Erythromelalgia is named after the patient’s clinical presentation of erythema and pain in the distal extremities. The disease was first described in 1879 by Silas, an American neurologist. The typical clinical manifestation of erythema extremities is severe burning pain in the hands and feet, especially the feet, accompanied by marked erythema and increased skin temperature in the painful area. Erythromelalgia is a descriptive diagnosis, and because of the late discovery of significant differences in etiology, clinical manifestations, and response to treatment in different patients with erythromelalgia, erythromelalgia is divided into two types: one is secondary erythromelalgia, in which the patient has a primary disease, the most common causes of which include thrombocytosis, true erythrocytosis, connective tissue disease, and diabetes mellitus, etc. These diseases cause secondary Erythromelalgia can usually be found with a clear primary cause, and the symptoms of erythromelalgia can be significantly relieved after treatment or improvement of the primary disease, as well as oral aspirin can temporarily reduce the symptoms significantly. The rest of erythema limbosum that cannot find a clear primary disease is classified as primary erythema limbosum.
I. Clinical characteristics and etiology of primary erythromelalgia
Unlike secondary erythromelalgia, patients with primary erythromelalgia are not associated with other primary underlying diseases. 1994, Drenth et al. proposed clinical diagnostic criteria for primary erythromelalgia by analyzing and comparing the characteristics of different erythromelalgia, whose clinical characteristics include: 1. episodes of burning pain in the hands and feet bilaterally; 2. The clinical features include: 1. episodes of burning pain in both hands and feet; 2. episodes and exacerbation of pain usually due to standing, movement, or heat; 3. relief by elevation or cooling of the affected limbs; 4. erythema, congestion, and increased skin temperature at the site of pain during episodes; 5. unexplained cause and no treatment; 6. early onset (usually in childhood or before puberty) and lifelong persistence; 7. familial cases with an autosomal dominant pattern of inheritance1. In the early stages of the disease, there may be intermittent episodes of erythema and pain in the lower extremities, and in the later stages, there may be persistent erythema and pain in the extremities. Since PEM patients keep their affected limbs, especially the feet, immersed in cold water or ice water for a long time to relieve symptoms, most of them may develop frostbite, necrotic ulcers and scarring after the ulcers heal. Some patients even amputate their feet or commit suicide (Figure 1).
By examining the skin histopathology of the lesions in three patients with primary erythema limbosum, Drenth et al. found that the patients had thickened capillary walls in the dermis, some vascular dilatation, mild to moderate perivascular mononuclear cell infiltration, and no arterial occlusive embolism, the last point being distinguishable from erythema limbosum secondary to thrombocytosis.2 However, the pathology of primary erythema limbosum However, the pathology of primary erythromelalgia is not specific, and its etiology remained unclear at that time.
In 2001, Drenth et al. performed a microsatellite linkage analysis to locate five families with autosomal dominant primary erythromelalgia and finally succeeded in identifying the cause of primary erythromelalgia as a single gene. In 2003, Yang Yong et al. of the Department of Dermatology, Peking University First Hospital, further narrowed the linkage region in a primary erythromelalgia family and finally identified the causative gene for primary erythromelalgia as SCN9A4. At this point, the causative gene of primary erythromelalgia was finally identified, and primary erythromelalgia was also called hereditary erythromelalgia.
II. Pathogenesis of primary erythema limbosum
SCN9A encodes the α subunit of sodium channel 1.7, which together with the β subunit forms the complete sodium channel and is expressed on the cell membrane as a voltage-dependent gated sodium channel protein. When stimulated by external factors, such as injurious thermal stimulation, the gating of sodium channels opens and a large amount of sodium ions flows into the cell plasma from the outside of the cell, leading to the generation of action potentials in the cell membrane. The action potential is transmitted via the nerve axon to enter the central pain sensory area, which eventually produces pain sensation.
