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Erythromelalgia: a cutaneous manifestation of neuropathy?*

The low prevalence of erythromelalgia, classified as an orphan disease, poses diagnostic and therapeutic difficulties. The aim of this review is to be an update of the specialized bibliography. Erythromelalgia is an infrequent episodic acrosyndrome affecting mainly both lower limbs symmetrically with the classic triad of erythema, warmth and burning pain. Primary erythromelalgia is an autosomal dominant inherited disorder, while secondary is associated with myeloproliferative diseases, among others. In its etiopathogenesis, there are neural and vascular abnormalities that can be combined. The diagnosis is based on exhaustive clinical history and physical examination. Complications are due to changes in the skin barrier function, ischemia and compromise of cutaneous nerves. Because of the complexity of its pathogenesis, erythromelalgia should always be included in the differential diagnosis of conditions that cause chronic pain and/or peripheral edema. The prevention of crisis is based on a strict control of triggers and promotion of preventive measures. Since there is no specific and effective treatment, control should focus on the underlying disease. However, there are numerous topical and systemic therapies that patients can benefit from.


INTRODUCTION
The skin is an organ of singular structure with several complementary functions. As a sensory organ, it has a refined sensitivity to detect a great variety of stimuli of variable intensity. It is in charge of peripheral thermoregulation to avoid heat dispersion. All functions of the skin are performed through a close interrelation among its structures: epidermis, dermis and an abundant network of blood vessels innervated by sympathetic and sensory endings. The complexity of the skin makes it susceptible to sensitive neuropathies and sweat alterations associated with chronic intractable pain. 1 Erythromelalgia (EM) is an episodic acrosyndrome that generally affects lower limbs bilaterally and symmetrically. The etymology of its name comes from the Greek: erythros "red", melos "limb" and algos "pain". During the crisis the skin becomes erythematous and warm, referred by the patient as a burning pain. 2,3 The somatosensory system allows the perception of tactile, pressure, pain, and temperature stimuli, body position, movement and vibration. The somatic and sensory nerves are displayed in the skin, muscles, joints and fascia including different receptors such as nociceptor permitting the distinction between innocuous or potential damaging stimuli, sending signals to the spinal cord and brain for processing. The neuropathic pain is produced by alterations in the somatic sensorial system. EM is classified along with the chronic painful syndromes. The chronic pain is associated with multiple medical consultations and high prescription of drugs (Chart 1). 3 The low prevalence of EM and it being an orphan disease pose diagnostic and therapeutic challenges. Mild or intermittent episodes could go unnoticed while the severe ones are difficult to control.
the myeloproliferative disease associated with secondary EM. In 1990, Drenth and Michiels, from the Netherlands, proposed to name erythromelalgia whenever it is secondary to other disorders or even to drugs, while the idiopathic form should be named as erythermalgia. Recently, different groups of researchers described vascular and neural dysfunction in both primary and secondary forms. In 2004 EM became the first human disease associated with a sodium (Na +) channel mutation and neuropathic chronic pain. 2,[4][5][6][7][8][9][10][11][12][13] Clinical forms Primary EM causes recurrent episodes characterized by painful bilateral neuropathy affecting limbs without other organic compromise, starting with intense pain and arterial hypertension.
Feet soles and hand palms could be affected primarily. Its progression could attain a greater compromise of both upper and lower limbs. The frequency of sporadic episodes could become daily or even constant leading to incapacity. 8,9 Primary EM is an autosomal dominant inherited disorder encoded by OMIN (Online Mendelian Inheritance in Man) as #133020. It is associated with an alteration on the α subunit protein of the sodium channel type 9 (SCN9A), affecting the Nav1.7 channel that is expressed mainly in dorsal root ganglia and the sympathetic ganglia neurons. The SCN9A gene mutation in the chromosome 2 (2q31-32) could be sporadic or familial. Another inherited form, not related to SCN9A, has been recently reported. Both must be differentiated from secondary EM, which is associated with systemic diseases, medications or toxins. The disease in children under 10 years old is mainly primary, sporadic and more rarely familial. In adulthood, it could be either primary or secondary. [8][9][10][11] A child with a parent carrying the SCN9A mutation has a 50% probability to inherit the disorder. On the other hand, it has been seen that 7% of patients have a first-degree family member affected. The severity of the disorder is variable within the family members of the affected pedigree. This behavior cannot be explained up to now. 5,[12][13][14][15] The primary form could be classified according the age of onset as "early" if it appears in the first two decades of life or "late". The age of onset of the symptoms has been correlated with Na+ channel voltage activation produced by pathogenic SCN9A variants. The late onset of symptoms could be associated with mutations producing less Na+ channel activation and lower neuron excitability. [16][17][18]

PATHOPHYSIOLOGY
First of all, we must take into account some concepts about the physiology of pain. The pathologic mechanisms are complex; neural and vascular dysfunction might be present in primary and secondary EM.  In the inflammatory process, groups of active factors act, as follows: -Hydrogen ions and adenosine triphosphate that exhibit a direct relation with the tissue lesion and activate the already excited nociceptor by the causal stimulus.
