Erythromelalgia

Published on 19/03/2015 by admin

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Last modified 19/03/2015

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Erythromelalgia

Cato Mørk and Knut Kvernebo

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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Erythromelalgia (erythros – redness; melos – extremity; algos – pain) is a symptom complex characterized by burning extremity pain, erythema, and increased temperature of affected skin. Pain is aggravated by warming and relieved by cooling. Symptoms and findings are usually intermittent and often missing during examination. Between attacks acrocyanosis, perniosis, and Raynaud’s phenomenon may occur. The severity of symptoms varies from mild discomfort (most common) to disabling pain and gangrene. In daily clinical work the terms mild, moderate, and severe may be useful. The diagnosis is often missed in cases with mild symptoms, whereas severe erythromelalgia is a rare condition.

There is growing evidence that symptoms can be triggered either by a primary microvascular event, or by a primary autonomic nervous dysfunction. The final common pathway of the pathogenesis is in both cases maldistribution of skin perfusion with arteriovenous shunt flow through anatomical or functional microvascular anastomoses. The consequence is increased thermoregulatory perfusion and a relative lack of nutritive perfusion with corresponding skin hypoxia.

Familial erythromelalgia is a rare disorder where recent studies have demonstrated a dysfunction of sensory and sympathetic neurons, with genetic variants within the SCN9A gene encoding for the Nav1.7, a voltage-gated sodium channel located on nerve endings. The genetic variants within this gene can cause a spectrum of diseases including erythromelalgia.

Management strategy

Before beginning a treatment regimen, the patient’s condition should be classified according to whether it is primary or secondary, the etiology (for secondary cases), and its severity. Erythromelalgia may be secondary to underlying diseases, such as myeloproliferative, connective tissue, cardiovascular, infectious and neurological diseases, diabetes mellitus, vasculitis, and neoplasia. If present, a primary condition should be optimally treated. There are many reports of remission following treatment of myeloproliferative disorders. Drug-induced erythromelalgia has been reported secondary to substances that may alter vasomotor tone, such as calcium channel blockers, bromocriptine, norepinephrine (noradrenaline), pergolide, ticlopidine, cyclosporine, iodine contrast, mushroom, and mercury poisoning.

All patients benefit from local skin cooling (applying cold towels or wet sand, walking on cold floors or even in the snow, air-conditioned rooms, or immersion in cooled water) and from elevation of the affected limb. Aggressive cooling may cause injury and worsen the erythromelalgia. Comfortable shoes to relieve pressure over the soles can help. Aggravating factors such as warmth, exercise, dependency of the extremity, tight shoes and gloves, and alcohol intake in some cases, should be avoided.

No single medication or other treatment modality has been found to be universally helpful. Spontaneous remissions have occurred without treatment. There is a marked variation in therapeutic responses. Few controlled clinical trials have been published. The main reason may be the low prevalence, the heterogeneity of patients, and the lack of laboratory diagnostic methods.

Analgesics, including opiate analgesics, often have limited effect. Numerous drugs have been used with varying success. A few patients become free of symptoms with acetylsalicylic acid. Case reports or series of patients have shown beneficial effect with vasodilators (prostaglandin E1/prostacyclin or analogs, sodium nitroprusside, naftidrofuryl, calcium channel blockers). Other drugs that may be of benefit are sodium channel blockers, antidepressants, and anticonvulsants.

Numerous treatment alternatives based on case reports have been presented in the literature. Anecdotally, nitroglycerin ointment, capsaicin cream, ketanserin, methysergide, pizotifen, β-blockers, cyproheptadine or other antihistamines, carbamazepine, clonazepam, corticosteroids or other immunosuppressants, pentoxifylline, phenoxybenzamine, opiates, prazosin have been presented as effective. Hyperbaric oxygen treatment, spinal cord stimulation, thalamic stimulation, epidural blocks have also been proposed. Sympathectomy has been beneficial in some patients and in other patients caused worsening of symptoms. Treatment modalities such as hypnosis, biofeedback and learning to avoid triggers can be beneficial for coping with pain. A survey of members of The Erythromelalgia Association (TEA, www.erythromelalgia.org) shows that more than 50 therapeutic regimes have been tried out. TEA is a non-profit organization that may be helpful in providing information, awareness and support.