Cite this asPerrotta G, Guerrieri E (2022) Erythromelalgia: Definition, clinical contexts, differential diagnosis, and therapy. Single case and literature update. Glob J Rare Dis 7(1): 001-007. DOI: 10.17352/2640-7876.000032
Copyright© 2022 Perrotta G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Clinical publications on this morbid condition report as many as 16 different Nav1 7 channel substitutions. They also report more than 40 pharmacological treatments, including agents with sodium channel blocking but nonspecific activity (mexiletine, lidocaine, carbamazepine), anti-neuropathic drugs (gabapentinoids and antidepressants), antidepressant drugs with efficacy on migraines (amitriptyline) vasoactive drugs for the management of hypertension, and analgesics (opioids and ketamine). Current research fails to address all patients’ clinical needs, although it recently suggests new genetic hypotheses yet to be tested and the central importance of genetic counseling, to inform patients and their families about the severity, likely course of symptoms, and risk of complications, and in some cases to guide clinical management. Current findings and the significant morbidity associated with the condition, even in light of the single case presented, highlight the need for mechanism-based therapies to improve clinical outcomes.
Erythromelalgia (or Gerhardt’s or Mitchell’s disease) is a rare disease of functional peripheral arteriopathy that is either primary (or idiopathic) or secondary (to other morbid conditions such as myeloproliferative diseases, hypertension, venous insufficiency, diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, gout, lichen sclerosus, spinal cord disease, multiple sclerosis, and rarely by drugs such as nifedipine and bromocriptine); manifests as painful episodic paroxysmal vasodilation primarily in the small arteries of the hands and feet, but may also progress proximally to include the arms and legs, and more rarely to the face and ears). Intense pain, heat, erythema, and redness of the feet or hands are typical symptoms and may last from a few minutes to several hours. In most patients, symptoms are triggered by heat (starting at temperatures above 29°C); the remedy used is localized cooling or immersion in ice water. Trophic lesions are not associated. Generalized vasomotor dysfunction and Raynaud’s syndrome are frequently associated [1,2].
The term erythromelalgia is derived from the Greek words erythrose, meaning “red,” Melos, meaning “limb,” and algos, meaning “pain”. It was first described in 1878 by Silas Weir Mitchell and was initially called “Mitchell’s disease”. Smith and Allen proposed another term, erythermia, in 1938 to emphasize the characteristic heat of this syndrome. Two Dutch gentlemen named Drenth and Michiels proposed the name erythromelalgia in 1990 .
The diagnosis has been based since its discovery on the clinical features described here, with pathophysiology previously attributed to vascular, inflammatory, and/or neuropathic causes. Symptoms in fact can remain modest for years or can evolve negatively so as to lead to a functional disability, especially in forms with early-onset, typical of birth or early childhood .
The term “erythromelalgia” was then differentiated from “erythermia” on the basis of the response to aspirin by Drenth and Michiels, establishing the following three categories .
a) Erythromelalgia in thrombocythemia: It is platelet-mediated and responds to aspirin. It occurs in association with essential thrombocytosis and polycythemia vera.
b) Primary Erythermia: Refers to an idiopathic or inherited disorder. Also called aspirin-resistant erythermia of unknown origin.
c) Secondary Erythermia: Aspirin-resistant and associated with a variety of medical conditions.
