What investigations are recommended to evaluate a patient with suspected erythromelalgia and exclude secondary causes?

Investigations for Erythromelalgia

All patients with suspected erythromelalgia require a complete blood count with differential to screen for myeloproliferative disorders, as these conditions can precede clinical diagnosis by a median of 2.5 years and are present in approximately 5% of cases. 1, 2

Essential Laboratory Screening

The diagnostic workup must systematically exclude secondary causes while confirming the clinical diagnosis:

Hematologic Evaluation

• Complete blood count with differential and platelet count is mandatory, as thrombocytosis from essential thrombocythemia or polycythemia vera underlies erythromelalgia in ~5% of patients 1, 3
• Abnormal hemoglobin, white blood cell count, platelet count, or immature cells in the differential are never seen in primary erythromelalgia and indicate underlying myeloproliferative disease 2
• Periodic monitoring with blood counts is essential even when initial testing is normal, since erythromelalgia symptoms preceded myeloproliferative diagnosis by a median of 2.5 years in documented cases 2

Metabolic and Autoimmune Screening

• Fasting glucose and HbA1c to exclude diabetes mellitus 3
• ANA and ENA panels to screen for autoimmune conditions including lupus erythematosus 3
• Comprehensive medication review for triggering drugs (calcium channel blockers, bromocriptine, ergot derivatives) 3, 4

Neurophysiological Testing

Small and large fiber neuropathy testing is strongly indicated, as neuropathy is present in the vast majority of erythromelalgia patients:

Small Fiber Assessment

• Thermoregulatory sweat testing reveals marked abnormalities in approximately 90% of patients and represents the most sensitive test for small fiber cutaneous neuropathy 1, 3
• Quantitative sudomotor axon reflex test (QSART) provides functional assessment of small fiber autonomic function 1, 3
• Skin biopsy for epidermal nerve fiber density is typically nonspecific, showing decreased density in only a minority of erythromelalgia cases 1

Large Fiber Assessment

• Electromyography and nerve conduction studies demonstrate abnormalities in almost 50% of patients with erythromelalgia 1, 3

Genetic Testing

SCN9A genetic testing should be performed in patients with early onset (childhood/adolescence) or positive family history:

• Approximately 5% of patients have familial erythromelalgia with autosomal dominant inheritance 1, 3
• SCN9A mutations (encoding Nav1.7 sodium channels) are identified in many familial cases 1, 3, 5
• However, some families with primary erythromelalgia lack detectable SCN9A variants, indicating other genes may be involved 1, 3

Clinical Documentation

The diagnosis remains primarily clinical and requires:

• Documentation of the classic triad during a symptomatic episode: intense burning pain of extremities (predominantly feet), erythema, and increased skin temperature 3, 6
• Confirmation that symptoms are triggered by warmth, exercise, or dependency and relieved by cooling and elevation 2, 6

Critical Pitfalls to Avoid

• Never dismiss normal initial blood counts—myeloproliferative disorders may not manifest for years after erythromelalgia onset, requiring ongoing surveillance 2
• Do not rely on skin biopsy as a primary diagnostic tool for erythromelalgia, as it lacks sensitivity compared to functional sweat testing 1
• Recognize that symptoms may be intermittent with normal examination between episodes, potentially leading to missed diagnosis 1

Algorithmic Approach

1. First-tier testing (all patients): CBC with differential and platelets, fasting glucose/HbA1c, medication review
2. Second-tier testing (most patients): Thermoregulatory sweat testing, EMG/nerve conduction studies, ANA/ENA
3. Third-tier testing (selected patients): SCN9A genetic testing if age <20 years or family history present 3
4. Ongoing surveillance: Repeat CBC every 6-12 months even if initially normal 2