Erythromelalgia

INTRODUCTION — Erythromelalgia is a rare, acquired or (very rarely) inherited clinical syndrome of intermittently red, hot, painful extremities (picture 1A-G). The syndrome usually affects the lower extremities (predominantly the feet) but may also involve the upper extremities (predominantly hands) and rarely concomitantly involves the face. Patients instinctively try to relieve symptoms by cooling the involved areas with fans, cold water, or ice.

There is no cure for erythromelalgia; therefore, treatment is focused on improving symptoms. Many patients can be successfully managed with behavioral interventions, topical medications, and aspirin. Other interventions may be beneficial when these measures are insufficient.

The epidemiology, clinical features, diagnosis, and management of erythromelalgia will be reviewed here.

EPIDEMIOLOGY — Epidemiologic data on erythromelalgia are limited, but erythromelalgia appears to be rare [1-4]. Population-based studies from the United States, Sweden, and Norway have found incidence rates of less than 2 per 100,000 people per year [1-3].

Erythromelalgia is more common in women than in men and most often occurs in adults [1,2]. In a population-based study in Olmsted County, Minnesota, the age-adjusted incidence rates were 2 (95% CI 1.2-2.7) per 100,000 women and 0.6 (95% CI 0.1-1.1) per 100,000 men [1]. The median age at diagnosis was 61 years (range, 16 to 90 years). Among 27 patients with erythromelalgia identified in a Swedish study, the median age was 49 years (interquartile range 34 to 68 years) [2].

Erythromelalgia is exceedingly rare in children. In the largest series reported of pediatric erythromelalgia, which included 32 patients (including 22 females) evaluated at an academic medical center between 1970 to 2007, the mean age was 14 years (range, 5 to 18 years) and the mean time to diagnosis was 5.2 years [5].

ASSOCIATED DISEASES — Although originally described in association with myeloproliferative diseases (eg, essential thrombocytosis, chronic myelogenous leukemia, polycythemia vera, myelofibrosis), erythromelalgia appears to be associated with underlying myeloproliferative diseases in less than 10 percent of cases [6]. A diagnosis of myeloproliferative disease may precede, follow, or coincide with the development of erythromelalgia. (See "Overview of the myeloproliferative neoplasms" and "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia" and "Clinical manifestations and diagnosis of polycythemia vera".)

A variety of other comorbidities (eg, autoimmune diseases, infections, neoplasms, neurologic diseases), pregnancy, and drug exposures have been reported in patients with erythromelalgia in case reports. However, the relationship between erythromelalgia and these diseases is unclear.

TERMINOLOGY — Some authors have used "primary erythromelalgia" to refer to idiopathic or inherited erythromelalgia and "secondary erythromelalgia" to refer to erythromelalgia that occurs in the setting of an underlying disease associated with erythromelalgia. However, the use of these terms is debated because of the uncertainty regarding the relationship between erythromelalgia and comorbidities other than myeloproliferative disease. Because of this confusion, the author suggests avoidance of the terms "primary" or "secondary" when referring to erythromelalgia.

PATHOGENESIS — The pathogenesis of erythromelalgia is not fully understood. Vascular, neural, and genetic factors may play roles:

●Vascular factors – A role for vascular changes in the pathogenesis of erythromelalgia is suggested by the finding of increased blood flow (up to 10-fold increase as measured by laser Doppler) and temperature in affected areas during symptomatic episodes. Paradoxically, transcutaneous oximetry stays unchanged or is decreased [7,8]. Microvascular arteriovenous shunting is a proposed mechanism for a deficit in skin nutritive perfusion and skin hypoxia [9,10].

●Neuropathy – There appears to be a strong association between erythromelalgia and both large and small fiber neuropathy, suggesting a role for neuropathy in the development of symptoms. Large fiber neuropathy is supported by the finding of abnormal electromyography in up to 60 percent of patients; small fiber neuropathy is supported by the detection of abnormal functional testing of small fibers: abnormal quantitative sudomotor axon reflex tests in up to 80 percent of patients and abnormal thermoregulatory sweat testing in up to 90 percent of patients [7,8,11,12]. Intriguingly, skin biopsies show decreased epidermal nerve fiber density in only 10 percent, suggesting that the small fiber neuropathy is a functional rather than structural/anatomic neuropathy [13].