The course of erythromelalgia is characterized by painful attacks (erythromelagic crisis) that last from several hours to several days. Excruciating, stabbing pain during an attack is so intense that it can drive the patient to despair. The affected limb turns red, acquires a cyanotic hue, becomes warm to the touch, and moist from sweat, in rare cases, a rash of urticaria appears. In addition, there is usually moderate swelling of the affected areas, in extensive stages, there may be necrosis. In this case, the bulb of the fingers thickens, thickens, or atrophies the skin, brittleness, and turbidity of the nails with disfigurement of the limb. Painful sensations may reduce in a horizontal position and with the application of cold, so patients try to reduce pain by removing shoes and warm clothing or lifting their legs upward. Conversely, when standing and walking, lowering one’s legs, from heavy shoes, the pain intensifies. A painful attack can be triggered by reactive hyperemia that occurs when walking, so even with early forms of the disease, patients often want to take off their shoes and walk barefoot while walking. Outside of the attack, the patient does not feel completely healthy, as the painful pain during the attack is accompanied by severe emotional disturbances. Erythromelalgia as an idiopathic form is somewhat more common in men than in women; mostly young people are sick. In rare cases, there is a type of steady-state course of the disease. The secondary syndrome of erythromelalgia is characterized by a milder course. The intensity of peripheral vascular disorders may vary from a periodic sensation of heat in the extremities with transient hyperesthesia and increased skin temperature to the development of classic erythoplasmic crises. Trophic disorders, as a rule, are not as pronounced as in the primary form of the disease. The course of the erythromelagic phenomenon, in this case, depends on the course of the underlying disease .
Clinical diagnosis of erythromelalgia should be based on the following symptoms: a) paroxysmal pain disorder; the nature of the pain pulses, burns, the duration of seizures from several minutes or hours to several days, interictal periods from 10-15 minutes to several weeks and more, sometimes with a steady increase in the duration of the attack; the dependence of the painful attack at the time of year, the time of day (usually in the evening, at night), the surrounding temperature, wearing warm shoes, physical stress, position of the limbs. Stimulation of pain from walking on wet sand, snow, and cold lotions with ice; b) the initial location of pain: in the first toe, sole, heel, followed by spread to the whole foot and beyond; c) symmetry of the lesion: the lower limbs are most often affected, sometimes all four limbs, rarely only the upper limbs, rarely other localizations; d) local changes: local hyperemia, sometimes with edema, hyperhidrosis; Skin coloration is most often cyanotic, maybe with cyanotic spots, sometimes marble. There are never trophic ulcers. In some cases, hyperkeratosis, and lamellar stratification of the epidermis with deep cracks are observed .
In the differential diagnosis of the primary and secondary forms of the disease, the following should be considered .
The differential diagnosis includes post-traumatic reflex dystrophies, shoulder-hand syndrome, peripheral neuropathy, causalgia, Fabry disease, and bacterial cellulitis .
Treatment of erythromelalgia consists of avoiding exposure to heat sources, rest, limb elevation, and cold packs, and in the case of primary erythromelalgia, the administration of gabapentin, while in secondary erythromelalgia the treatment must be modulated based on the underlying pathology. Even when the primary disease with its treatment is not lost meanings in idiopathic form rhodonalgia vasoconstrictors the enamel, vitamin B12, gistaminoterapiya introduction Novocaine, assigning different species of physiotherapy (galvanic collar on Scherbakov, galvanizing zone sympathetic ganglia, alternation of hot and cold baths, bath two chambers - sulfide, radon, mud baths on segmental zones, ultraviolet irradiation paravertebral region dI, DXII), shown blo procaine nodes hells DII - DIV with the defeat of upper limbs, LI - LII - lower. Sufficiently effective is the use of acupuncture, and deep X-ray therapy on the spinal cord area. Patients should wear light shoes, and avoid overheating. In severe cases, resort to surgery (periarterial sympathectomy, preganglionic). In the idiopathic form of the disease, accompanied by a marked pain syndrome, a significant effect is produced by a stereotactic operation on the basal ganglia .
