Erythromelalgia Research Articles

No mutations in the voltage‐gated NaV1.7 sodium channel α1 subunit gene SCN9A in familial complex regional pain syndrome

Mutations in the voltage-gated Na(V)1.7 Na(+) channel alpha1 gene SCN9A have been linked to pain disorders, such as inherited primary erythromelalgia and paroxysmal extreme pain disorder. Both show clinical overlap with complex regional pain syndrome (CRPS), a condition that is characterized by pain in association with combinations of vasomotor, sudomotor, sensory, and motor disturbances. Therefore, we here investigated the involvement of the SCN9A gene in familial CRPS. We performed a mutation analysis of the SCN9A gene in four index cases of families with CRPS. All 26 coding exons and adjacent sequences of the SCN9A gene were analyzed for mutations using direct sequencing analysis. No causal gene mutations were identified in the SCN9A gene in any of the patients. Despite the fact that the SCN9A gene is an excellent candidate, we did not find evidence that it plays a major role in familial CRPS.

Sympathetic Block for Treating Primary Erythromelalgia

Primary erythromelalgia is a rare condition that's characterized by erythema, an increased skin temperature and burning pain in the extremities. The pain is often very severe, and treating erythromelalgia is frustrating and difficult. We report here on the case of a 12-year old girl with primary erythromelalgia in both lower extremities. The pain was refractory to medical treatment, but a bilateral sympathetic block with lidocaine and triamcinolone resulted in relief from the pain. Our experience with this disease demonstrates that sympathetic blocks are effective in improving the symptoms and they may be attempted on erythromelalgia patients who do not respond to other treatments, including medication and epidural blocks.

Functional vascular diseases: Raynaud’s syndrome, acrocyanosis and erythromelalgia

Raynauds syndrome, acrocyanosis and erythromelalgia are functional vascular diseases that differ with respect to prevalence, clinical picture, therapy, prognosis, and impairment of quality of life. Raynauds syndrome occurs in 5 to 20 % of the population in Europe, is observed four times more often in women than in men and appears first at the age of 40 (3 to 80), on the average. Raynauds attacks are characterized by a paroxysmal white-blue-red or just white and blue discoloration of the fingers and toes; the attacks are induced by cold or stress, usually, cease after no more than some minutes (average 23 min.), but can also persist for hours. A distinction must be made between primary (aetiology unknown), secondary (aetiology known) and suspected secondary Raynauds syndromes (causal underlying disease suspected). There are several different therapy options, but not all of them have been substantiated by evidence. Acrocyanosis is rarer than Raynauds syndrome, and contrary to the latter, is characterized by nonparoxysmal, in most cases persistent, painless bluish-red symmetrical discolorations of the hands, feet and knees. It is more frequent in women than in men and becomes manifest before the 25th year of age, on the average (15th to 70th year of age). A distinction is made between primary acrocyanosis without detectable underlying disease and secondary acrocyanosis with a specific underlying disease. No effective therapy for primary acrocyanosis is known, but secondary forms can sometimes be treated. Patients with primary and secondary erythromelalgia, a very rare condition, sustain paroxysmal burning pain with marked reddening of the legs, feet and less often the hands. The attacks are triggered by warmth. Women are affected more often than men. The age of first manifestation is 40 to 55 years, but the first attacks may just as well occur during childhood. There are different therapeutic approaches with occasional success, but no general recommendations.

A case of primary erythromelalgia

Journal of the European Academy of Dermatology and VenereologyVolume 23, Issue 11 p. 1338-1339 A case of primary erythromelalgia D Galimberti, Corresponding Author D GalimbertiCorrespondence: D Galimberti. E-mail:daniel.galimberti@hospitalitaliano.org.arSearch for more papers by this authorA Pontón, A Pontón Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this authorL Rubio, L Rubio Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this authorA Torre, A Torre Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this authorV Angles, V Angles Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this authorE Soriano, E Soriano Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this authorR Galimberti, R Galimberti Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this author D Galimberti, Corresponding Author D GalimbertiCorrespondence: D Galimberti. E-mail:daniel.galimberti@hospitalitaliano.org.arSearch for more papers by this authorA Pontón, A Pontón Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this authorL Rubio, L Rubio Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this authorA Torre, A Torre Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this authorV Angles, V Angles Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this authorE Soriano, E Soriano Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this authorR Galimberti, R Galimberti Department of Dermatology and School of Medicine of the Hospital Italiano, Buenos Aires, ArgentinaSearch for more papers by this author First published: 08 October 2009 https://doi.org/10.1111/j.1468-3083.2009.03212.xCitations: 2 Conflict of interest: No affiliation or significant financial involvement from any organization in the subject matter or material discussed in the manuscript. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume23, Issue11November 2009Pages 1338-1339 RelatedInformation

