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Original Investigation
February 2017

Epidermal Nerve Fiber Quantification in Patients With Erythromelalgia

Author Affiliations
  • 1Department of Neurology, Mayo Clinic, Rochester, Minnesota
  • 2Department of Dermatology, Mayo Clinic, Rochester, Minnesota
JAMA Dermatol. 2017;153(2):162-167. doi:10.1001/jamadermatol.2016.4404
Key Points

Question  Is the evaluation of abnormally decreased epidermal nerve fiber density a useful tool in the diagnosis of erythromelalgia?

Findings  In this cohort study of 52 consecutive patients with a clinical diagnosis of erythromelalgia, most patients had abnormalities on functional nerve testing, but less than 10% of patients had decreased epidermal nerve fiber density.

Meaning  Skin biopsy for evaluation of epidermal nerve fiber density is not useful in the diagnosis of erythromelalgia; instead, physicians may wish to focus on functional nerve testing, which more reliably identifies this disease.

Abstract

Importance  Erythromelalgia is a clinical diagnosis based on intermittent warmth, erythema, and pain in the distal extremities. One problem facing physicians is how to objectively test for this disease. Given that other painful conditions of the distal extremities (ie, neuropathy related to human immunodeficiency virus, diabetes, or Fabry disease) can be evaluated with a skin biopsy to visualize pathologically decreased densities of the small nerve fibers that innervate the epidermis, one hypothesis is that erythromelalgia could similarly be associated with a loss of epidermal nerve fiber density (ENFD).

Objectives  To examine whether erythromelalgia is associated with a structural loss of small fibers using the ENFD technique and to compare this with functional studies of small nerve fibers.

Design, Setting, and Participants  In a retrospective study of 52 consecutive patients with erythromelalgia who were seen between September 1, 2010, and September 22, 2015, patients were interviewed and examined and their conditions clinically diagnosed by a board-certified dermatologist at a large tertiary referral center, where ENFD testing became a routine part of evaluating erythromelalgia in 2010. Thus, all 52 consecutive patients were included solely based on their clinical diagnosis of erythromelalgia. For quantification of ENFD, observers were masked to all patient information except for name and clinic number.

Main Outcomes and Measures  The hypothesis that patients with erythromelalgia would have decreased ENFD was formulated before data collection. Epidermal nerve fiber density, the primary outcome, is a measurement of the density of small nerve fibers within the epidermis. Secondary measures included functional small fiber evaluation, such as autonomic (heart rate, blood pressure, and sweat testing) and subjective testing of pain.

Results  In this cohort study, 52 consecutively seen patients were identified (female, 42 [80%]; median age, 44 years; age range, 13-82 years). Whereas only 5 of 52 patients (10%) had ENFD at or below the fifth percentile of healthy control individuals, most patients had functional abnormalities of these small fibers; 29 patients (60%) had abnormal sweat test results, 21 (42%) had abnormal pain thresholds, and 20 (38%) had abnormal blood pressure or heart rate control.

Conclusions and Relevance  Unlike other diseases of the small nerve fibers that cause acral pain syndromes, erythromelalgia is not characterized by loss of ENFD. However, most patients have impaired function of these small fibers. Physicians would benefit from performing functional rather than structural small fiber studies when evaluating erythromelalgia.

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