Since 2004, however, cases of hereditary erythromelalgia (IEM) have been linked to dominant gain-of-function mutations in the SCN9A gene and subsequent alterations in the function of the voltage-gated sodium channel Nav1.7.5. In addition, similar symptoms associated with autoimmune or myeloproliferative disorders have been reported in adults and termed “secondary erythromelalgia”, but are extremely rare in children. Thus, sodium channels (Nav1.1 through Nav1.9) have been encoded from one gene family (SCN) and are differentially distributed in the nervous system, heart, and muscles. In children, sporadic or inherited mutations affecting several voltage-conducting sodium channels have been associated with epilepsy, cardiac conduction, and skeletal muscle abnormalities, with treatment often based on nonspecific sodium channel blockers such as mexiletine. Nav1.7 channels are then expressed in peripheral nociceptive sensory neurons within the Dorsal Root Ganglia (DRG) and trigeminal ganglia, and in sympathetic ganglia neurons, and therefore play a key role in pain sensitivity. Gain-of-function mutations with IEMs typically increase the excitability of DRG neurons by hyperpolarizing the voltage-dependence of Nav1.7 channel activation (making the channels easier to activate), effectively slowing channel deactivation (which remains open longer), and consequently increasing the response to slow stimuli. It is also important to note that the site of mutation can influence both abnormalities of Nav1.7 channel function and age of onset and severity of symptoms, and while reports in adults have assessed phenotype-genotype relationships, details of clinical evaluation during childhood and/or genetic testing results have not been available in all pediatric case series .
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed . To identify the reported symptoms, management, and complications of SCN9A-positive IEM in Children and Youth (CYP), we searched PubMed (January 2019 to December 2021) using the search term “erythromelalgia” (which also identified “erythermia”), as a systematic review had already been published in March 2019 that examined all profiles of clinical interest .
The search, thus structured, revealed the presence of 19 manuscripts, including a clinical trial, meta-analysis, and randomized controlled trial and excluding reviews, systematic reviews, books, and documents, for the purpose of the clinical update.
The present work aims at the one hand to enrich that work by adding recent data from the last 3 years and on the other hand to present a single case that presents special characteristics. No additional eligible publications were found from the search in PsycINFO, EMBASE, or Cochrane databases. Records were screened and limited to those published in English. Citations deemed relevant and inclusive of the criteria were screened full-text.
The state of the art through 2019 captured a total of twenty-eight publications describing erythromelalgia associated with 15 different SCN9A gene variants in 25 children. The pain was severe and often refractory to multiple treatments, including nonspecific sodium channel blockers. Skin damage or other complications of cold immersion for symptomatic relief were common (60%). SCN9A mutations that resulted in increased hyperpolarizing shifts in Nav1.7 sodium channels were related to symptom onset at younger ages. Variability in reporting and potential publication bias toward severe cases limited any estimate of overall prevalence, and in this research, symptoms were similar but comorbidities were more common in children with SCN9A mutations; quantitative sensory testing also revealed marked dynamic warm allodynia. It concluded that: “Inherited erythromelalgia in children is associated with difficult-to-manage pain and significant morbidity. Standardized reporting of outcome and management in larger series will strengthen the identification of genotype-phenotype relationships. More effective long-term therapies are a significant unmet clinical need” . However, another study from 1999 that suggested the use of Pramipexol  for erythromelalgia as well was not considered in this research. It is a novel non-ergot dopamine agonist that has high selectivity for interaction with dopamine D2 receptors (especially the D3 receptor subtype). It has been effective in early Parkinson’s disease as monotherapy and as adjunctive therapy with L-dopa in advanced stages of the disease. Clinical improvement can be observed after 3 to 4 weeks of treatment. The adverse event profile of pramipexole is similar, in general, to that of other dopamine receptor agonists, although it can be expected that pramipexole should not induce side effects related to the chemical structure of ergot, such as erythromelalgia, distal vasospasm, retroperitoneal fibrosis, or pleural effusions. However, the study concludes, that the potential benefits of this promising dopamine agonist should be tested in well-designed prospective comparative studies with other ergot dopamine agonists and not;In the following years, several studies have focused on the use of this molecule on diseases such as Parkinson’s , fibromyalgia , bipolar depression , restless legs syndrome , Tourette’s syndrome , sleep disorders [16,17] and several other neurodegenerative conditions , but not erythromelalgia.
