STUDY Natural History of Erythromelalgia Presentation and Outcome in 168 Patients Mark D. P. Davis, MB, MRCPI; W. Michael O’Fallon, PhD; Roy S. Rogers III, MD; Thom W. Rooke, MD Objective: To describe the demographics, presenta- male, and 46 (27.4%) were male. At presentation, the pa- tion, and outcome in patients with erythromelalgia—a tients’ mean age was 55.8 years (age range, 5-91 years). rare and poorly understood clinical syndrome defined by Symptoms had been present since childhood in 7 pa- the triad of red, hot, painful extremities. tients (4.2%). Six patients (3.6%) had a first-degree rela- tive with erythromelalgia. Symptoms were intermittent Design: Retrospective medical record review with fol- in 163 patients (97.0%) and constant in 5 (3.0%). Symp- low-up by survey questionnaire. toms predominantly involved feet (148 patients [88.1%]) and hands (43 patients [25.6%]). Kaplan-Meier sur- Setting: Large tertiary care medical center. vival curves revealed a significant decrease in survival com- pared with that expected in persons of similar age and Subjects: Patients with erythromelalgia examined at the of the same sex (P,.001). After a mean follow-up of 8.7 Mayo Clinic, Rochester, Minn, between 1970 and 1994. years (range, 1.3-20 years), 30 patients (31.9%) re- ported worsening of, 25 (26.6%) no change in, 29 (30.9%) Intervention: The medical records of 168 patients were improvement in, and 10 (10.6%) complete resolution of analyzed. Follow-up data, which consisted of answers to the symptoms. On a standard health status question- 2 survey questionnaires or the most recent information naire, scores for all but one of the health domains were in the medical record from patients still alive and death significantly diminished in comparison with those in the certificates or reports of death for those deceased pa- US general population. tients, were obtained for all but 13 patients. Conclusion: Erythromelalgia is a syndrome with sig- Main Outcome Measures: Survival, morbidity, and nificantly increased mortality and morbidity compared quality of life. with the US general population. Results: All patients were white; 122 (72.6%) were fe- Arch Dermatol. 2000;136:330-336 RYTHROMELALGIA is a rare We provide the first available data on the clinical syndrome charac- natural history of disease and quality-of- terized by the triad of red- life measures in these patients and demon- ness, increased tempera- strate that erythromelalgia is a clinical syn- ture, and pain usually of the drome associated with significant mortality extremities. The term erythromelalgia was and morbidity. E 1 coined in 1878 by Mitchell : erythros (red), melos (extremity), and algos (pain). Other For editorial comment terms have been used,2,3 such as “ery- see page 406 thermalgia”4 and “erythralgia.” Babb et al,5 in an article describing 51 patients from our institution in 1964, suggested that an RESULTS increased incidence of myeloprolifera- tive disease was associated with the dis- PATIENT DEMOGRAPHICS order. To better define the demographics, One hundred sixty-eight patients with dis- presentation, role of therapy, and out- ease fulfilling the diagnosis of erythrome- come of erythromelalgia, we studied pa- lalgia were seen at the Mayo Clinic be- From the Department of tients with erythromelalgia examined at the tween 1970 and 1994; 122 (72.6%) were Dermatology (Drs Davis and Rogers), Section of Biostatistics Mayo Clinic, Rochester, Minn, between female, and 46 (27.4%) were male. All were (Dr O’Fallon), and Section of 1970 and 1994. This is the largest retro- white. Average age of these patients was Vascular Medicine (Dr Rooke), spective study of the syndrome of erythro- 55.8 ± 18.9 years; median age, 60 years; Mayo Clinic and Mayo melalgia thus far reported describing pa- and age range, 5 to 91 years. Three pa- Foundation, Rochester, Minn. tients with the diagnosis of erythromelalgia. tients were 11 years old or younger. ARCH DERMATOL / VOL 136, MAR 2000 WWW.ARCHDERMATOL.COM 330 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 PATIENTS, MATERIALS, is a self-administered standard survey that measures health- related quality-of-life outcomes that are not specific to age, AND METHODS disease, or treatment and that are known to be most di- rectly affected by disease and treatment. It provides a com- PATIENTS WITH ERYTHROMELALGIA mon yardstick to compare patients who have chronic health problems with those sampled from the US general popu- The medical records of 271 Mayo Clinic patients with a mas- lation. United States general population norms were esti- ter index diagnosis of erythromelalgia between 1970 and mated from responses to the National Survey of Func- 1994 were reviewed. Erythromelalgia was defined as a con- tional Health Status, a 1990 cross-sectional survey that vincing history of unexplained red, hot, and painful ex- included the SF-36. Respondents were drawn from the tremities. The subjective elements of redness, heat, and pain sample frames of the 1989 and 1990 