Erythromelalgia

Etiology

Erythromelalgia in thrombocythemia occurs in association with essential thrombocytosis and polycythemia vera. 

Primary erythromelalgia may be idiopathic or inherited. The inherited form of erythromelalgia is an autosomal dominant neuropathy caused by a gain-of-function mutation in the SCN9A, SCN10A, and SCN11A gene, which encodes the alpha subunit of the voltage-gated NaV 1.7, NaV 1.8, and NaV 1.9 sodium channel, respectively. This peripheral channel is expressed within the dorsal root ganglion of the sympathetic ganglion neurons. This mutation leads to hyperexcitability of the nociceptive fibers causing them to fire at subthreshold stimuli. This, in turn, leads to a previously nonpainful stimulus eliciting a painful response.[7][8]

Secondary erythromelalgia has been attributed to a number of different medical conditions. The most prevalent being myeloproliferative disorders, including essential thrombocytosis, polycythemia vera, and myelofibrosis. Other underlying causes include infectious agents (HIV, influenza, syphilis, and poxvirus), autoimmune diseases (systemic lupus erythematosus and rheumatoid arthritis), diabetes mellitus type 1 and 2, solid tumors (astrocytoma, colon, and breast cancer), medications (bromocriptine, nifedipine, verapamil, topical isopropanol, pergolide, simvastatin), gout, multiple sclerosis, hypertension, venous insufficiency, pernicious anemia, thrombotic thrombocytopenic purpura, mushroom intoxication, and mercury poisoning. The symptoms of patients with secondary erythromelalgia are often milder and are relieved after the treatment of the underlying disease.[9][10]

Epidemiology

Primary erythromelalgia typically presents in the first two decades of life in comparison to secondary erythromelalgia, which has a mean onset of 49.1 years. The incidence rate of primary erythromelalgia ranges varies, ranging from 0.25 to 2 per 100,000 people per year. Various studies show no gender preference, while others state that the disease is more prevalent in females. Reported cases come from various geographical backgrounds and include patients from diverse nationalities, including Chinese, American, French, Dutch, and Norwegian. Erythromelalgia is extremely rare in children. However, if it occurs, it is associated with high morbidity and sometimes death.[11]

Pathophysiology

Abnormal aggregation and consumption of platelets result in erythromelalgia associated with thrombocythemias like essential thrombocytosis and polycythemia vera. It is believed that prostaglandins and cyclooxygenase play an important role in this pathophysiology.

Primary erythromelalgia is due to alterations of voltage-gated NaV 1.7 sodium channels. These sodium channels are found primarily on nociceptive neurons and play a crucial role in determining the threshold necessary to cause an action potential. Mutations in the SCN9A are responsible for erythromelalgia cause the sodium channels to become hyperexcitable, which leads to nociceptive neuron firing at subthreshold stimuli. This, in turn, leads to a previously nonpainful stimulus eliciting a painful response resulting in a burning pain seen in erythromelalgia. Most of the cases of primary erythromelalgia have been found to be early-onset (onset in the first decade of life); however, late-onset (onset in the second decade of life) is found to have a new mutation in Na V1.7, Q10R. This mutation is found to have a smaller degree of dorsal root ganglion excitability and hence later onset of symptoms. This theory also suggests a genotype-phenotype relationship at three levels (clinical, cellular, and molecular/ion channel).[12]

Secondary erythromelalgia is due to a variety of causative agents, and the pathophysiology is not always well understood. When associated with hematological conditions, it is believed that platelet activation causes thrombi to form within arterioles. The thrombi occlude the vessels causing tissue hypoxia and, ultimately, pain.[9]

There is a common shunting hypothesis proposed for both primary and secondary erythromelalgia. This hypothesis states that the symptoms of erythromelalgia are due to skin hypoxia as a result of increased arteriovenous shunting leading to an imbalance between thermoregulatory and nutritive perfusion.[13]

Histopathology

The skin biopsy of patients with erythromelalgia associated with thrombocythemia showed arteriolar fibrosis and occlusion with platelet thrombi that spared the venules, capillaries, and nerves. In less than 10% of cases, skin biopsies showed decreased epidermal nerve fiber density. Biopsy specimens in patients with primary and secondary erythromelalgia are non-specific.[14] 