Experience with oral mexiletine in primary erythromelalgia in children

Primary erythromelalgia is characterized by burning pain, redness, and warmth in the extremities. We present two cases of primary erythromelalgia both of whom presented with a history of several months of severe burning pain in both hands and feet. Both patients had received multiple pain medications with no improvement in symptoms. Pain was relieved by putting affected parts in ice cold water, which resulted in immersion injury of the affected parts. Both patients stopped taking part in school and social activities. We tried oral mexiletine, a class Ib antiarrythmic agent, in view of its reported role in various chronic painful conditions. Dramatic improvement was observed with its use. Both patients improved after several weeks of use, and there were fewer soaking episodes. We observed no adverse effects with mexilitine therapy.

Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota

To estimate the population-based incidence of erythromelalgia. Background Only one report describing the incidence of erythromelalgia has been published previously. A population-based analysis of data from the Rochester Epidemiology Project. Tertiary care medical centre in Olmsted County, Minnesota (a rural county in the south-eastern portion of the state). Thirty-three residents of Olmsted County with a diagnosis of erythromelalgia during the study period. Age- and sex-specific incidence rates of erythromelalgia were determined. None. Population-based incidence rate. The overall age- and sex-adjusted incidence rate (95% confidence interval, 95% CI) was 1.3 (0.8-1.7) per 100,000 people per year. The incidence of primary and secondary erythromelalgia was 1.1 (0.7-1.5) and 0.2 (0.02-0.4) per 100,000 people per year, respectively. The age-adjusted incidence rates (95% CI) were 2.0 (1.2-2.7) per 100,000 women and 0.6 (0.1-1.1) per 100,000 men. The study was limited by the small sample size and potential variability in recognition of erythromelalgia. The population-based incidence of erythromelalgia has increased with each decade in Olmsted County over the past three decades; overall incidence was 1.3 per 100,000 people per year, approximately 5 times higher than previously reported.

Mutation I136V Alters Electrophysiological Properties of the NaV1.7 Channel in a Family with Onset of Erythromelalgia in the Second Decade

BackgroundPrimary erythromelalgia is an autosomal dominant pain disorder characterized by burning pain and skin redness in the extremities, with onset of symptoms during the first decade in the families whose mutations have been physiologically studied to date. Several mutations of voltage-gated Na+ channel NaV1.7 have been linked with primary erythromelalgia. Recently, a new substitution NaV1.7/I136V has been reported in a Taiwanese family, in which pain appeared at later ages (9–22 years, with onset at 17 years of age or later in 5 of 7 family members), with relatively slow progression (8–10 years) to involvement of the hands. The proband reported onset of symptoms first in his feet at the age of 11, which then progressed to his hands at the age of 19. The new mutation is located in transmembrane segment 1 (S1) of domain I (DI) in contrast to all NaV1.7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III.ResultsIn this study, we characterized the gating and kinetic properties of I136V mutant channels in HEK293 cells using whole-cell patch clamp. I136V shifts the voltage-dependence of activation by -5.7 mV, a smaller shift in activation than the other erythromelalgia mutations that have been characterized. I136V also decreases the deactivation rate, and generates larger ramp currents.ConclusionThe I136V substitution in NaV1.7 alters channel gating and kinetic properties. Each of these changes may contribute to increased excitability of nociceptive dorsal root ganglion neurons, which underlies pain in erythromelalgia. The smaller shift in voltage-dependence of activation of NaV1.7, compared to the other reported cases of inherited erythromelalgia, may contribute to the later age of onset and slower progression of the symptoms reported in association with this mutation.

Erythromelalgia: two case reports and literature review

Erythromelalgia is a rare disease of unclear etiology characterized by recurrent erythema, burning pain and warmth of the affected extremities. In this paper we reported 2 cases of primary familial erythromelalgia and difficulties with achieving a significant improvement with the currently available treatment. Moreover, this paper provides a brief update on pathophysiology, prognosis and treatment of erythromelalgia.

Characterization of a familial case with primary erythromelalgia from Taiwan

Familial primary erythromelalgia is a rare autosomal dominant disease characterized by redness and painful episodes of the feet and hands, which is often triggered by heat or exercise. In this report, a Taiwanese family with the characteristic features of erythromelalgia is described. Genetic linkage studies established that the disease locus maps to human chromosome 2. Sequence analysis indicated that the disease segregates with a novel mutation in the alpha subunit of the voltage-gated sodium channel (SCN9A or Na(v)1.7). The change observed is predicted to cause the substitution of a highly conserved isoluecine 136 for a valine within the first segment of the transmembrane domain (D1S1). Using immuno-histochemistry to stain a skin biopsy specimen from the affected region, we demonstrate that there is a significant reduction in the number of small fibers.