reports of the Gen- were required to fulfill the diagnosis. Because of the inter- eral Social Survey, conducted by the National Opinion Re- mittent nature of this disorder, it was impossible to dem- search Center. The General Social Survey has surveyed the noninstitutionalized, adult US population annually over the onstrate objective signs in some patients. One hundred sixty- 6 eight cases fulfilled these criteria for inclusion in the study. past 20 years. Physical and mental health concepts are mea- sured. The SF-36 includes 1 multi-item scale measuring each DATA ABSTRACTED of 8 health concepts (or domains): (1) physical function- ing, (2) role limitations due to physical health problems, The history of erythromelalgia at presentation, duration of (3) bodily pain, (4) general health, (5) vitality (energy and disease at presentation, associated illnesses at presenta- fatigue), (6) social functioning, (7) role limitations due to tion, characteristics of the presentation, distribution of the emotional problems, and (8) mental health (psychologi- disease, laboratory results, and findings on clinical exami- cal stress and psychological well-being). These scales were nation were recorded and compared. scored by the 5-point Likert scale. The SF-36 was scored so that a higher score indi- FOLLOW-UP cated a better state of health. The scores were compared with scores from persons from the US general population. Follow-up of all patients was attempted. When necessary, The SF-36 has been validated, and there are at least 260 clinical trials using the SF-36 to assess general health out- death certificates were obtained, or the cause of death was 7 established by contacting the deceased’s family by tele- comes from the patient’s viewpoint. phone or mail. All living patients were sent 2 survey questionnaires STATISTICAL ANALYSES (an erythromelalgia survey questionnaire and a health sur- vey questionnaire) by the Mayo Survey Research Center. Appropriate summary statistics (eg, means, medians, SEs, If there was no reply to a first or second mailing, contact and SDs) were used to describe these data. Kaplan-Meier was made by telephone. If a patient signed a letter refus- survival curves were obtained to estimate survival from di- ing to fill out the surveys (10 patients did so), the patient agnosis. A 1-sample log rank test was performed to test sur- was documented as being alive on that date for the Kaplan- vival compared with that expected for persons of similar Meier survival curves. If the patient could not be traced, age and same sex with use of 1980 Minnesota white refer- the latest follow-up in the clinic medical record within the ence rates. The Cox proportional hazards model was used past 2 years was reviewed. If there was no follow-up within to assess the influence that certain characteristics at diag- that time, the patient was deemed to have been lost to fol- nosis had on survival. Statistical significance was set at low-up and was excluded from compilation of the Kaplan- P,.05. All values are reported as mean ± SD. Meier survival curve. NEUROPHYSIOLOGICAL AND VASCULAR STUDIES Erythromelalgia Survey Questionnaire We assessed the frequency and types of abnormalities ob- The questions covered symptoms, coincident diseases, qual- served during tests of vascular, peripheral neurophysiologi- ity of life, and the effectiveness of various treatments tried. cal, and autonomic function in patients with erythromel- algia. These will be reported in detail in a separate article.8 Health Survey Questionnaire Briefly, 5 patients had detailed vascular studies performed in 10 affected lower extremities before and during symp- Along with the erythromelalgia survey questionnaire, a gen- toms. Fifty-four patients underwent neurophysiological test- eral health questionnaire (Medical Outcome Survey Short- ing, 27 had autonomic reflex screening, and 2 had record- Form 36-Items [SF-36])6 was sent to the patients. The SF-36 ings of peripheral autonomic surface potentials. Fifteen patients were from Olmsted County, Minne- tients have since reported a first-degree relative with the sota, and 32 from eleswhere in the State of Minnesota. In- disorder. cidence could not be calculated, because we did not screen other possible codings of the disorder and thus could not CLINICAL PRESENTATION be sure of complete population-based case assessment. Six patients (including 3 from 1 family) had a first- At the time of presentation, the average duration of symp- degree relative with erythromelalgia. Two more pa- toms varied from less than 1 month to 26 years (mean, ARCH DERMATOL / VOL 136, MAR 2000 WWW.ARCHDERMATOL.COM 331 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 1. Cause of Death in 45 Patients With Erythromelalgia No. of Cause Patients Unknown 12 Cardiovascular 11 Myeloproliferative disease 6 Solid cancers (all) 5 Lung 2 Breast 1 Prostate 1 Ovarian 1 Suicide 3 Accidents 2 Connective tissue disease 2 Pulmonary 2 Cerebrovascular 1 Gastrointestinal hemorrhage 1 tients (8.1%).