●Genetics – Inherited erythromelalgia (MIM #133020) is an autosomal dominant disorder that accounts for a small proportion of cases of erythromelalgia [14,15]. In the largest series of consecutive patients with erythromelalgia (n = 168), only six patients (4 percent) had a first-degree relative with erythromelalgia, including three members of the same family [6].

Inherited erythromelalgia is caused by a heterozygous mutation in the SCN9A gene on chromosome 2q24, which encodes a voltage-gated sodium channel. The mutant channels confer hyperexcitability to peripheral sensory and sympathetic neurons, an effect that may contribute to the intense pain associated with erythromelalgia [16,17]. Exonic mutations in SCN9A (NaV1.7) are found in a minority of patients with erythromelalgia [18-20].

CLINICAL MANIFESTATIONS — Characteristic precipitating factors for episodes of erythromelalgia include an increase in ambient heat or exercise.

Signs and symptoms — During episodes, affected areas (typically distal extremities) become red or violaceous, hot, and painful (picture 1A-G). Swelling occasionally occurs. The episodes are intermittent and generally last for minutes to hours before resolving.

Episodes occur in association with precipitating factors (eg, increase in ambient heat or exercise) and often occur at night (perhaps associated with increased ambient heat in bed). The number of episodes per day is highly variable.

Erythromelalgia affects the feet (eg, toes, soles of the feet, dorsum of the feet, or entire feet) in approximately 90 percent of patients [6]. The fingers, dorsal hands, or entire hands are affected in approximately 25 percent. Occasionally, erythromelalgia extends to involve more proximal portions of the extremities. Symptoms are usually symmetrical but may be unilateral or more prominent on one side of the body.

Head and neck involvement (eg, ears, nose, cheeks) is infrequent, occurring in 2 to 3 percent of patients. Whether painful flushing of the face (eg, ears, nose, cheeks) alone can be considered to represent erythromelalgia is debated; we favor a diagnosis of erythromelalgia only if feet and/or hands are also involved [21].

Pain during episodes is most commonly described as a burning sensation. The pain can be extreme and may seem out of proportion to the observed clinical findings [6].

Between episodes, the characteristic features of redness, heat, and pain in affected body areas are absent. However, in up to two-thirds of patients, the affected areas are cool to the touch and purple in color (acrocyanosis) between episodes (picture 2). Features of Raynaud phenomenon also have been reported [22].

Clinical course — Erythromelalgia usually remains intermittent. Some patients report that symptoms become more frequent and prolonged over months to years. Occasionally, episodes of erythromelalgia become continuous.

Cooling behaviors — A characteristic feature of erythromelalgia is patient use of cooling techniques to achieve symptom relief. In addition to stopping precipitating actions (eg, stopping exercise, decreasing ambient heat by decreasing room temperature) upon onset of an episode, patients often engage in:

●Use of fans on affected area

●Immersion of the affected area in ice water, snow, or equivalents

●Application of ice packs, bags of frozen vegetables, battery-powered cooling socks or gloves

Potential complications of cooling techniques that may be present in patients with erythromelalgia include "windburn" from fans, signs and symptoms of frostbite secondary to overuse of ice (picture 3), Raynaud phenomenon, and acrocyanosis associated with cold exposure. Chronic immersion of the feet in water may lead to skin maceration, edema, and ulcerations, also known as "immersion foot" or "trench foot" [23].

Quality of life — Erythromelalgia can have a profound negative effect on quality of life. Patients usually avoid precipitating exposures (eg, exercise, warm rooms), which in severe cases can result in becoming housebound, anxious, or depressed secondary to fear of precipitating episodes. Patients with severe symptoms may need to use a wheelchair or remain in bed [6].

PATHOLOGY — Skin biopsies of affected areas show nonspecific findings [24]. Examples of reported findings include smooth muscle cell hyperplasia and/or swelling in arterioles; thickened, arteriolar basement membranes; mild, perivascular, lymphocytic inflammation; and mild, perivascular edema [24].

