Erythromelalgia

The name erythromelalgia is derived from Greek: erythros (“red”), melos (“limb”), and algos (“pain”). Mitchell first described erythromelalgia in the 1870s. Smith and Allen further categorized it in 1938, proposing the term erythermalgia to emphasize the characteristic warmth. They also suggested a distinction between primary (idiopathic) erythromelalgia and secondary erythromelalgia due to underlying neurologic, hematologic, or vascular problems.

Drenth and Michiels distinguished between erythromelalgia and erythermalgia on the basis of responsiveness to aspirin and established the following three categories[3] :

• Erythromelalgia (platelet-mediated and aspirin-sensitive)
• Primary erythermalgia (idiopathic or inherited; aspirin-resistant)
• Secondary erythermalgia (aspirin-resistant)

The first insights into the pathophysiology of erythromelalgia associated with thrombocythemia were gained when skin biopsy samples revealed arteriolar fibrosis and occlusion with platelet thrombi.[4] In this setting, platelets may have abnormal hyperaggregability. Platelet kinetic studies show decreased platelet survival, predominantly due to consumption. Prostaglandins and cyclooxygenase apparently play an important pathogenetic role.

For erythromelalgia not associated with thrombocythemia, the pathophysiology is less clear, but it is known to not involve platelet-mediated inflammation and thrombosis. This is the major reason why Drenth and Michiels distinguished primary erythromelalgia (erythermalgia) from secondary erythromelalgia.[3, 5] Factors postulated to contribute to primary erythromelalgia include the following:

• Postganglionic sympathetic dysfunction
• Hypersensitivity of C-fibers ^[6]
• Maldistribution of skin perfusion resulting from arteriovenous shunting, which leads to an imbalance between thermoregulatory and nutritive perfusion ^{[7, 8]}

Molecular biology may provide the key to understanding this disorder.[9] Drenth et al examined 5 kindreds with familial erythermalgia and found a linkage to chromosomal arm 2q.[10] Novel mutations of voltage-gated sodium channels that are selectively expressed in peripheral nerves have been discovered.[11, 12, 13, 14]

Han et al, in a study investigating whether a genotype-phenotype association exists in early- and late-onset inherited erythromelalgia, found a shift in the patient’s mutation hyperpolarization activation that was smaller than that seen in early-onset disease mutations but similar to another mutation associated with late-onset inherited erythromelalgia.[15]  The test was done by conducting a voltage-clamp and current-clamp analysis of a new sodium channel Na(v)1.7 mutation, Q10R, in a patient who presented with erythromelalgia in the second decade.[15] With current-clamp analysis, Q10r expression induced hyperexcitability in dorsal root ganglion neurons, but the increase in excitability was smaller than that produced by a mutation in early-onset disease. Han et al suggested that their findings reflected a genotype-phenotype relation at the clinical, cellular, and molecular/ion channel levels in inherited erythromelalgia; mutations that produce smaller effects on sodium channel activation appear to correlate with smaller degrees of dorsal ganglion root neuron excitability and later onset of clinical signs.[15]

Primary erythromelalgia may be idiopathic or genetic in origin. Early-onset erythromelalgia can show a familial occurrence. Adult-onset erythromelalgia is idiopathic in the majority of cases, although an inherited case has been reported.[15] In the Mayo Clinic series, 3.6% of cases were familial.[16]

Hereditary erythromelalgia is an autosomal dominant disorder caused by gain-of-function mutations in SCN9A, which encodes a voltage-gated sodium channel, subtype Nav1.7.[10, 11, 12, 13, 14] More than 20 SCN9A mutations have been reported in patients with primary erythromelalgia.[17]

Causes of secondary erythromelalgia include[2] :

• Myeloproliferative disorders
• Infection (eg, HIV, poxvirus ^[18] )
• Medications
• Mercury poisoning
• Mushroom poisoning

Most reported cases of secondary erythromelalgia are due to myeloproliferative disorders with thrombocytosis (most commonly polycythemia vera or essential thrombocytosis). The actual prevalence of erythromelalgia in myeloproliferative disorders is uncertain.