Histopathologic findings in primary erythromelalgia are nonspecific: Special studies show a decrease in small nerve fiber density

The histopathology of primary erythromelalgia has been poorly characterized. A total of 33 skin biopsy specimens from 29 patients with a diagnosis of primary erythromelalgia were re-examined. Histopathologic findings were nonspecific. Vascular thrombi were not identified. A relative decrease in small nerve fiber density was noted in specimens from 13 of 16 patients.

Thalamic Stimulation as a Treatment for Primary Erythromelalgia: Technical Case Report

We report the use of bilateral thalamic stimulation in a case of primary erythromelalgia with immediate and important pain relief for 3 years. A 12-year-old boy experiencing primary erythromelalgia had a 4-year history of recurrent attacks of severe burning pain in both feet, accompanied by local reddening, swelling, and heating of the skin. The attacks were triggered by warmth and exercise. The pain was relieved only by elevation and cooling of the lower limbs, which he achieved by immersing his legs in a bucket of ice water, resulting in severe ulceration of the skin. Because of the gradual aggravation of the signs and symptoms and resistance of the patient's condition to several medical therapies, the patient received spinal cord stimulation. The implants were removed twice because of recurrent infection. Finally, the patient was treated with bilateral electrical stimulation of the ventral posterolateral thalamic nucleus, which resulted in important pain control until 3 years later. The patient was able to avoid water immersions, and all ulcerations disappeared. We conclude that thalamic stimulation was successful in this case of primary erythromelalgia.

Erythromelalgia: Small-Fiber Neuropathy by Any Other Name?

In Reply.I thank Dr Oaklander for her informative letter and comments. I share her view that symptom-based diagnostic names are often imprecise and the use of diagnostic names that describe an underlying pathophysiologic mechanism are preferred. Certainly, as stated in our case report and her letter, there is mounting evidence that some, if not all, patients with primary erythromelalgia have mutations involving the Nav1.7 sodium channel located on chromosome 2q.1–3 Yet, those responsible for elucidating this defect refer to the disease as erythermalgia or erythromelalgia in recent reports, and they have not suggested a new name for the condition.1–3 It would be presumptive of me to rename erythromelalgia based on my clinical experience with this patient.When I first saw this patient, he had a 9-year history of bilateral episodic burning foot pain associated with redness and warmth in the painful regions. The pain was brought on by heat and activity and relieved by rest and cooling. Other than the physical findings of reddened, warm, and thickened skin primarily of his feet and to a lesser extent in his hands, this patient's general physical examination on presentation and now is entirely normal. Neurologic examination reveals no deficits in sensory or motor function, normal deep-tendon reflexes, and the absence of allodynia. Many of the conditions suggested by Dr Oaklander were ruled out by his history, physical examination, and laboratory investigations as outlined in the report, which were entirely normal. One notable exception was Fabry's disease, and thus we ran the appropriate tests. However, our evaluation of this patient continues today. Before receiving Dr Oaklander's letter, the patient and parents consented to undergo genomic DNA analysis to determine if he possesses the “primary erythermalgia-susceptibility gene.”3 I am awaiting these results. I am also now planning, at Dr Oaklander's suggestion, to obtain quantitation of nerve endings in PGP9.5-immunolabeled skin biopsies. This test is not currently available at my institution, however, and the family has not given consent to undergo the test at this time.Our intention in publishing this brief report was to bring attention to the fact that continuous intravenous lidocaine infusion and oral mexiletine may be useful in some adolescent patients with erythromelalgia who do not respond to aspirin, anticonvulsants, tricyclic antidepressants, sodium nitroprusside, or epidural anesthesia. An added benefit to me and other readers has been to spur the interest of Dr Oaklander.

SCN9A Mutations Define Primary Erythermalgia as a Neuropathic Disorder of Voltage Gated Sodium Channels

Primary erythermalgia is a rare disorder characterized by recurrent attacks of red, warm and painful hands, and/or feet. We previously localized the gene for primary erythermalgia to a 7.94 cM region on chromosome 2q. Recently, Yang et al identified two missense mutations of the sodium channel alpha subunit SCN9A in patients with erythermalgia. The presence of voltage-gated sodium channels in sensory neurons is thought to play a crucial role in several chronic painful neuropathies. We examined four different families and two sporadic cases and detected missense sequence variants in SCN9A to be present in primary erythermalgia patients. A total of five of six mutations were located in highly conserved regions. One family with autosomal dominantly inherited erythermalgia was double heterozygous for two separate SCN9A mutations. These data establish primary erythermalgia as a neuropathic disorder and offers hope for treatment of this incapacitating painful disorder.

