Erythromelalgia in a patient with feet erythema and cyanosis

Background

Erythromelalgia is a rare disabling disorder that can be acquired or inherited. Familiarity in diagnosing erythromelalgia is crucial for better management of this disease, especially that no treatment showed superiority or lead to a definitive cure. Following up on patients diagnosed with erythromelalgia is also important and necessary to be able to rule out any underlying disorder and to monitor for the possible progression of erythromelalgia into a myeloproliferative disease. A multidisciplinary approach with education and counselling is needed for the improvement of the quality of life of the patients affected by this disease.

Case presentation

Erythromelalgia is a rare disease, mostly acquired but very rarely inherited and is characterised by a triad of a clinical syndrome of redness, warmth and painful extremities.1 2 Epidemiologic studies show that the incidence of erythromelalgia is less than 2 per 100 000 per year from studies conducted in the USA, Sweden and Norway. It is more common in women, usually occurs in adults and is very rare in children and adolescence.3 This rare disease is classified into primary and secondary erythromelalgia.4 Primary erythromelalgia might be idiopathic or inherited. The inherited form is an autosomal dominant disorder due to gain of function mutations in the SCN9A gene encoding a voltage-gated sodium channel (Nav1.7).4 This mutation leads to a hyperexcitability of the sodium channels, resulting in previously non-painful stimuli causing painful responses and burning pain.4 5

Secondary erythromelalgia has been associated with different underlying medical conditions mainly the myeloproliferative disorders (in less than 10% of cases) such as polycythemia vera and thrombocytosis; also the autoimmune diseases such as connective tissue disorders, rheumatoid arthritis and systemic lupus erythematosus as well as certain medications exposures, neoplasia and others.3 6

We present the case of a male adolescent with no prior medical history who presents to our family medicine clinic with a 3-month history of bilateral feet erythema followed by episodes of cyanosis in bilateral toes. The patient denies smoking or alcohol consumption. The symptoms are associated with heat exposure and stress and are exacerbated when the legs are dangling or with strenuous exercising. They rarely occur at rest and significantly improve on leg elevation. The patient does not report any pain, fever or chills. The rest of the review of systems is also negative except for occasional acne flares and one episode of urticaria over the trunk and upper extremities few months prior to presentation that was treated with first-generation antihistamines and resolved completely afterwards. As for the family history, his maternal aunt also has similar symptoms of bilateral feet erythema that are relieved by salicylate administration.

On physical examination, mild toe cyanosis is observed associated with feet warmth, but there is no tenderness on palpation (figures 1 and 2). Exposure of legs to ice during the visit does not exacerbate the cyanosis. However, when placed in warm water, the feet turn red with clear demarcation of the areas that are in contact with the water (figures 3 and 4). A thorough neurological examination is performed with no abnormal findings. There is no change between standing and sitting blood pressure. The remainder of the physical examination is normal.

Laboratory evaluation includes complete blood count (CBC) and erythrocyte sedimentation rate (ESR), which are found to be in their normal ranges according to age. An auto-immune workup including antineutrophil antibody (ANA) titre and ANA profile are negative. A transthoracic echocardiogram and venous and arterial doppler ultrasonography of the lower limbs are also normal.

The patient presents to the clinic for follow-up on the laboratory and imaging results and is asked to report the frequency and duration of the episodes when they occur at home. He is also advised to avoid heat and activities that could exacerbate his symptoms such as excessive exercising. When the episodes recur, he is instructed to elevate his legs and use cooling techniques such as using a fan or putting his feet in cold water until the symptoms resolve. Safety measures while practising these techniques are also reinforced.

The patient is re-evaluated after 4 weeks and reports that the frequency of episodes is increasing almost daily and each episode is lasting a few minutes. Given his history, findings on clinical examination, and a lack of any pathology on the diagnostic testing, the patient is diagnosed with erythromelalgia. He is then counselled on both pharmacological and non-pharmacological treatments for his condition. The patient refuses to take salicylate and resorts to non-pharmacological options such as leg elevation, cooling with a fan and limiting exposure to heat. He is also advised on performing an annual CBC given the association of erythromelalgia with myeloproliferative disorders. The patient is then re-evaluated 6 weeks later and reports that the symptoms start to decrease in frequency and severity after applying the techniques learnt at the clinic. The patient denies taking any pharmacological treatment for his symptoms. Given the high suspicion of primary erythromelalgia due to young age and presence of a family member with similar symptoms, a genetic testing for SCN9A gene and electromyography (EMG) were requested but refused by the patient due to financial limitations.