-Bradykinin, histamine, serotonin, prostaglandins, leukotriene, proinflammatory cytokines, nerve growth factor, all associated with the inflammatory process and sensitizing the nociceptor in order to respond to physical stimuli and to other active substances.
-Substance P, neurokinin A, CGRP released by the nociceptor.
The amplification of the message is assured not only by the release in the inflammatory injury but also through supplementary recruitment of the adjacent activated or sensitized fibers, mainly through the axonal reflex, e.g. the so called neurogenic inflammation. Consequently, the primary afferents contribute to this multifaceted inflammatory process, releasing neuropeptides that take part in a sort of "oil spot nociceptor sensitization." (Figure 1). 2,[40][41][42][43][44] Neural alterations Sensorial peripheral alterations, adrenergic dysfunction and distal neuropathy of small fibers might be present in EM. The damage to the nociceptor could produce chronic pain leading to phantom pain if the damaged nociceptor starts randomly triggering other nerves. [45][46][47][48] In EM A-Delta afferent and C efferent sympathetic fibers could be damaged. Nevertheless, the nerves with greater caliber could be intact and consequently conduction velocity is normal. The small fibers are part of the autonomous neural system controlling sweat, heart rate and blood pressure. Small fiber neuropathy involves preferentially the axon terminals of long neural nerves affecting frequently the feet. 49,50 The altered electric excitability of neurons can increase pain.
In primary familiar and sporadic EM cases there is an alteration of the alpha subunit of the Nav1.7 sodium channel due genetic mu-  Other authors point out to both types of dysfunctions since they are exposed to the same pathological mechanism. As above mentioned, the altered activity of the sodium channel Nav1.7 is present in both sympathetic and sensory nerves. It has been recently demonstrated that sodium channels are present also in skin myocytes and vascular endothelium of arterioles and arterialvenous shunts. Other authors consider that both dysfunctions are exposed to the same pathological alterations. Since the altered activity of Nav1.7 sodium channels is present in both sympathetic and sensory nerves, and it is known that in the innervations of these vessels both nerves converge, these complex interrelations may contribute to produce skin erythema and pain in EM. 1,9,58 CLINICAL FEATURES Primary and secondary EM are characterized by episodes of erythema, warmth and burning sensation of the limbs. The erythema could be mild to moderate with clear or ill-defined limits (Figures 2-3). During the episode, the warmth sensation is perceived by the patient and confirmed by the clinician. Pain is described by the patient as a burning sensation or as an electric shock or a throb. The prevention is based on a strict control of triggering events, i.e. heat exposure or pressure, standing position for a long time, physical activity, emotions, and/or stress, alcohol ingestion, spicy food, vasodilator drugs, night time, exposure to chronic vibration or even light skin contact in severe cases. 8,9 Symptoms could be improved with cold water or ice contact and raising the limb, nevertheless there is no improvement with analgesics. 2,18,62,66 Regarding evolution, Davis et al. reported that after an eight-year follow up, 31% of patients exhibit deterioration, 25% had no change, 30% improved and 10% had a complete remission. There is a tendency for chronicity, with sleep and appetite disturbances, as well as anxiety and depression. The patients use open shoes and sleep with uncovered feet even in cold weather. They cannot walk long distances or be in a standing position for long time, nor practice any sport or dance. Due to these symptoms, both children and adults loose days of study, sport or work with resentment of their ludic and social activity. Due to their condition, they are prone to accidents at work and at home. If the episodes continue for a prolonged time, bed rest is recommended, otherwise a wheel chair must be considered. The affected quality of life could become a disability. Morbidity and mortality rates are higher in these patients in comparison with individuals matched by sex and age in the general population. 2,4,5,18

COMPLICATIONS