In the Mayo Clinic series, only 9% of erythromelalgia cases were associated with myeloproliferative disorders.[16] In the Norwegian series, 19% of cases were associated with myeloproliferative disorders.[19]

Medications implicated in erythromelalgia include:

• Bromocriptine ^[20]
• Nifedipine, felodipine, and nicardipine
• Epoprostenol
• Topical isopropanol
• Alemtuzumab
• Fumaric acid
• Simvastatin
• Eltrombopag ^[21]
• COVID-19 vaccines ^{[22, 23]}
• Pergolide (withdrawn from the US market in 2007)

Zaza et al screened the World Health Organization pharmacovigilance database for drugs associated with erythromelalgia, to identify drugs that could possibly be repurposed for treatment of Raynaud phenomenon, and found 179 drugs associated with at least 1 case of erythromelalgia. The cluster of drugs with the highest Jaccard index stability consisted largely of calcium channel blockers, along with epoprostenol, alemtuzumab, and fumaric acid.[24]

Other disorders with a reported association with erythromelalgia include:

• Systemic lupus erythematosus (SLE)
• Diabetes mellitus
• Venous insufficiency
• Astrocytoma
• Rheumatoid arthritis
• Gout

Whether the above associations are coincidental is not clear. In one patient with SLE, biopsy results showed vasculitis, and symptoms resolved with immunosuppressive therapy.[25]

Reports in Europe and Japan describe cases due to the ingestion of different species of Clitocybe mushrooms.[26, 27]

United States statistics

Brown reported an incidence of one case per 40,000 patients at the Mayo Clinic in the 1930s. This rate overestimates the incidence in the general population; however, difficulty recognizing mild cases may cause an underestimation of the frequency of these conditions. Early-onset erythromelalgia (primary erythermalgia in the Drenth-Michiels classification) is rare, with fewer than 30 cases reported in the literature. In patients with myeloproliferative disorders, the reported prevalence of erythromelalgia is 3-65%.

International statistics

A case series from Norway shows data similar to that from the Mayo Clinic series.[19] In China, more than 70 outbreaks of epidemic erythromelalgia, with over 80,000 cases reported, have occurred since the mid-20th century; most have been reported between February and March and have coincided with a sharp temperature decline followed by a rapid temperature rise within a few days.[28, 18] A retrospective study in Sweden reported an incidence of 0.36 cases per 100,000 population.[29]

Age-related demographics

In early reports, the median age of onset of the early-onset form was 10 years. Adult-onset erythromelalgia has a wide age distribution, with most cases occurring in the fifth and sixth decades.

An analysis of 32 pediatric cases treated over a 37-year period at the Mayo Clinic concluded that the majority of cases are not inherited and that progress of the disease is variable. No safe or reliable treatment has been established, and erythromelalgia in the pediatric population is associated with substantial morbidity and, sometimes, death.[30]

In the Norwegian case series, patients were classified as having primary or secondary erythromelalgia.[19] The age range in the primary group (which could include patients with early-onset and idiopathic adult-onset disease) was 7-76 years, and the age range in the secondary group was 18-81 years. In the Mayo Clinic series, the median age was 60 years and the age range was 5-91 years.

Sex-related demographics

The early-onset (primary) form is reported to have a male-to-female ratio of 1:2.5. Secondary erythromelalgia was reported to have a male-to-female ratio of 3:2 in a review of 60 cases of erythromelalgia associated with myeloproliferative disorders.

The 1997 case series from Norway showed a female predominance (male-to-female ratio of 1:2), which included a variety of associated factors, of which only 19% were myeloproliferative disorders.[19] The Mayo Clinic series of 168 patients showed a male-to-female ratio of 1:3.[16]

A retrospective review of 168 patients with erythromelalgia examined at the Mayo Clinic between 1970 and 1994 showed a significant decrease in survival compared with that expected for age- and sex-matched control subjects.[16] However, a recent Swedish study that collected data retrospectively for a period of 10.5 years reported no mortality directly related to erythromelalgia, although three patients developed intra-abdominal malignancies on follow-up.[29]

Patients who respond to aspirin have little morbidity. Spontaneous remissions may occur. Early-onset disease is relatively unresponsive to treatment and generally is unremitting.

Patients with erythromelalgia should be aware that a multidisciplinary care team is beneficial to cater to the different aspects of erythromelalgia care. Examples of team members and their roles include:

• Hematologist, to assist with the workup of a potential underlying myeloproliferative disorder
• Psychiatrist and/or primary care physician, to manage anxiety related to future disease episodes
• Dermatologist, to manage skin lesions and any complications

Patients with erythromelalgia require education about the etiology, manifestations, and possible triggers of the disease. 