DIAGNOSIS — Erythromelalgia is a clinical syndrome. The diagnosis is made based upon recognition of characteristic signs and symptoms (ie, intermittent episodes of red, hot, painful extremities that may be precipitated by heat or exercise and improve with cooling). Asking the patient to take photographs of the affected areas during an episode is helpful for confirming redness in patients who are asymptomatic at the time of clinical evaluation (the majority of patients) [22].

Skin biopsies do not aid in the diagnosis of erythromelalgia [24]; the usefulness of biopsies is limited to ruling out other suspected conditions. There are no serologic tests that confirm the diagnosis.

ADDITIONAL EVALUATION — Given the association of erythromelalgia with myeloproliferative disease, a complete blood count with differential should be obtained to assess for signs of underlying myeloproliferative disease. (See 'Associated diseases' above.)

Additional tests, such as electromyography, nerve conduction velocity, and tests for small fiber neuropathy (eg, quantitative sudomotor axon reflex test or thermoregulatory sweat testing), are often abnormal in patients with erythromelalgia, but routine performance of these tests is not essential. The results of these tests do not influence the management of erythromelalgia but provide support for the use of medications for neuropathy in patients with erythromelalgia. (See 'Pathogenesis' above and 'Pharmacologic therapy' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of erythromelalgia includes other causes of extremity pain, such as large or small fiber neuropathy (which can also be a comorbid condition with erythromelalgia) and peripheral artery disease; other causes of red or discolored extremities, such as lipodermatosclerosis, acrocyanosis, Raynaud phenomenon, and cellulitis; and metabolic diseases, such as Fabry disease. The occurrence of red, hot extremities in conjunction with painful episodes distinguishes erythromelalgia form these diseases.

Of note, acrocyanosis and Raynaud phenomenon can occur in patients with erythromelalgia [22]. In particular, the hyperemic phase of Raynaud phenomenon is characterized by skin blushing and can be mistaken for an episode of erythromelalgia. Moreover, Raynaud phenomenon is often triggered by cold (rather than heat) exposure. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)

MANAGEMENT — There is no cure for erythromelalgia. Therefore, interventions are directed at improving quality of life and reducing symptoms.

Data on treatments for erythromelalgia are primarily limited to case reports and small case series, precluding conclusions regarding the best approach to treatment. Treatment typically involves a combination of nonpharmacologic interventions, management of identified underlying myeloproliferative or neurologic disease, pharmacologic interventions, and patient counseling. Pain rehabilitation programs may be useful for patients with debilitating symptoms. A summary of our typical approach to treatment is provided. (See 'Our approach' below.)

Nonpharmacologic measures — Nonpharmacologic measures should be included in the management of patients with erythromelalgia as they can reduce symptoms and may reduce requirements for pharmacologic therapy. In our experience, the following interventions can be helpful for alleviating episodes:

●Avoidance of precipitating factors (increased ambient heat, exercise) as much as possible while maintaining as normal a lifestyle as possible

●Exposure of the affected area to cool water for short periods of time (eg, 5 to 10 minutes every one to two hours)

●Limb elevation

●Fan use for short periods of time (5 to 10 minutes every one to two hours)

Cooling measures can result in complications if used inappropriately or excessively [23]. Patients should avoid applying ice or very cold water directly to the skin. (See 'Cooling behaviors' above.)

Pharmacologic therapy — A variety of topical and systemic therapies have been used for erythromelalgia. Efficacy data are limited and insufficient for conclusions on the best approach to treatment and best treatment regimens. Comparative trials have not been performed.

For most patients, nonpharmacologic measures and topical pain-relieving medications improve symptoms, although the response to individual treatments varies widely.

Topical treatments — Case series and retrospective studies suggest that topical lidocaine (we prefer lidocaine patches since they gradually release lidocaine over a prolonged period [25-27]) and compounded amitriptyline and ketamine [28,29] may improve the pain associated with erythromelalgia. Benefit from topical capsaicin is described in a case report [30]. Other topical treatments that have been suggested, but not formally studied, include nonprescription pain-relieving rubs or patches, diclofenac 1% gel, and gabapentin 6% ointment.

