Are You Confident of the Diagnosis?
Erythromelalgia was first described by Mitchell in 1878. In 1938, Smith and Allen first used the term “erythermalgia” to emphasize the increased skin temperature. The two terms are usually used as synonyms, although some authors prefer the latter, in particular for the primary form.
Drenth and Michiels created the set of diagnostic criteria for primary erythromelalgia in 1994. It includes: (1) attacks of bilateral or symmetrical burning pain in the hands or feet; (2) initiation or aggravation of attacks by standing, exercise, or exposure to heat; (3) relief by elevation and cold; (4) warmth, flushedness, and congestion of the affected parts during attacks; and (5) the disorder’s being refractory to treatment.
Yang et al identified mutations of the SCN9A gene in patients with primary erythromelalgia in 2004, indicating that it is a kind of ion channel disorder.
There are two forms of erythromelalgia, primary and secondary. Primary erythromelagia is an autosomal dominantly inherited disorder. It usually occurs in the first decade (early-onset) or second decade (late-onset). The pain and redness are symmetrical and episodic, mainly involving feet at the beginning. Symptoms can extend to the lower legs, hands, and even the ears or face. Severity may progress with age and become constant.
Secondary erythromelalgia is an acquired disorder associated with systemic diseases or drug side effects. The systemic conditions include thrombocytosis, erythrocytosis, systemic lupus erythematosus, diabetes mellitus, hypertension and rheumatoid arthritis. The causative medicines include verapamil, nifedipine and bromocriptine. Secondary erythromelalgia may affect patients of any age, but the elderly are more frequently affected. The symptoms are often milder than the primary form, and relief is obtained after the underlying diseases are properly treated or the offending drug is discontinued.
Characteristic findings on physical examination
Erythromelalgia is a rare disorder characterized by recurrent burning pain, erythema and increased skin temperature in the distal extremities, especially the feet and hands (Figure 1, Figure 2). This condition is induced or aggravated by exercise or warmth, and relieved by cooling the affected sites.
Expected results of diagnostic studies
No specific histopathologic findings are helpful for the diagnosis, although decreased skin autonomic nerves may be seen. For secondary erythromelalgia, serologic tests frequently demonstrate a positive antinuclear antibody or a higher red blood cell and platelet count. For primary erythromelalgia, mutations of SCN9A gene should be strong evidence for diagnosis. This can be performed using a blood sample in several labs around the world.
The differential diagnosis includes:
-Small fiber peripheral neuropathy, sciatica and neuritis. May be distinguished by nerve conduction studies;
-Mercury or mushroom poisoning. Patients have a contact or ingestion history; symptoms are transient, not episodic;
-Fabry’s disease, Raynaud phenomenon and cellulitis. These are distinguished by other accompanying clinical features, such as angiokeratomas in Fabry’s disease, the characteristic finger blanching of Raynaud’s, and the rapid repsonse of appropriate antbibiocs to cellulitis.
Who is at Risk for Developing this Disease?
Epidemiologic studies are limited for this rare disorder. Primary erythromelalgia seems more common than secondary form. Reed and Davis performed a population-based study in Olmsted County MN, USA. They found the incidence of primary and secondary erythromelalgia is 1.1 and 0.2 per 100,000 persons per year respectively. The median age at diagnosis was 61. Women were more often affected than men (2:0.6). But the study is limited by the small sample size.
Patients of less than 20 years old are more likely belong to primary form. Family history is very important, although sporadic onset of the primary form is not rare.
What is the Cause of the Disease?
In primary erythromelalgia, the etiology and pathophysiology are well clarified in recent years. But for the secondary form, these are still poorly understood.
Gain-of-function mutations of the SCN9A gene underlie the pathogenesis of primary erythromelalgia. SCN9A encodes a voltage-gated sodium channel alpha subunit, Nav1.7, which is mainly expressed in nociceptor of peripheral nerves. The mutations can alter the electrophysiologic properties of the channel, lead a series of changes, such as a hyperpolarizing shift in channel activation, depolarizing shift of inactivation, increased deactivation time, lower threshold of action potential and higher frequency firing in neurons. All these alterations can make the channel easier to open and the neuron hyperexcitable, are considered as gain-of-function and contribute to the symptoms in primary erythromelalgia, notabley pain and redness.
By now, more than 10 different point mutations of SCN9A gene have been found in patients of distinct ethnic background. Among these mutation points, I848T and L858F have been reported in several unrelated cases. Most causative mutations are located in the first two domains of the Nav1.7 molecule.
Genotype-phenotype correlation of primary erythromelalgia was illustrated by Han et al in 2009. Using cellular and molecular studies, they found that the mutations in late-onset (usually in second decade) patients produced smaller changes in neuron excitability and channel activity.
In secondary erythromelalgia, increased number and abnormal function of platelets, aberrant vascular dynamics, vasoactive substances and inflammatory mediators may play important roles.