Primary Erythromelalgia in a Child Responding to Intravenous Lidocaine and Oral Mexiletine Treatment

Erythromelalgia is a rare, chronic, debilitating condition characterized by redness, warmth, and severe burning pain of the distal extremities. The feet are more commonly affected than the hands. Pain is precipitated by increases in temperature and by exercise. Patients often obtain relief by immersing the affected extremity in cold water. The pain is often refractory to treatment. For many patients, multiple pain medications have been useless in achieving complete relief of pain symptoms. Previous reports of erythromelalgia among adolescents indicated prolonged relief of pain with sodium nitroprusside infusions, epidural infusions of local anesthetics, or gabapentin treatment. We present a case of an 11-year-old, white, male child with primary erythromelalgia, whose initial symptoms started in his preschool years and whose childhood was marked by escalating episodes of pain with warmth and redness of his feet, precipitated especially by increases in temperature and by activity. All conventional pain management techniques had failed to relieve our patient of his symptoms, and he obtained some relief only by soaking his affected extremities in ice water. He had experienced minimal benefit from seeing a pain psychologist, who helped him develop techniques to cope with the pain. At the time of presentation, the patient's episodes of pain had increased to 15 to 20 per day, and there was evidence of chronic immersion injury to the skin of his feet. Before his most recent hospitalization, the pain had spread to involve his hands as well. The patient was overwhelmed with anxiety and could not participate in school or social activities at the time of admission. During his current hospitalization, he did show some therapeutic response to sodium nitroprusside infusion, which unfortunately had to be discontinued because of side effects and because his family desired to leave the ICU environment, which was stressful to the patient. He also had some response to lumbar epidural infusion of local anesthetics, which could not be continued because he found the motor blockade that accompanied his analgesia intolerable. However, intravenous lidocaine infusion, with subsequent transition to oral mexiletine therapy, proved very effective in reducing the frequency and severity of the pain episodes. The patient was discharged from the hospital with oral mexiletine therapy and has been monitored at the pain management clinic. He returned to and completed school, attended summer camp, and enjoys an active happy life. He walks without precipitating pain in his feet and sleeps 9 to 10 hours every night. He has needed to soak his feet on only 4 occasions in the 6 months since his discharge from the hospital. His quality of life has improved significantly. He has shown no evidence of liver toxicity, and his mexiletine levels have been stable.

Erythromelalgia

A 22‐year‐old woman has suffered for almost a year from bilateral erythema, swelling and warmth of hands and feet (Figure 1) progressing to severe pain. The pain was relieved by cold compresses several times a day and by elevating the affected extremities. For a few years she has had a recurrent respiratory infection, and 2 years before erythromelalgia (EM) symptoms she had infectious mononucleosis. A month before the onset of symptoms she had received an influenza vaccine with no unusual immediate reaction. All our patient's routine blood tests including platelet count were within normal limits. EM is a rare, poorly understood, chronic, sometimes progressive, and disabling disease that greatly affects the quality of life. EM is characterized by intermittent or constant intense burning pain, marked erythema and increased skin temperature, usually symmetrically on the lower extremities.1 When admitted to our department there was a symmetrical striking redness, swelling, tenderness, and warmth of the skin along with severe burning pain in distal limbs (Figure 1). At the beginning her symptoms appeared late during the day, but later on she had also these symptoms during the day, which were provoked by heat, exercise, and sometimes even by walking. The duration of her attacks lasted minutes to hours. The discomfort markedly affected her daily activities; she stopped hiking, playing sports, and even gave up her usual social activities. The diagnosis of EM was based on her medical history, clinical findings, and laboratory tests (hematological, biochemical, microbiological, immunological). Immunoglobulin G in enzyme‐linked immunosorbent assay test to Epstein‐Barr virus and cytomegalovirus was positive, while Immunoglobulin M was negative. Clinical and laboratory trials indicated that there was no systemic organ involvement. Peripheral pulses, tendon reflexes, neurological and electromyographic examination were normal. Plain radiography showed no specific findings of her feet and hands. Thermography revealed elevated skin temperature in the affected areas (hands and feet) and thermic amputation of the fingers on both hands (Figure 2). Treatment was extremely difficult. There is no consistently effective treatment for EM. Her symptoms were aggravated by heat and relieved by cold (ice). A multidisciplinary approach was necessary (instruction to the patient, learning how to avoid episodes, controlling secondary and underlying factors, use of drugs). At the beginning of The disease, aspirin was administered. Unfortunately, a few days after aspirin was administered, she developed an allergic drug eruption, which was confirmed by allergy testing. There was no improvement of her symptoms with combination of oral prostaglandin (misoprostol) in 800 mg daily dose and 10% capsaicin cream. Two months later, cyproheptadine (Periactin; Merck & Co., Whitehouse Station, NJ) 3 tablespoons daily (thereafter 2 tablespoons daily) was administered. Since she was using wet dressings frequently (a few hours a day for 5 months), she developed acrocyanosis on her hands and feet. The attacks were still present. Wet dressings during a few hours daily were useful. The symptoms were relieved upon cooling for the next few hours. For the time being, spontaneous remissions have not occurred. Since EM symptoms are still present, the patient tried seeking further help. Marked erythema and swelling producing tightness of both feet image Thermography. Elevated skin temperature in the affected areas and thermic amputation of the fingers on both hands. image

