common identifiable cause of erythema nodosum (32% of cases) 2

• Tuberculin skin test (PPD) or interferon-gamma release assay (IGRA): Primary tuberculosis accounts for 7% of erythema nodosum cases 1, 2

• Mycoplasma serology: Accounts for 3% of secondary erythema nodosum cases 2

Dermatologic Assessment

• Skin biopsy of nodular lesions: Confirm septal panniculitis pattern characteristic of erythema nodosum and rule out other panniculitides; look for Miescher's radial granulomas 7, 1

• Direct examination for vasculitis: True erythema nodosum shows septal panniculitis without vasculitis, which helps differentiate from other conditions 7, 8

Additional Targeted Testing

• Serum electrolytes including magnesium and potassium: Electrolyte disturbances can contribute to ventricular arrhythmias, particularly in conjunction with certain medications 3

• Behçet's disease evaluation: If clinical suspicion exists, assess for oral/genital ulcers, pathergy test, and HLA-B51 typing 1

• Inflammatory bowel disease screening: Fecal calprotectin, colonoscopy if gastrointestinal symptoms present 1

Critical Clinical Pitfalls

• Do not assume normal 2D echocardiography excludes structural heart disease: Cardiac MRI is far superior for detecting infiltrative cardiomyopathies, myocardial inflammation, and early fibrotic changes that may not be visible on standard echocardiography 4

• Avoid premature corticosteroid therapy: Before initiating steroids for erythema nodosum, rule out underlying infections (particularly tuberculosis) as steroids can disseminate occult infections 7, 8

• Do not dismiss ventricular trigeminy as benign: In the context of systemic inflammatory disease, this may represent early cardiac involvement requiring aggressive management and potential ICD consideration 5, 4

• Recognize that approximately 32% of erythema nodosum cases remain idiopathic: However, in a young male with concurrent cardiac arrhythmias, exhaustive evaluation for secondary causes is warranted before accepting an idiopathic diagnosis 2

Risk Stratification for Sudden Cardiac Death

• If cardiac sarcoidosis is confirmed: The presence of ventricular arrhythmias in this context represents a major risk factor for sudden cardiac death, and ICD implantation should be strongly considered per ACC/AHA guidelines 5, 4

• Serial cardiac imaging: If initial workup is negative but symptoms persist, repeat cardiac MRI in 3-6 months as inflammatory cardiomyopathies can evolve over time 6, 4