It is essential to inform patients about the association of erythromelalgia with myeloproliferative disorders and the need to undergo evaluation for such a potential underlying disorder. 

Follow-up with a provider familiar with erythromelalgia is important. An annual complete blood count with differential should be performed to monitor for signs of a developing myeloproliferative disorder.

The classic description of erythromelalgia is a triad of redness, pain, and warmth in the extremities, brought on by warming or dependency and relieved by cooling (see the image below).

Cardinal symptoms of erythromelalgia.

Paroxysmal burning pain has also been reported as a presenting symptom of erythromelalgia.[31] Erythromelalgia has rarely been reported to involve parts other than the extremities (eg, ears, face, genitals).[32, 33, 34]

Symptomatic episodes may last minutes to days. They often begin with an itching sensation and later progress to more severe pain with a burning quality. Pain may be so intense that the patient cannot walk; some must even keep their feet immersed in ice water.

The lower extremities are affected more often than the upper extremities. The soles of feet and toes are most commonly involved. In rare cases, involvement may reach as high as the knees. Involvement is usually bilateral, though not necessarily symmetric. Warming the extremity or placing and maintaining the extremity in a dependent position can exacerbate symptoms; cooling and elevating the extremity can relieve symptoms.

Raynaud phenomenon has been reported to occur between episodes of erythromelalgia, but this may be coincidental.

In cases associated with a myeloproliferative disorder, erythromelalgia usually precedes the diagnosis of the myeloproliferative disorder by a median of 2.5 years. Rapid relief with aspirin is typical of this type of erythromelalgia and can be supportive diagnostically.

Given the association with myeloproliferative disorders, the clinician should inquire about other possible clinical manifestations of myeloproliferative disorders, such as:

• Pruritus
• Thrombotic episodes (eg, transient visual loss)
• Constitutional symptoms
• Abdominal discomfort 

Between episodes, examination findings may be normal.

The affected extremity becomes warm and tender during an episode and appears dusky, red, and sometimes mottled.

Peripheral pulses may be normal or bounding. Acrocyanosis may be observed; rarely, it progresses to distal digital necrosis. Ischemic ulcers may be observed and may become infected secondarily.

Checking for splenomegaly and lymphadenopathy should be part of a comprehensive physical examination in a patient with suspected erythromelalgia.

Complications appear to be more frequent in patients who clearly have platelet-mediated disease.

Ulceration, necrosis, and gangrene of affected extremities are possible. Digital necrosis or skin ueration with secondary infection can lead to amputation. At least one patient had near-fatal hypothermia related to constant cooling required to control symptoms.

In patients with thrombocythemia, skin biopsy results have shown arteriolar endothelial cell swelling, with sparing of venules, capillaries, and nerves. Thickening of the vessel wall and narrowing of the lumen occur as a consequence of smooth muscle cell proliferation. Thickened arterioles may contain occlusive thrombi and ultimately may become fibrotic.

Biopsies from patients with primary erythromelalgia show mild mononuclear perivascular infiltrates with edema, thickened vascular basement membranes, and moderate endothelial swelling. The intimal thickening and thrombi seen in secondary erythromelalgia are lacking.

A complete blood count (CBC) with differential should be obtained to search for evidence of a myeloproliferative disorder. In particular, it is important to look for a platelet count higher than 600 × 109/L (600 × 103 µg/L), a hematocrit greater than 50%, or an elevated granulocyte count (with all stages of maturation). Other laboratory results are nonspecific.

No specific findings are present on plain radiography of the feet and hands. Triple-phase technetium bone scanning is warranted for patients with a history of trauma or stroke and those in whom complex regional pain syndrome type 1 (reflex sympathetic dystrophy) is a strong possibility (particularly if the symptoms are unilateral).

Thermography reveals elevated skin temperatures in the affected areas, but this finding is not necessary to establish the diagnosis. Striking differences in surface temperature can occur between involved and uninvolved areas.

Evaluation and treatment can be conducted in an outpatient setting. Treatment is primarily medical and supportive. Local measures, such as cooling or elevating the extremity, may relieve symptoms. Avoid excessive warming or dependency of the extremity. The environment should be modified so that it is not too hot.