History and Physical

The classic presentation of erythromelalgia is a triad of redness, warmth, and burning pain in the extremities that occur in episodes. Erythromelalgia most commonly affects the feet (in 90% of patients) and less commonly the fingers and hands (in 25% of patients). Occasionally in 2% to 3% of patients, it can involve the head, neck region, and genitals. The symptomatic episodes are generally triggered by exercise, warm climates, standing, and wearing tight-fitting shoes, which may last minutes to days, and the symptoms typically get relieved by cooling (use of fans, ice packs) and elevating the affected area. Episodes most commonly precipitate at night, probably due to increased ambient temperature. The symptoms often begin with an itching sensation of the affected area, progressing to a more severe burning pain. The involvement is typically bilateral but can be asymmetric.[15]

Between the episodes, the affected area is typically normal, i.e., no redness, warmth, and burning pain. Reports suggest that in some patients, the features of Raynaud phenomenon have been reported in between the episodes.[16]

Myeloproliferative disorders like essential thrombocytosis and polycythemia vera have a median onset of approximately 2.5 years after the onset of clinical symptoms of erythromelalgia. Rapid improvement with aspirin is typical of erythromelalgia in thrombocythemia that can aid in the diagnosis of myeloproliferative disorders. Other clinical features of myeloproliferative disorders like easy fatigability, weight loss, pruritus, headache, blurring of vision, and abdominal discomfort secondary to splenomegaly should be carefully asked with the patient presenting with symptoms of erythromelalgia.

It is important to ask the history of fever, recent trauma, joint pain, and malar rash/oral ulcer to rule out conditions like cellulitis, systemic lupus erythematosus (SLE), and rheumatoid arthritis that can cause erythromelalgia. Drug history and blood pressure should be carefully noted.

Physical exam findings that may be present during the episode include warmth or erythema of the affected extremity. Mild edema might be present in the affected extremity. Acrocyanosis (persistent blue discoloration of the extremities), normal joint mobility, and normal or bounding peripheral pulse may be observed. In chronic cases, distal ulcers may be seen. In addition, it is important to look for characteristic signs of underlying disease processes such as splenomegaly and lymphadenopathy in the case of polycythemia vera or skin findings associated with systemic lupus erythematosus.

Evaluation

The diagnosis of erythromelalgia is made with the help of classic signs and symptoms: redness, warmth, and burning pain, most commonly affecting the extremities precipitated by heat or exercise and relieved by cooling. As this syndrome occurs in episodes, the clinicians face diagnostic challenges with this disease. The clinicians may ask to take photographs of the involved region during flare-up episodes that might aid in the diagnosis of this condition.

It is important to differentiate between primary and secondary forms of erythromelalgia. The diagnosis of primary erythromelalgia is made by the presence of classic signs/symptoms and screening for mutations in the SCN9A gene. The secondary form of erythromelalgia is diagnosed by ruling out different diseases associated with this condition. A complete blood count with differential is done to look for the evidence of myeloproliferative disorder (elevated hematocrit greater than 50% with red blood cells or platelets) and cellulitis (elevated white blood cell count and neutrophils). Serologic tests for antinuclear antibody (ANA), HIV, rheumatoid factor (RF) are done to look for systemic lupus erythematosus (SLE), HIV, and rheumatoid arthritis, respectively. Blood uric acid is done to rule out gout. For a patient with a positive history of trauma or surgery, triple-phase technetium bone scanning is done.[17][18]

A skin biopsy is usually not performed due to its lack of specificity. However, when performed, subtle decreased epidermal and perivascular nerve density has been observed.

Electromyography and nerve conduction velocity tests are generally abnormal in patients with erythromelalgia, and these tests provide evidence for the use of medications for neuropathy in patients with erythromelalgia.

Treatment / Management

Management of erythromelalgia can be quite challenging and necessitates an interprofessional approach. Treatment should encompass patient education, behavior modifications, and the avoidance of triggers. Various treatment options have been suggested, though none are fully curative, rather aimed at symptom management and improving quality of life. While treatment of erythromelalgia is primarily focused on symptom control, secondary erythromelalgia can improve or resolve with treatment of the underlying disease process.

The mainstay of therapy for both primary and secondary erythromelalgia aims to avoid triggers, most often heat, exercise, and standing. Commonly used strategies include remaining in cool environments, decreased physical activity, limb elevation, and avoiding excess clothing. In addition, some patients find relief with cool water immersion or portable fans. It should be noted that excessive cooling via ice water immersion can lead to maceration, infection, and ulceration.[17]

Some studies have shown that topical lidocaine patches, compounded topical amitriptyline-ketamine, and topical capsaicin applied three times daily may improve the pain associated with erythromelalgia. While 0.2% midodrine compounded in a moisturizing cream applied thrice a day might improve redness associated with erythromelalgia. Topical therapy should be continued for two to four weeks to assess the efficacy.[19](B2)

Aspirin is the drug of choice for erythromelalgia associated with thrombocytopenia or myeloproliferative disorder. Other NSAIDs like anagrelide may be used as an alternative. Diagnosing and treating the underlying myeloproliferative disorder is of utmost importance for the improvement of erythromelalgia. In this patient population, the addition of hydroxyurea (chemotherapy) to reduce the platelet count may also improve the symptoms of erythromelalgia, while phlebotomy might be useful for patients with polycythemia vera.