Topical vasoactive medications may be helpful for improving redness, such as compounded midodrine 0.2% [31]. In theory, topical brimonidine tartrate 0.33% and topical oxymetazoline 0.05% might help.

Systemic treatments — Systemic therapy also may be beneficial. Aspirin is a common initial treatment that may be particularly useful for patients with myeloproliferative disease based upon data from case reports and case series [32-34]. In patients with myeloproliferative disease, aspirin may relieve symptoms within days. Other systemic therapies are implemented when behavioral interventions, topical therapies, and aspirin are insufficient.

Common treatments described as beneficial in case reports are agents used for neuropathic pain, including gabapentin [35-39], pregabalin [40,41], venlafaxine [42], and oral amitriptyline [43]. Oral misoprostol appeared beneficial in a double-blind, crossover, nonrandomized study in which 21 patients were treated with placebo for six weeks, followed by misoprostol for six weeks [44].

Additional systemic agents that have appeared useful for improving symptoms in small numbers of patients include sertraline [45], sodium channel blockers (mexiletine [46-52], mexiletine with intravenous lidocaine [52], carbamazepine [37,53]), a variety of vasoactive drugs (beta blockers, calcium antagonists [eg, diltiazem] [6,54], sodium nitroprusside [55-58], high-dose oral magnesium [59], and cyproheptadine [60]), and intravenous immunoglobulin [61].

There have been reports of benefit from systemic glucocorticoids in patients with sudden-onset, severe erythromelalgia who were treated within weeks after the onset of symptoms [62]. In a retrospective study in which 17 of 31 patients (55 percent) treated with systemic glucocorticoids for erythromelalgia had improvement of symptoms, the median duration of disease prior to treatment was shorter among responders (3 months [range 3 to 12 months]) compared with nonresponders (24 months [range 17 to 45 months]) [62].

Rarely, epidural anesthesia or surgical intervention is used for erythromelalgia. Benefit from epidural bupivacaine hydrochloride [63-65] and thoracic or lumbar sympathectomy is described in case reports [66-71].

Treatment of myeloproliferative disease — Although rapid responses to aspirin can occur in patients with underlying myeloproliferative disease, the underlying myeloproliferative disease also should be treated if possible. Limited data from case reports and case series suggest that treatment of myeloproliferative disease may contribute to improvement in erythromelalgia [32,33]. (See 'Pharmacologic therapy' above and "Overview of the myeloproliferative neoplasms".)

Pain rehabilitation programs — In our experience, patients with refractory, debilitating pain may benefit from pain rehabilitation programs. Pain rehabilitation programs use a multidisciplinary and behavioral therapy approach to help restore physical activities and improve the quality of life for patients with chronic pain. In an uncontrolled study of eight patients with incapacitating erythromelalgia who underwent a pain rehabilitation program, scores on all measures of physical and emotional functioning improved [72].

Patient counseling — Fear of precipitating episodes of erythromelalgia may prompt patients to dramatically alter their lifestyles to avoid potential triggers for symptoms. Provided pain is adequately controlled, patients should be encouraged to engage in a normal lifestyle as much as possible. There are no data to show that engaging in precipitating activities will worsen the long-term outcome of erythromelalgia. Many patients can tolerate swimming as a form of exercise that may be less likely to precipitate episodes.

Support groups, such as the Erythromelalgia Association, can be a valuable resource for patients.

Our approach — Given the paucity of data on the management of erythromelalgia, various approaches to treatment are reasonable. Our typical approach for adults with erythromelalgia is as follows:

●Step 1:

•Counseling regarding nonpharmacologic measures to minimize symptoms. (See 'Nonpharmacologic measures' above.)

•Aspirin (325 mg per day, discontinue after one month if no response; aspirin may be particularly beneficial in patients with myeloproliferative disease).