Thus, if the second form is well identified as a consequence of a primary disorder to be identified and corrected, the primary (or idiopathic) form still remains a clinical mystery. Many hypotheses are at stake [1,2].
A possible cause of the disease was considered peripheral neuritis, in relation to which in some patients by resection of peripheral nerves the impulses from the affected nerve endings were eliminated. The similarity of erythromelagic phenomenon was observed in patients with middle nerve damage .
In contrast, however, to the view of the peripheral origin of the disease, Degio believed that this disease had a central medullary origin. A similar view was shared by other researchers. According to their ideas, at the heart of erythromelalgia is the change in the gray matter of the lateral and posterior horns of the spinal cord, accompanied by paralysis of vasomotor fibers. This has been confirmed by observations on the development of erythromelagic syndrome in patients with various spinal cord injuries .
The phenomenon of rhodonalgia then is explained by the injury of the centers of the diencephalic regions (thalamic and subthalamic XYZ) around ventricle III, based on the monitoring of patients with pathology of the relevant areas of the brain .
At the same time, the connection between the manifestations of erythromelalgia and Raynaud’s disease is emphasized. These hypotheses are confirmed by observations on the positive outcome of the erythromelagic phenomenon, which developed in the framework of the third phase of the Reino phenomenon, which arose after sympathectomy .
Denying the role of the nervous system in erythromelalgia, some authors have considered the cause of the disease in the various changes in the arterial wall. Thus, a combination of erythromelalgia with Osler-Randu disease (hereditary hemorrhagic telangiectasia) is described. There is evidence that other diseases with primary vascular wall injury often lead to erythromelalgic attacks. Cases of erythromelalgia combined with polycythemia (Vakez disease) are still described .
There is a view that erythromelalgia is vasomotor neurosis and can occur in people with mental features. The development of erythromelalgia in children with psychosis has been observed. There were also some humoral aspects of the theory of the pathogenesis of erythromelalgia. The onset of the disease is associated with a violation of serotonin metabolism, as indicated by the relief of patients after taking reserpine and the appearance of the erythromelagic syndrome in serotonin-producing tumors .
But the real discovery was the correlation with the SCN9A gene. The SCN9A gene belongs to a family of genes that provide instructions for making sodium channels. These channels, which transport positively charged sodium atoms (sodium ions) into cells, play a key role in a cell’s ability to generate and transmit electrical signals. The SCN9A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.7. NaV1.7 sodium channels are found in nerve cells called nociceptors that transmit pain signals. Nociceptors are part of the peripheral nervous system, which connects the brain and spinal cord to cells that detect sensations such as touch, smell, and pain. Nociceptors are primarily involved in transmitting pain signals. The centers of nociceptors, known as the cell bodies, are located in a part of the spinal cord called the dorsal root ganglion. Fibers called axons extend from the cell bodies, reaching throughout the body to receive sensory information. Axons transmit the information back to the dorsal root ganglion, which then sends it to the brain. NaV1.7 sodium channels are also found in olfactory sensory neurons, which are nerve cells in the nasal cavity that transmit smell-related signals to the brain. Several are the pathologies related to mutations of this gene; among the most important we find the congenital pain insensitivity syndrome, the extreme pain disorder paroxysmal, the small fiber neuropathy, genetic epilepsy with high fever, the type II autosomal hereditary sensory neuropathy, and finally the erythromelalgia itself. More than 10 mutations in the SCN9A gene have been found to cause erythromelalgia, a condition characterized by episodes of pain, redness, and swelling in various parts of the body, particularly the hands and feet. All identified mutations change one protein building block (amino acid) in the NaV1.7 sodium channel. These mutations result in a NaV1.7 sodium channel that opens more easily than usual and stays open longer than normal, increasing the flow of sodium ions that produce nerve impulses within nociceptors. This increase in sodium ions enhances the transmission of pain signals, leading to the signs and symptoms of erythromelalgia. However, an estimated 15% of cases of erythromelalgia are caused by mutations in the SCN9A gene. Other cases are thought to have a nongenetic cause or may be caused by mutations in one or more as-yet-unidentified genes or being confirmed with a more representative statistical sample [28-43].