Primary erythromelalgia can be particularly resistant to treatment. Medications affecting the voltage-gated sodium channels (lidocaine, mexiletine, and carbamazepine) have shown promise in primary erythromelalgia. There is some evidence for the use of mexiletine 100 mg to 200 mg three times a day. An alternative regimen consists of carbamazepine 300 mg twice per day with gabapentin, which is titrated up to 300 mg five times a day. Secondary erythromelalgia may be responsive to aspirin, 81 mg to 640 mg daily, and is often used as a first-line agent.[20][21](B3)

Other agents that may be effective in treating primary and secondary erythromelalgia include gabapentin, pregabalin, venlafaxine, amitriptyline, iloprost, and misoprostol, calcium channel blockers, and beta-blockers. However, these agents are less well studied, and no specific treatment regimen has been proposed.[17]

Alternative therapies used rarely for refractory cases are epidural infusions of bupivacaine/ropivacaine, transcranial magnetic stimulation, subcutaneous injection of botulinum toxin A, and thoracic or lumbar sympathectomy.[22][23][24][25](B3)

Some studies postulate that pain rehabilitation programs and patient counseling can improve physical and emotional functioning in a patient with erythromelalgia.

Approach to the management in steps: (a) Avoid triggers (b) Aspirin for one month (c) Topical drugs for two to four weeks (c) Systemic drugs like gabapentin or pregabalin or venlafaxine for two to four months (d) Consider other systemic drugs and pain rehabilitation programs.

• Try the next step only after the failure of previous steps and treat underlying myeloproliferative disorder if present.

Differential Diagnosis

The differential diagnosis for primary and secondary erythromelalgia include polyneuropathy (large or small fiber neuropathy), acrocyanosis, peripheral arterial disease, lipodermatosclerosis, Raynaud phenomenon, cellulitis, gout, Fabry disease, vasculitis, and frostbite. These disorders should be distinguished from erythromelalgia with the help of typical features associated with these disorders like angiokeratomas and corneal opacities in Fabry disease, history of fever/trauma in cellulitis that responds quickly to antibiotics, high uric acid in gout, and abnormal nerve conduction test results in polyneuropathy. The episodes of Raynaud phenomenon are precipitated by cold exposure and relieved by warming. A presentation limited to the face, which is extremely rare, can often be mistaken and mistreated as rosacea, seborrheic dermatitis, or contact dermatitis.[4][8][23]

Complex regional pain syndrome (CRPS), which is also known as reflex sympathetic dystrophy, can mimic many of the symptoms of erythromelalgia. However, CRPS is more often unilateral and can present more proximally in a limb, while erythromelalgia is more likely to be symmetric and located in the distal limb. In addition, CRPS is often preceded by trauma or surgery, whereas episodes of erythromelalgia can often be triggered by heat and relieved with cooling agents.[21]

Prognosis

Most patients with primary and secondary erythromelalgia are difficult to manage and are often resistant to treatment. One exception is secondary disease due to polycythemia vera and essential thrombocythemia, as these patient populations often have a favorable response to aspirin therapy. Currently, data is conflicting as to the severity and prognosis of primary versus secondary erythromelalgia. Some studies postulate that aspirin responsive patients have little morbidity, and complications occur more frequently in patients who have platelet-mediated disease.[21]

Over time, ulceration, necrosis, and gangrene can develop in response to repeated ice water immersion or other forms of chronic cooling of the extremities. Quality of life has been shown to be dramatically affected and can lead to chronic depression due to fear of precipitating episodes.

Complications

To alleviate the burning pain associated with the disorder, patients often will attempt to cool the affected extremity. Some patients even report sitting in front of the refrigerator to alleviate discomfort. Many of the methods used can lead to maceration of the affected tissue, followed by damage to the skin barrier. The most commonly reported complication is infection secondary to blistering, ulceration, cyanosis, and gangrene that might lead to amputation in chronic untreated cases. Malnutrition and hypothermia have been seen in a few cases.[5]