A 52-year-old woman with controlled hypothyroidism presented for symptoms of painful burning and discolored feet. She reported 1 to 2 years of progressive disabling lower limb burning pain and numbness associated with fluctuating skin discoloration. Her symptoms were worsened with lower limb dependency, warmth, and exertion. Examination was notable for erythema of the distal legs and feet associated with slightly increased palpable warmth. There was distal pain and temperature sensation loss with relative preservation of vibration and position sense. Distal pulses were normal as were strength and muscle stretch reflexes. Her workup included electromyography and nerve conduction studies that confirmed a length-dependent, predominantly axonal neuropathy. Skin biopsy showed severely diminished intraepidural nerve fiber density consistent with small fiber neuropathy. Laboratory evaluation demonstrated an elevated hemoglobin A1c of 9%, but otherwise no additional contributing factors were identified. She was diagnosed with small fiber predominant neuropathy related to diabetic mellitus and secondary erythromelalgia (EM). Management of her diabetes and symptomatic treatment with gabapentin resulted in partial pain relief.
EM describes a complex group of distinct disorders associated with overlapping, nonspecific symptoms of distal limb (melos) burning pain (algos) and redness (erythos). This largely unrecognized and infrequently diagnosed syndrome was originally described and named by S. Weir Mitchell in 1878.1 Later the modified term, erythermalgia, was suggested due to the presence of exacerbation with heat, but this term is infrequently used today.2
EM is usually broadly categorized as either primary or secondary. Primary forms are usually idiopathic in nature, but a very small fraction of patients have a hereditary or familial form. Secondary cases occur with other medical conditions or as a side effect related to certain medications.
Rare painful condition with an incidence of 1.3 per 100,000 people per year.3
Primary EM is significantly more common, accounting for approximately 85% of all cases.
Most cases of primary EM are idiopathic, but exceedingly rare cases have been described in association with a mutation in the voltage-gated sodium channel alpha-subunit gene (SCN9A) on chromosome 2.4
Secondary EM may be seen in association with various myeloproliferative disorders.5 Over 50% of patients with polycythemia vera may develop EM. The symptoms of EM may precede diagnosis of the underlying myeloproliferative disorder by over 2 years.5,6
ETIOLOGY AND PATHOPHYSIOLOGY
The etiology of most cases of EM remains obscure.
The discovery of a gain-of-function mutation in the voltage-gated SCN9A gene on chromosome 2 in patients with familial EM prompted significant progress in the understanding of idiopathic EM.4,9 The mutation in the SCN9A gene results in a lower threshold for action potential generation in the dorsal root ganglia and sympathetic ganglia causing vascular changes and severe pain that is poorly responsive to treatment. The pattern of inheritance is usually autosomal dominant, but sporadic cases have been described.10
Other conditions or exposures reported in association with EM include but are not limited to toxins associated with certain species of mushrooms, diabetes mellitus, lupus, rheumatoid arthritis, lichen sclerosis, gout, spinal cord disorders, multiple sclerosis, and some drugs (pergolide, nifedipine, verapamil, diltiazem, bromocriptine).6,13,14, and 15
In isolation, each of the cardinal features of EM is nonspecific. However, when clustered in a single patient the symptoms are quite characteristic. Thompson reported criteria that are helpful in excluding other disorders with overlapping symptoms.16 Typically patients present with erythema and burning of the distal limbs, especially the hands and feet (Figures 89-1 and 89-2). Usually the lower limbs are more severely affected. Asymmetric symptoms are unusual in primary EM but common in secondary forms.