The pathophysiology of secondary erythromelalgia is not very well established.1 Studies suggest that when erythromelalgia is associated with haematological conditions, platelet activation and aggregation lead to the formation of microthrombi in the arterioles, resulting in the occlusion of those vessels, hypoxia and pain.6 In addition, the platelet activation results in the production of prostaglandins and the activation of the coagulation pathways, which is thought to be contributing to the inflammatory nature of the disease.6

In both primary and secondary erythromelalgia, the hypoxic tissue injury is also attributed to the increased arteriovenous shunting of blood causing more ischaemic damage and leading to the further release of inflammatory markers and hyperemia, inflammation and pain to the affected body areas.7 8

Erythromelalgia affects most commonly the distal extremities, as reported in our case, but the involvement of the face, cheeks and ears can also be seen.7 9 10 A symmetric bilateral involvement is more common than asymmetrical signs and symptoms and the patients typically describes a burning pain in the extremities; however, pins and needles-like sensation, electric shocks, throbbing pain and severe itching might also be present.7 Our patient suffers from the feet erythema, cyanosis and warmth; however, no pain is reported.

Triggering factors that elicit pain are usually increased skin temperature either internally secondary to an increase in the metabolism such as running or doing a physical activity or externally through environmental factors such as increased temperature during hot weather.7 8 This makes patients find relief to their pain by cooling their extremities by using cold water, fans, open shoes and/or limiting their physical activities; however, this can sometimes lead to complications such as frost bite, skin injuries and infections (cellulitis) as well as hypothermia.7 8

The diagnosis of erythromelalgia is made clinically based on the identification of the characteristic signs and symptoms, which include alternating episodes of erythematous, warm and painful extremities that can be precipitated by heat exposure or exercises and relieved by cooling.3 Patients diagnosed with erythromelalgia, however, should undergo several tests to rule out other underlying conditions such as myeloproliferative disorders or other underlying pathologies. Managing this rare disease is often challenging as the pathophysiology is not fully understood and includes both pharmacologic and non-pharmacologic treatments. The mainstay non-pharmacologic treatment is avoiding triggers, exposing the affected areas to cool water or fans for short periods of time (5–10 min every 1–2 hours) and extremities elevation.11 Patients should be educated on the possible complications of the cooling measures if used inappropriately or excessively.7 Limited data exist on the efficacy of pharmacologic interventions, which includes topical treatments such as lidocaine patches that can improve the pain associated with erythromelalgia.12 13 Others include topical vasoactive drugs like midodrine 0.2%, which can improve the erythema.14 Antiplatelets and prostaglandins are used with the aim of maintaining an adequate perfusion to the affected areas; serotonine and norepinephrine reuptake inhibitors and calcium channel blockers can also be used as they reduce tissue hypoxia through vasodilatory effect.7 Studies have also shown that serotonin and norepinephrine reuptake inhibitors (SNRIs) improve thermoregulation by decreasing sympathetic nerves firing through blockage of norepinephrine uptake and medications such as non-steroidal anti-inflammatory drugs and anticonvulsants (gabapentinoids) might also be used with limited benefit.3 7 Salicylate (aspirin) is usually the initial treatment for patients suffering from erythromelalgia associated with myeloproliferative disorders.15 16

Investigations

Erythromelalgia is a clinical diagnosis; however, laboratory tests can aid the physician in diagnosis. These include CBC which is usually normal in early stages but should be monitored on yearly basis due to risk of developing myeloproliferative disease (increased WBCs, RBCs or platelets). ESR and C reactive protein are usually mildly elevated. ANA and ANA profile can be done to assess for autoimmune causes. Doppler ultrasound can be ordered to rule out other causes of limb swelling but is usually negative in erythromelalgia. Transthoracic echocardiogram to rule out cardiac aetiologies and assess the heart chambers, valves and assess for any thrombus or emboli that could be causing the symptoms. EMG can reveal axonal neuropathy in erythromelalgia and help in differentiating it from other causes of peripheral neuropathy. Skin biopsies are usually abnormal in erythromelalgia but are widely variable and non-specific

Differential diagnosis

Differential diagnosis of erythromelalgia is broad and can include Raynaud’s phenomenon, acrocyanosis, peripheral vascular disease, cellulitis, peripheral neuropathy, Fabry disease, shoulder–hand syndrome causalgia, post-traumatic reflex dystrophy.

Treatment

Treatment of erythromelalgia is usually challenging and is done in a stepwise approach.

Step 1 includes counselling about non-pharmacological treatments such as limb elevation, cooling techniques such as using a fan or applying cold water to the affected area for a short period of time along with avoiding precipitating factors. Addition of aspirin 325 mg per day can be done and discontinued if no improvement is observed. A trial of amitriptyline 2% combined with ketamine 0.5% applied three times daily or lidocaine patch applied for 12 hours over the affected area daily.

Step 2 includes initiation of systemic drugs such as gabapentin 300 mg at night and can be gradually increased to 2400 mg per day. Pregabalin 75 mg two times per day or venlafaxine 75 mg divided into three doses daily can also be used instead of gabapentin.

Step 3 is reserved for patients who have failed the first two steps and includes systemic amitriptyline, sertraline or misoprostol along with pain rehabilitation.

Outcome and follow-up

Follow-up for symptoms control, blood count and differential to rule out myeloproliferative disease should be done on a yearly basis.

1-year follow-up was done for our patients with improvement of symptoms and normal CBC and differential.