A.A., the male, was born in 2008, to non-consanguineous parents. A.’s clinical history begins with the symptomatic manifestation of restlessness and pain, in the first summer month at only 8 months and a half; symptoms regressed once he returned from his summer vacation in a cooler place. Symptoms seemed to disappear until the following summer when he began to suffer from localized pain, intense heat, and itching; symptoms again disappeared after returning from the vacation. Typical pediatric diseases were excluded. In the summer of 2011, the patient began to experience severe malaise, consisting of continuous crying, as if he had been struck by sunstroke; all symptoms that regressed by using fans and cold air conditioners. In the summer of 2012, the symptoms became more acute, and only compresses with ice and water from the refrigerator were able to alleviate, to the point that further medical checks focused on allergy and autoimmune profiles. It was only in those months that the diagnosis of erythromelalgia arrived for the first time, although in the absence of complete serum and genetic investigations, and the assumption of paracetamol, codeine, acetylsalicylic acid, and ketoprofen helped to reduce but not to make disappear the symptomatology suffered; useless the attempts to find remedy in oriental and Chinese medicine (acupuncture and local applications of Wang Bu Liu Xin seeds). Myalgic crises become more and more intense and unbearable, often lasting more than two weeks: “during the crises, A. does not sleep because his body burns so much that he tries to rest but is awakened by the pains, so the problem is not only his pathology that involves a danger for the high body temperature and the damage it can cause to the organs but the risk that the lack of sleep can bring to the heart brain”. In these cases, only morphine could provide relief and extinguish these symptoms. In 2016, after several attempts also with non-traditional medicines, the young patient uses prescription mexiletine, an antiarrhythmic for the treatment of dystrophic and non-dystrophic myotonia and alterations of the function of the chlorine or sodium channel, with excellent general benefits. Currently, the clinical picture is not yet stable because the drug therapy followed and prescribed (mexiletine 150mg for 2/days, ketotifen 20mg for 1/day only for the spring-summer period, indomethacin 50 mg for 1 day only for migraines, cannabidiol 5 drops for 2/days, carbamazepine 200mg for 2 / day, in addition to supplements of vitamin C, D, omega 3, multivitamins and probiotics such as lactobacillus, bifidobacteria e Streptococcus thermophilus) does not prevent the onset of symptoms, although the situation is more under control. The investigations carried out show a picture of microcytosis, low lymphocytes, anemia, and hypochromia, beyond a pediatric reference of slow growth and significant thinness (13y, 156cm/36kg), however compatible for symptomatology to the “idiopathic erythromelalgia on the genetic basis”, although in the absence of positivity to the genetic investigation on the gene SCN3A, 9A, 10A and 11A, Fabry disease and mutations in NALP3 and NALP12.
Although clinical publications on this morbid condition report as many as 16 different Nav1 channel substitutions 7 and more than 40 pharmacological treatments including agents with predominant but not specific sodium channel blocking activity (mexiletine, lidocaine, carbamazepine), anti-neuropathic drugs (gabapentinoids and antidepressants), antidepressant drugs with efficacy on migraines (amitriptyline), vasoactive drugs for the management of hypertension and analgesics (opioids and ketamine) , current research suggests new genetic hypotheses yet to be tested and the central importance of genetic counseling, to inform patients and their families about severity, likely course of symptoms, and risk of complications, and in some cases to guide clinical management. Current findings and the significant morbidity associated with the condition, including in light of the single case presented, highlight the need for mechanism-based therapies to improve clinical outcomes.
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