Systemic Implications and Complications
To relieve pain, patients often immerse their extremities in icy cold water. Skin perniosis, infection, ulceration and necrosis are frequently induced by excess cooling (Figure 3). In severe cases, skin gangrene or secondary infection may lead to amputation. Hypothermia and malnutrition are occasionally seen.
The unbearable pain may cause psychiatric problems. Some patients have committed suicide because of the pain.
For primary erythromelalgia, the pain is refractory to treatment. Nonsteroidal antiinflammatory drugs (NSAIDS) are of little help. Some antiarrhythmic agents, such as mexiletine and lidocaine, which block sodium channel nonspecifically, may be of value in some patients. Anticonvulsant agents, such as carbamazepine and gabapentin, also have similar effects.
Topical capsaicin or ketamine cream may be helpful in some cases. Sympathetic block and sympathectomy have been tried in some individuals with severe symptoms, but results have been mixed.
For secondary erythromelalgia, treatment of the underlying disease or discussing the causative drugs are vitally important. Symptomatic treatment with NSAIDS can be effective in these patients.
Optimal Therapeutic Approach for this Disease
For primary erythromelalgia, medication response is highly variable. No well-accepted therapeutic order can be recommended. Proper cooling of the affected sites may reduce pain sensation temporarily. NSAIDS can always be used first. When ineffective, mexiletine, lidocaine, carbamazepine or gabapentin can be tried. Sympathetic block may be tried in severe refractory cases.
For secondary erythromelalgia, physicians can choose aspirin first, since it is often effective.
Psychiatric evaluation (help/support) and pain medicine consultations are recommended for both forms of erythromelalgia.
Patients should be followed up constantly because lifelong treatment is necessary, particularly for those with primary erythromelalgia. Factors that trigger erythrolmelalgia, such as heat, hot drink, alcohol and spicy food should be avoided. Air conditioning and cooling fans are safer than icy water immersion. Elevating the affected extremities may relieve symptoms in some cases.
Unusual Clinical Scenarios to Consider in Patient Management
Erythromelalgia is a rare disorder; the diagnosis may be missed or delayed for years. In some atypical cases, laboratory studies (genetic testing and ruling out secondary causes, combined with vascular studies) can be helpful.
What is the Evidence?
Mitchell, SW. “On a rare vasomotor neurosis of the extremities, and on the maladies with which it may be confounded”. Am J Med Sci. vol. 76. 1878. pp. 17-36. (This article first described and named erythromelalgia.)
Drenth, JP, Michiels, JJ. “Erythromelalgia and erythermalgia: Diagnostic differentiation”. Int J Dermatol. vol. 33. 1994. pp. 393-7. (This article created the set of diagnostic criteria for primary erythromelalgia.)
Yang, Y, Wang, Y, Li, S, Xu, Z, Li, H, Ma, L. “Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia”. J Med Genet. vol. 41. 2004. pp. 171-4. (This article first identified SCN9A mutations in patients with primary erythromelalgia.)
Reed, KB, Davis, MD. “Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota”. J Eur Acad Dermatol Venereol. vol. 23. 2009. pp. 13-5. (This article reported the incidence of erythromelalgia in a county of the US.)
Han, C, Rush, AM, Dib-Hajj, SD, Li, S, Xu, Z, Wang, Y. “Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7”. Ann Neurol. vol. 59. 2006. pp. 553-8. (This article reports performance of a gene test and electrophysiologic study for a case of primary erythromelalgia.)
Dib-Hajj, SD, Yang, Y, Waxman, SG. “Genetics and molecular pathophysiology of Na(v)1.7-related pain syndromes”. Advances in Genetics. vol. 63. 2008. pp. 85-110. (This article provided a detailed review for primary erythromelalgia and other related syndromes, mainly focused on the pathophysiology.)
Han, C, Dib-Hajj, SD, Lin, Z, Li, Y, Eastman, EM, Tyrrell, L. “Early- and late-onset inherited erythromelalgia: genotype–phenotype correlation”. Brain. vol. 132. 2009. pp. 1711-22. (This article first described the genotype–phenotype correlation of primary erythromelalgia.)
Choi, J, Zhang, L, Dib-Hajj, SD, Han, C, Tyrrell, L, Lin, Z. “Mexiletine-responsive erythromelalgia due to a new Nav1.7 mutation showing use-dependent current fall-off”. Exp Neurol. vol. 216. 2009. pp. 383-9. (This article reported a patient with primary erythromelalgia, who carried a new mutation in SCN9A and had a good response to mexiletine.)
Fischer, TZ, Gilmore, ES, Estacion, M, Eastman, E, Taylor, S, Melanson, M. “A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia”. Ann Neurol. vol. 65. 2009. pp. 733-41. (This article reported a patient of primary erythromelalgia got improvement after using carbamazepine.)
Davis, MD, O’Fallon, WM, Rogers, RS, Rooke, TW. “Natural history with erythromelalgia: presentation and outcome in 168 patients”. Arch Dermatol. vol. 136. 2000. pp. 330-6. (This article summarized 168 patients of erythromelalgia, with various treatments and outcomes.)
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