Misoprostol Effective in Management of Erythromelalgia

Erythromelalgia is a difficult disease to treat. Iloprost, a prostacyclin analog, was shown to be effective by an investigative team; the investigators

Pain in primary erythromelalgia—a neuropathic component?

Erythromelalgia is a condition characterized by attacks of red, hot, painful extremities with relief of symptoms by cooling and aggravation by warmth. Although the main emphasis has been on pathophysiological mechanisms related to circulatory changes, recent reports have focused on an involvement of efferent small nerve fibers indicating a neuropathic component. Since the symptoms resemble those described in neuropathic pain, we wanted to investigate the possible affection of afferent nerve fibers. Twenty-five patients with primary erythromelalgia were examined by neurological testing, neurography and quantitative sensory testing. Thresholds for heat, cold, heat-pain and cold-pain detection were compared with those of a group of 29 healthy controls. The patients had significantly higher median heat (39.5 (36.1–40.8) and cold (29.3 (27.1–30.8)-detection thresholds at the dorsal aspects of their feet compared to the controls (37.0 (35.4–37.7) and 31.2 (30.3–31.5) respectively). These findings show an impaired small fiber function inside or close to the symptomatic area in this group of erythromelalgia patients. Seven patients had brush-evoked allodynia and fourteen had punctate hyperalgesia inside or close to the symptomatic areas in their feet. When comparing the individual results, there is a tendency to clustering of patients in two separate groups; reduced small fiber input/no hyperalgesia and normal thermal thresholds/hyperalgesia. Our results showing an affection of afferent small nerve fibers together with the nature of the symptoms, suggest that the pain experienced by erythromelalgia patients could have a neuropathic component.

Erythromelalgia -- Cutaneous Pain Syndrome or Vascular Abnormality?

Erythromelalgia, a clinical syndrome characterized by intense redness, heat, and pain, usually affects the lower extremities and is more common in

Cyclosporin was effective in the treatment of a patient with primary erythromelalgia,

Cyclosporin was effective in the treatment of a patient with primary erythromelalgia,

Impaired Neurogenic Control of Skin Perfusion in Erythromelalgia

Erythromelalgia is a clinical diagnosis characterized by erythema, increased temperature and burning pain in acral skin. The pain is relieved by cooling and aggravated by warming. The symptoms have been hypothesized to be caused by skin hypoxia due to increased arteriovenous shunting. We examined skin microvascular perfusion in response to vasoconstrictory and vasodilatory stimuli, to characterize local and central neurogenic reflexes as well as vascular smooth muscle and vascular endothelial function, using laser Doppler perfusion measurements in 14 patients with primary erythromelalgia and healthy control persons. Skin perfusion preceding provocative stimuli was significantly reduced in patients with erythromelalgia (p < 0.01). The laser Doppler flowmetry signal after sympathetic stimulation of reflexes mediated through the central nervous system, was significantly diminished in patients with erythromelalgia as compared with healthy controls (Valsalva's maneuver p < 0.01; contralateral cooling test p < 0.05). Local neurogenic vasoconstrictor (venous cuff occlusion and dependency of the extremity) and vasodilator reflexes (local heating of the skin), as well as tests for vascular smooth muscle and vascular endothelial function (postocclusive hyperemic response) were maintained. These results indicate that postganglionic sympathetic dysfunction and denervation hypersensitivity may play a pathogenetic role in primary erythromelalgia, whereas local neurogenic as well as endothelial function is unaffected.