Complications are related to the impairment of the barrier function, ischemia and neuropathy. The most frequent is second-  The positive test using warmth exposure is frankly positive when the patient describes the symptoms at 32º-36ºC range. Thermography usually shows an increase in temperature in the affected areas during episodes. This test could be useful regarding the differential diagnosis with the complex regional pain syndrome. The neurological study and the electromyography are indispensable to rule out peripheral neuropathies of other etiologies. 20,29,66 A complete clinical study of the patient would make possible to discriminate between a primary or secondary disorder rendering easier the differential diagnosis. Due to the complex pathogenesis of the diseases with chronic pain and/or peripheral edema the differential diagnosis is important (Chart 4). 29,72,77 TREATMENT Preventive measures should be taken into account. Peripheral vasodilator drugs are contraindicated as well as exposure to exces-Leroux MB should be recommended and also yoga and swimming. 77,78 Since there are no specific and effective treatments, the main primary disorder treatment that ameliorates the symptoms should be proposed. Acetylsalicylic acid is useful in EM secondary to polycythemia vera or others hematological entities. Aspirin prevents platelet aggregation through irreversible inhibition of cyclooxygenase in doses of 325 to 650mg/daily. A 500mg dose could be administered during 3 days. This treatment is also pathognomonic since it could be used as a diagnostic test in EM associated with proliferative syndromes. The maintenance dose prescribed is 75 mg/daily. Nevertheless, not all patients respond to aspirin treatment. Thus, EM secondary to polycythemia vera can respond to aspirin associated with hydroxyurea while in other patients, alpha-2b interferon and epidural analgesia are necessary. 20,28,29,79,80 It has been recently described a subgroup of EM patients responding to systemic corticoids. Thus, it is postulated that in EM cases associated with infections, surgery, trauma or subacute diseases, high or very high systemic corticosteroid doses could be effective. A high dose is considered 40 mg of prednisone or higher, or its equivalent, administered daily during 5 or more days. The medication must be given early, before the installation of irreversible damage of the nociceptor. The time of treatment is dependent of the symptoms evolution. 81 There are alternative therapies either topical applications or systemic ones (Chart 5). 43,[81][82][83][84][85][86][87][88][89][90][91][92][93][94][95] Topical applications are currently in development considering the interrelations between non-neural cells in the skin and free nerve endings. Some authors argue that with topical therapy the magnitude of pain relief in the patient cannot be predicted, nevertheless is a more secure option and free of serious side effects. Others propose to combine the analgesic topical preparations associated with anti-inflammatory drugs. Regarding useful components, lipophilic and hydrophilic ones are recommended. It is also proposed the use of liposome as drug delivery. The most used are lidocaine and capsaicin. Other options are analgesics such as ketamine, amitriptyline, and phenytoin as cream, gels, or ointments. Phenytoin cream acts on the voltage regulated sodium channel. There is a good response with a topical preparation containing 0.2% midodrine, which is an alpha agonist. The role of autacoids, such as palmitoylethanolamide as restorer of the neuroimmunologic homeostasis is under evaluation 43,[82][83][84]96 Moreover, topical lidocaine inhibits the voltage regulated neuronal sodium channel, thus stabilizing the neuron membrane potential of the hyperexcited peripheral nerve fibers. This mechanism diminishes both allodynia and hyperalgesia. Its presentation as patch is disadvantageous when applied to feet. 82 the peripheral neuropathic pain since it is an agonist of the vanilloid receptor. The first application triggers a sensitivity that decreases progressively to attain a persistent desensitization. Capsaicin depletes and prevents the accumulation of substance P in peripheral sensory neurons. 85,86 Systemic regulation of sodium channels could be obtained through several pharmacological agentes, i.e,. anesthetics, antiarrhythmic drugs and anticonvulsants, among others. Lately, it has been reported that EM patients carrying the S241T mutation on the Nav1.7 sodium channel could benefit with oral carbamazepine that acts on cerebral pain regulation. 94 Among efficient therapies on microcirculation, peripheral vasodilators are restricted. Buflomedil is indicated during long periods of cyanosis and coolness, since it opens the pre-capillaries sphincters restoring the microcirculation and through their hemorheological effect increases the erythrocyte membrane elasticity.
These actions improve the blood flow, increasing tissue oxygenation turning it into a valid therapeutic option in EM. The addition of two or more therapeutic agents in lower dose could enhance their action and at the same time reduce side effects. 58,77,90 Cyproheptadine and antihistamines such as pizotifen and paroxetine have also been evaluated. Magnesium in high doses decreases pain. 18,32,95 Ziconotide has been used for the amelioration of chronic pain, although its mechanism in human beings it is not known. In animals, it blocks the type N calcium channels in the primary no-