Published online July 1, 2005
PEDIATRICS Vol. 116 No. 1 July 2005, pp. 293-294 (doi:10.1542/peds.2005-0697)

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Erythromelalgia: Small-Fiber Neuropathy by Any Other Name?

Anne Oaklander, MD, PhD
Department of Neurology,
Harvard Medical School,
Boston, MA 02214

To the Editor.

We read the report of Nathan et al1 with interest but regret reuse of the descriptive diagnosis "erythromelalgia" ("red painful limb" in Greek), also known as erythermalgia.2,3 Symptom-based diagnostic names are notoriously imprecise. Patients with similar symptoms from limb cellulitis or large-vessel thrombosis get lumped in and cause the rare unilateral cases. However, the child described by Nathan et al, similar to most erythromelalgia patients, almost certainly has small-fiber axonopathy (SFA) caused by dysfunction or degeneration of the small-diameter unmyelinated and/or thinly myelinated C-fiber and/or A- axons that subserve pain and autonomic function.4 The distal-most parts of axons are damaged first, so symptoms begin in the feet and can progress up the legs and to the hands, as they did in this case. Chronic distal pain is the common denominator of small-fiber dysfunction; the severity and specifics of autonomic involvement vary.5 Neurogenic vasodysregulation produces the characteristic limb color and temperature abnormalities, which can be accompanied by edema and/or sweating abnormalities. The advantage of diagnosing SFA rather than erythromelalgia is that SFA can be confirmed or refuted by neurologic examination and objective tests.

Neuropathies are often equated with large-fiber signs (eg, weakness, muscle atrophy, reflex loss), but these are absent in pure SFA. It is unfortunate that this case report did not present the general physical examination, let alone the neurologic findings. The differential diagnosis and rationale for specific tests performed were also omitted. Conventional electrodiagnostic tests are insensitive for pure SFA (as here) because electromyography reflects only the function of muscles and motor axons, and nerve-conduction studies detect only the high-amplitude, rapidly conducted signals of large-diameter, thickly myelinated axons. Ultrastructural examination of surgically biopsied sural nerves was the classical diagnostic test for SFA, but it leaves focal numbness and sometimes neuralgia.6 A newer test, quantitation of nerve endings present in PGP9.5-immunolabeled skin biopsies,7 is minimally invasive and more sensitive8 and thus useful for testing children. The test could have confirmed whether small-fiber axonal degeneration was present or merely dysfunction. Quantitation of the small-fiber–mediated skin flare induced by intradermal administration of histamine is noninvasive but still experimental.9

Some SFAs are caused by treatable diseases (eg, HIV, diabetes, autoimmune or endoneurial small-vessel disease), and thus additional testing of this child might be considered. A 1-page summary of recommended tests for adults is available at http://neuroskinbiopsy.mgh.harvard.edu. In idiopathic SFA with pediatric onset, genetic causes must be considered, even in sporadic cases. In addition to Fabry's disease, other hereditary sensory and autonomic neuropathies could be considered.10 Mutations affecting the Na_v1.7 sodium channel on chromosome 2q have been associated with this phenotype2,3 and might explain the efficacy of mexiletine, a sodium-channel blocker. The apparent temperature dependence of symptom onset also might prompt consideration of abnormalities of the transient receptor potential superfamily of cation channels that mediate pain and thermal sensation on small-fiber nerve endings.11 Abandoning older, descriptive disease names for those that identify underlying pathologic, physiologic, or molecular causes can improve the quality of medical care as well as advancing knowledge.

REFERENCES

1. Nathan A, Rose JB, Guite JW, Hehir D, Milovcich K. Primary erythromelalgia in a child responding to intravenous lidocaine and oral mexiletine treatment. Pediatrics.2005; 115 (4). Available at: www.pediatrics.org/cgi/content/full/115/4/e504
2. Drenth JPH, Finley WH, Breedveld GJ, et al. The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32. Am J Hum Genet.2001; 68 :1277 –1282[CrossRef][Web of Science][Medline]
3. Yang Y, Wang Y, Li S, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet.2004; 41 :171 –174[Abstract/Free Full Text]
4. Mendell JR, Sahenk Z. Clinical practice. Painful sensory neuropathy. N Engl J Med.2003; 348 :1243 –1255[Free Full Text]
5. Novak V, Freimer ML, Kissel JT, et al. Autonomic impairment in painful neuropathy. Neurology.2001; 56 :861 –868[Abstract/Free Full Text]
6. Dahlin LB, Eriksson KF, Sundkvist G. Persistent postoperative complaints after whole sural nerve biopsies in diabetic and non-diabetic subjects. Diabet Med.1997; 14 :353 –356[CrossRef][Web of Science][Medline]
7. Amato AA, Oaklander AL. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 16-2004. A 76-year-old woman with pain and numbness in the legs and feet. N Engl J Med.2004; 350 :2181 –2189[Free Full Text]
8. Herrmann DN, Griffin JW, Hauer P, Cornblath DR, McArthur JC. Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology.1999; 53 :1634 –1640[Abstract/Free Full Text]
9. Bickel A, Kramer HH, Hilz MJ, Birklein F, Neundorfer B, Schmelz M. Assessment of the neurogenic flare reaction in small-fiber neuropathies. Neurology.2002; 59 :917 –919[Abstract/Free Full Text]
10. Mendell JR. Hereditary and sensory autonomic neuropathies. In: Mendell JR, Kissel JT, Cornblath DR, eds. Diagnosis and Management of Peripheral Nerve Disorders. New York, NY: Oxford University Press; 2001: 460–476
11. Gunthorpe MJ, Benham CD, Randall A, Davis JB. The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci.2002; 23 :183 –191[CrossRef][Medline]

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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics

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This Article Extract Full Text (PDF) Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Oaklander, A. Search for Related Content PubMed PubMed Citation Articles by Oaklander, A. Related Collections Blood Related AAP Red Book topics: Human Immunodeficiency Virus... Social Bookmarking                         What's this?