Investigations for Erythromelalgia
All patients with suspected erythromelalgia require a complete blood count with differential and platelet count to screen for myeloproliferative disorders, thermoregulatory sweat testing to assess small-fiber neuropathy, and consideration of SCN9A genetic testing in early-onset or familial cases. 1
Mandatory Hematologic Screening
Obtain a complete blood count with differential and platelet count in every patient to detect underlying myeloproliferative disorders (essential thrombocythemia, polycythemia vera), which are present in approximately 5% of erythromelalgia cases. 1, 2
Recognize that erythromelalgia symptoms can precede the diagnosis of a myeloproliferative disorder by a median of 2.5 years, making initial normal results insufficient to exclude this association. 1, 3
Maintain periodic CBC monitoring every 6–12 months even after an initially normal result, as myeloproliferative disorders may remain subclinical for years after symptom onset. 1
Any abnormal hemoglobin level, white blood cell count, platelet count, or immature cells in the differential should prompt immediate hematologic evaluation, as these findings are not seen in primary erythromelalgia. 3
Neurophysiological Testing (Highest Diagnostic Yield)
Perform thermoregulatory sweat testing as the primary functional assessment, which reveals marked abnormalities in approximately 90% of erythromelalgia patients and represents the most sensitive test for small-fiber cutaneous neuropathy. 1
Conduct quantitative sudomotor axon reflex testing (QSART) to provide additional functional evaluation of small-fiber autonomic function. 1
Obtain electromyography and nerve conduction studies, which demonstrate abnormalities in nearly 50% of patients, supporting the presence of large-fiber involvement. 1, 2
Avoid relying on skin biopsy for epidermal nerve fiber density as a primary diagnostic tool, as it shows decreased density in only a minority of cases and has inferior sensitivity compared to functional sweat testing. 1
Genetic Testing
Consider SCN9A genetic testing in patients with early-onset disease (childhood or adolescence) or positive family history, as approximately 5% of cases are familial with autosomal-dominant inheritance. 1, 2
Identify SCN9A mutations encoding Nav1.7 sodium channels in many familial cases to confirm a molecular basis for the disorder. 1, 4
Understand that some families with primary erythromelalgia lack detectable SCN9A variants, indicating involvement of additional unidentified genes. 1, 2
Screening for Secondary Causes
Test blood glucose levels to exclude diabetes as a potential cause of small-fiber neuropathy presenting with erythromelalgia-like symptoms. 1
Screen for autoimmune conditions using ANA and ENA testing to identify systemic lupus erythematosus or other connective tissue diseases that can cause secondary erythromelalgia. 1, 5
Consider antiphospholipid antibody testing if digital necrosis or other thrombotic manifestations are present. 5
Conduct a thorough medication review to identify potential triggering drugs, particularly calcium channel blockers and ergot derivatives. 1, 2
Critical Pitfalls to Avoid
Do not dismiss normal initial CBC results as definitive exclusion of myeloproliferative disease; ongoing surveillance is essential because these disorders may emerge years after erythromelalgia onset. 1, 3
Do not use skin biopsy as a primary diagnostic modality because its sensitivity is markedly inferior to functional sweat testing. 1
Be aware that symptoms are intermittent with normal examinations between episodes, increasing the risk of missed diagnosis if evaluation is not performed during a symptomatic period. 1
Avoid allowing patients to engage in excessive cooling behaviors (prolonged ice or water immersion) while awaiting diagnostic workup, as this can lead to complications such as immersion foot or tissue damage. 2