•Trial of topical therapies:

-Compounded amitriptyline 2% combined with ketamine 0.5% in a Lipoderm base (applied three times daily as needed)

Or

-Compounded midodrine 0.2% cream (applied three times daily as needed)

Or

-Lidocaine patch (up to three patches applied to affected areas for 12 hours every 24-hour period)

Patients should be treated with topical therapies for at least two to four weeks to assess efficacy.

•Treatment of underlying myeloproliferative disease.

●Step 2 (patients who fail to respond adequately to step 1):

•Initiation of other systemic treatments:

-Gabapentin (300 mg once daily at bedtime; may be titrated gradually up to a maximum of 2400 mg per day as needed and as tolerated)

Or

-Pregabalin (75 mg twice daily; may be titrated up to 300 mg twice daily as needed and as tolerated)

Or

-Venlafaxine (75 mg per day [in two to three divided doses])

Patients should be treated with these agents for at least two to four months to assess efficacy.

●Step 3 (patients who fail to respond adequately to step 1 and step 2):

•Consider other medications (eg, amitriptyline [43], misoprostol, sertraline [45], sodium channel blockers [mexiletine [46-52], carbamazepine [37,53]]) (see 'Pharmacologic therapy' above)

•Pain rehabilitation (see 'Pain rehabilitation programs' above)

PROGNOSIS — Prognostic data on erythromelalgia are limited. In a review of 168 patients with erythromelalgia, of the 94 patients available for a follow-up questionnaire (mean follow up 8.7 years [range 1.3 to 20 years]), 30 (32 percent) reported worsening of symptoms, 25 (27 percent) reported stable symptoms, 29 (31 percent) reported decreased symptoms, and 10 (11 percent) had experienced disappearance of symptoms [6]. Kaplan-Meier survival curves revealed a decrease in survival compared with that expected in persons of similar age and of the same sex. Notably, three patients committed suicide.

FOLLOW-UP — The frequency of clinical follow-up for erythromelalgia is dependent upon the response to treatment. Once disease is reasonably controlled, patients can return for evaluation as needed.

Patients with erythromelalgia should be monitored for the development of myeloproliferative disease. We obtain a complete blood count with differential once yearly.

SUMMARY AND RECOMMENDATIONS

●Erythromelalgia is a rare syndrome characterized by the intermittent occurrence of red, hot, painful extremities (picture 1A-G). Erythromelalgia most often occurs in adults and is more common in women than in men. (See 'Epidemiology' above.)

●Erythromelalgia is associated with myeloproliferative disease in less than 10 percent of affected patients. A diagnosis of myeloproliferative disease may precede, follow, or occur concurrently with a diagnosis of erythromelalgia. The relationship between erythromelalgia and other systemic diseases is unclear. (See 'Associated diseases' above.)

●The pathogenesis of erythromelalgia is not well understood. Vascular, neural, and genetic factors may play roles. A small subset of patients with erythromelalgia have inherited erythromelalgia. Inherited erythromelalgia is an autosomal dominant disorder caused by mutations in the SCN9A gene. (See 'Pathogenesis' above.)

●Increased ambient heat and exercise are common precipitators of episodes of erythromelalgia. During episodes, the affected areas become red, hot, and painful. The feet are the most common sites of involvement. Symptoms are typically bilateral, and episodes may last from seconds to hours. (See 'Clinical manifestations' above.)

●The diagnosis of erythromelalgia is made based upon the recognition of the classic signs and symptoms. Photographs of the red extremities are helpful in confirming the history and for documenting the redness (picture 1A-G). The histopathologic findings of erythromelalgia are nonspecific, and no serologic tests confirm the diagnosis. (See 'Diagnosis' above.)

●Patients with erythromelalgia should be evaluated for myeloproliferative disease. Patients without evidence for myeloproliferative disease at the time of diagnosis should be monitored over time for the development of myeloproliferative disease. (See 'Additional evaluation' above and 'Follow-up' above.)

●Data on treatment of erythromelalgia are limited, and responses to individual treatments vary widely. We suggest an initial therapeutic approach that includes patient counseling regarding methods to minimize symptoms, topical therapy, and aspirin (Grade 2C). For patients with underlying myeloproliferative disease, we also suggest treatment of the myeloproliferative disease (Grade 2C). (See 'Management' above.)