Yang et al. first identified two heterozygous missense mutation sites in the SCN9A gene in two patients with primary erythromelalgia, i.e., the conversion of amino acid 848 from isoleucine to threonine (I848T) and amino acid 858 from leucine to histidine (L858H) in the protein encoded by the gene. By expressing the mutated SCN9A protein in vitro and studying its electrophysiological function, Waxman et al. found that the I848T and L858H mutants underwent acquired functional changes in electrophysiology, i.e., the sodium channels encoded by the mutants became prone to open and generate action potentials, resulting in severe pain sensations at lower temperature stimuli5. Since then, mutations in the SCN9A gene have been identified in patients with primary erythema limbosum, and the relationship between mutations in the SCN9A gene and the clinical manifestations of primary erythema limbosum has been gradually established.
Diagnosis and treatment of primary erythromelalgia
According to the diagnostic criteria proposed by Drenth et al. in 1994, combined with the progress of etiological research, the best diagnostic criteria for primary erythromelalgia include the following six points.
1. episodes of burning pain in the hands and feet bilaterally.
2. the onset and exacerbation of the pain is usually due to standing, movement or heat.
3. relief by elevation or cooling of the affected limb.
4. erythema, congestion and increased skin temperature at the site of pain during the attack.
5, resistance to aspirin therapy.
6. The patient has a pathogenic mutation in the SCN9A gene.
According to the above diagnostic criteria, the diagnosis of primary erythema limbicum is not difficult. Prior to SCN9A gene testing, other primary diseases, including thrombocytosis, true erythrocytosis, lupus erythematosus and severe diabetes mellitus, need to be actively screened. It is important to note that although some patients with primary erythromelalgia present with clinical symptoms at age 61 years6, most patients with primary erythromelalgia have a younger age of onset, usually no older than 30 years, and most develop in childhood or adolescence.
Until the causative gene for primary erythromelalgia was identified, many treatments were tried for this disease, including topical topical capsaicin or lidocaine gel, and oral aspirin, calcium antagonists, tricyclic antidepressants, and misoprostol, but all were ineffective. Lidocaine dosing works well for most patients, but relapses quickly after discontinuation and the mode of administration affects the long-term application of the period. Some physicians have tried using lumbar sympathectomy or chemical lumbar sympathectomy, which provides some relief of erythema during attacks but limited pain relief.7 One case of chemical lumbar sympathetic nerve block has been reported in China as an effective treatment for erythema limbicum, however, despite the authors’ diagnosis of primary erythema limbicum, the patient’s SCN9A gene test did not In addition, some patients were treated with amputation, but disappointingly, the skin at the amputated end reappeared with significant pain, suggesting that amputation is not a treatment for primary erythromelalgia.3
Since primary erythromelalgia is caused by an abnormal over-opening of sodium channels, closure of sodium channels is the best option for the treatment of this disease. Nathan et al. reported that a patient with severe clinical manifestations of PEM responded well to intravenous lidocaine and oral mexilate.9 Sheets et al. found that patients with PEM with N395K mutation in the SCN9A gene responded much better to treatment with lidocaine than did PEM patients with the F216S mutation, due to the fact that the former was located at the binding site for lidocaine while the latter was not.10 Carbamazepine has been shown to be more effective for primary erythromelalgia with the SCN9A mutation site near the carboxyl terminus. In addition, effective treatment with gabapentin has also been reported.11 However, none of these drugs is a specific blocker of SCN9A, so inevitably all of them may bring some potential side effects, including adverse effects such as arrhythmia, drowsiness, constipation, dizziness, and severe drug allergic reactions.
IV. Outlook
In the past decade, the relationship between SCN9A gene and pain has entered an era of molecular biology, which has greatly accelerated the progress of pain research, and the relationship between various pain disorders and SCN9A gene is becoming a hot topic of research. Since mutations in the SCN9A gene can also cause a disease called congenital anosmia, in which only pain is absent and other senses are normally present.12 This is highly suggestive that SCN9A may have a highly specific role in peripheral sensory effects on pain. Thus, the development of SCN9A-specific sodium channel blockers may be able to bypass the non-analgesic side effects of existing sodium channel blockers and become novel analgesic agents, thus providing the best therapeutic option for the treatment of various chronic painful diseases.