A number of topical and systemic medications have been used for treatment of erythromelalgia.[35] Case reports describe successful use of spinal cord stimulation and ganglion stimulation and blocks.[36, 37, 38, 39]

With secondary erythromelalgia, treatment of the underlying disease process may lead to improvement or resolution of the erythromelalgia.[35] In patients with myeloproliferative disorders, chemotherapy to reduce the platelet count often alleviates symptoms, but it is not universally effective. Some patients with polycythemia vera have responded to phlebotomy. A hematologist may be consulted if an associated myeloproliferative disorder is present.

Surgery probably has no role in the management of erythromelalgia except to treat the rare complication of gangrene. Surgical sympathectomy has been attempted, with variable results.

No specific dietary restrictions are necessary. Vigorous exercise may induce an acute episode and should therefore be avoided.

For primary erythromelalgia, the best therapy is unknown. A wide range of agents has been studied, including the following[34] :

• Vascular agents - Aspirin, prostaglandins
• Sodium channel blockers - Lidocaine, mexiletine, carbamazepine, oxcarbazepine
• Calcium channel blockers - Amlodipine, nifedipine, diltiazem, high-dose oral magnesium ^[40]  
• Antidepressants - Tricyclic antidepressants, serotonin reuptake inhibitors
• Anticonvulsants - Gabapentin, pregabalin
• Antihistamines
• Immunosuppressants

Case reports of treatment with propranolol, epinephrine, biofeedback, sodium nitroprusside, gabapentin, and typhoid vaccine appear in the literature, as well as case series with intravenous bupivacaine, and lidocaine plus mexiletine.[41]  

Medications that affect voltage-gated sodium channels (eg, lidocaine and its oral form, mexiletine) show promise. In hereditary erythromelalgia, however, sensitivity to lidocaine may be determined by the patient's specific SCN9A genotype.[42, 43, 44, 34]

Prostacyclin may provide some benefit.[45]  In a pilot study of 12 patients, iloprost (a synthetic prostacyclin analogue) improved symptoms.[45]  A double-blind, crossover, placebo-compared study of the prostaglandin E1 analog misoprostol in 21 patients with erythromelalgia found that it reduces symptoms and microvascular arteriovenous shunting.[46]  

Topical therapy has been studied, including transdermal lidocaine.[47]  A study in 12 patients reported benefit with the alpha1-agonist midodrine, 0.2%, compounded in a moisturizing skin cream and applied topically three times a day during symptoms.[48]  Poterucha et al treated 36 patients with compounded topical amitriptyline-ketamine; 75% of those patients reported a reduction in pain.[49]

A Mayo Clinic study in 31 patients found that response to treatment with corticosteroids was more likely to occur in patients who reported a precipitant for their erythromelalgia (eg, surgery, trauma, or infection) and in those who had a subacute temporal profile to disease zenith (< 21 days). In addition, patients who responded to steroids started treatment sooner—at 3 (3-12) versus 24 (17-45) months (P = 0.003).[50]

In cases that are associated with other disorders, treating the original disease might improve symptoms. One case report described a patient with seronegative polyarthritis who developed erythromelalgia and was successfully treated with intravenous immunoglobulins.[51]

For erythromelalgia related to thrombocytosis, aspirin is usually the treatment of choice. Other nonsteroidal anti-inflammatory drugs (NSAIDs) provide relief of short duration. Anagrelide may be an alternative. Other platelet-inhibiting agents (eg, ticlopidine and dipyridamole) have no effect.

Monitor for complications, response to treatment, and development of a myeloproliferative disorder because erythromelalgia often precedes the clinical appearance of polycythemia vera or essential thrombocythemia.

Platelet inhibition is helpful in patients with thrombocytosis. Aspirin is most often used, but anagrelide may also be effective.[52] The optimal pharmacologic therapy in primary erythromelalgia is still unknown.

Class Summary

Aspirin is preferred because it provides relief lasting longer than that of indomethacin or other nonsteroidal anti-inflammatory drugs (NSAIDs), presumably because of irreversible platelet inhibition.

Aspirin

Aspirin inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.

Anagrelide (Agrylin)

Anagrelide may inhibit cyclic nucleotide phosphodiesterase and the release of arachidonic acid from phospholipase possibly by inhibiting phospholipase A2. A decrease in megakaryocyte hypermaturation may result in a reduction in platelet production.