Definition and Historical Perspective

Erythromelalgia is a rare condition of the extremities characterized by the triad of redness, warmth, and pain. The symptom complex of intermittent acral warmth, pain, and erythema that defines erythromelalgia has been well documented in the medical literature for more than 150 years. Graves¹ described cases of “hot and painful legs” in 1834. The term erythromelalgia was coined in 1878 by Mitchell² from erythros (red), melos (extremity), and algos (pain); some have since referred to it as Mitchell’s disease. As we discover more about the link between a vasculopathy and neuropathy in this syndrome, it seems that Mitchell was prophetically accurate when he entitled the original manuscript “On a Rare Vasomotor Neurosis of the Extremities.” Smith and Allen³ emphasized another essential component of this syndrome when they renamed it erythermalgia in 1938 to denote the heat (thermé) in the affected extremity during periods of redness. Although many authors agree that erythermalgia is perhaps more accurate, erythromelalgia is the term most commonly used, and it is the term used in this chapter.

Although poorly characterized inititally,^4–6 there have been considerable advances in the characterization of this clinical syndrome, with large case series^7–10 published. Although the condition is mysterious, it is not as mysterious as was once believed.^9,10 It has been argued that William Harvey could have had erythromelalgia, not gout.¹¹ Much of our current understanding of erythromelalgia derives from the larger case series reported.^7,8,10,12,13

Nomenclature

Considerable confusion exists regarding the nomenclature of erythromelalgia.¹⁴ Many terms have been used, and some authors have proposed that these terms should refer to different forms of erythromelalgia, as detailed later. However, these synonyms are not widely used, and most authors now use the term erythromelalgia as originally used by Silas Weir Mitchell (1829-1914). Related names used by some include Weir-Mitchell’s disease, Mitchell’s disease, and acromelalgia. Michiels et al.¹⁵ proposed that the term erythromelalgia be restricted to cases due to myeloproliferative disorders responsive to aspirin therapy. They used the term erythermalgia to describe idiopathic conditions or conditions due to other diseases that are unresponsive to aspirin therapy. An unwieldy term, erythermomelalgia, accounts for the four cardinal symptoms and signs of the condition, but it is not in general use.¹⁶ Erythralgia has been used.^5,17 Erythroprosopalgia, derived from prosopon (face), is used in the German literature to describe facial erythromelalgia.^5,14,17

Criteria for Diagnosis

No objective criteria exist for the diagnosis of erythromelalgia, making it difficult to interpret some of the cases reported in the literature.¹⁴ The diagnosis is most often clinically based, dependent on the medical history and physical findings, because no objective diagnostic or laboratory tests are available,¹⁴ and because the physical findings of erythromelalgia may be absent owing to the frequently intermittent nature of the condition.⁸

Different diagnostic criteria have been suggested by different authors. Weir Mitchell^2,8 applied the three inclusion criteria used in the original description of the syndrome: red, hot, and painful extremities. Brown¹⁸ added three additional criteria in 1932: induction and exacerbation of symptoms by warming, relief by cooling, and unresponsiveness to therapy. The criteria were described as follows: (1) during attacks (bilateral or symmetrical burning pain in hands and feet), affected parts are flushed, congested, and warm; (2) attacks are initiated or aggravated by standing, exercising, or exposing the extremity to temperatures warmer than 34 °C; (3) symptoms are relieved by elevation of the extremity or exposure of the extremity to cold; and (4) the condition is refractory to treatment. Thompson et al.¹⁹ suggested the following five criteria: (1) burning extremity pain, (2) pain aggravated by warming, (3) pain relieved by cooling, (4) erythema of the affected skin, and (5) increased temperature of the affected skin. These five criteria have been used in several publications.^{10,14,20–23}

Lazareth et al.²⁴ used three major and two of four minor criteria to satisfy the diagnosis. Major criteria were paroxysmal pain, burning pain, and redness of affected skin. Minor criteria were typical precipitating factors (heat exposure, effort), typical relieving factors (cold, rest), elevated skin temperature in affected skin, and response of symptoms to acetylsalicylic acid. Drenth et al.^25–28 distinguished three types of red, congested, and painful conditions of the extremities that must be distinguished for effective treatment according to their cause: (1) erythromelalgia in thrombocythemia, (2) primary erythermalgia, and (3) secondary erythermalgia. Kurzrock and Cohen²⁹ used a classification of early-onset erythromelalgia and late-onset erythromelalgia, irrespective of the cause.

Littleford et al.³⁰ used a classification of type 1 erythromelalgia (the typical form) and type 2 erythromelalgia (the abortive form), in which the burning nature of the pain is absent and symptomatic relief is not always provided by cooling or elevation of the limb. Mørk and Kvernebo¹⁴ made the following distinctions: (1) Syndrome is used when initial and gradual symptoms localized to the feet and legs appear in childhood or adolescence, and when there is a family history of erythromelalgia; phenomenon is used for all other cases. (2) Erythromelalgia is primary when it is idiopathic. It is secondary when symptoms are caused by a primary disease such as a hemorrheological, metabolic, connective tissue, musculoskeletal, or infective disease; are induced by drugs; or are part of a paraneoplastic phenomenon. (3) Acute is used when symptoms reach maximal strength within 1 month after onset of symptoms. (4) Borderline erythromelalgia, erythromelalgia, and severe erythromelalgia may be useful.¹⁴

Clinical Controversies

Several controversies persist concerning erythromelalgia: nomenclature, diagnostic criteria, scoring systems for clinical severity, and pathogenesis. Classification of erythromelalgia into primary and secondary types may be controversial when comorbid conditions are mislabeled as underlying diseases that cause erythromelalgia. Classification of incomplete forms of erythromelalgia is also controversial; for example, some patients report that their feet are blue when symptoms are present. The problem with all definitions is that each criterion depends on clinical subjective judgment. The diagnosis of erythromelalgia is based on history because there are no objective physical findings. This may lead to an erroneous diagnosis.

Clinical Presentation

The essential elements of this clinical syndrome, as described by its name, are intermittent (occasionally continuous) redness of an acral area (i.e., extremities, head and neck area) associated with heat and pain. Common terms used to describe the pain include “piercing,” “burning,” and “discomfort.”⁸ The pain and burning sensation can be extremely severe. Patients report that they make major adjustments to their lifestyles to avoid precipitating an event. During an episode, they try to cool their feet in many ways, sometimes resorting to extraordinary measures to alleviate the pain, such as putting their feet in ice or walking barefoot in snow.

Erythromelalgia involves the feet in most circumstances (Fig. 50-1A-B); a minority of these patients have similar symptoms involving the hands.⁸ Occasionally, only the hands are involved. Erythromelalgia may extend proximally to the knees in the lower extremities (Fig. 50-1C) and to the elbows in the upper extremities. Involvement of the extremities is generally symmetrical. Rarely, erythromelalgia involves the ears and face. In the largest reported series (168 patients), symptoms predominantly involved feet (148 patients, 88.1%) and hands (43 patients, 25.6%).⁸

Figure 50-1 Erythromelalgia (red, hot, acral areas) involving lower extremities may affect toes only, distal forefoot (A), entire foot (B), or may extend up the leg, even beyond the knee (C). It is usually bilateral (C).

In the majority of patients, symptoms are intermittent; episodes, precipitated by specific triggers, can last from minutes to hours. In a minority of patients, erythromelalgia symptoms are continuous, although they may wax and wane. Patients with continuous symptoms usually report that their symptoms started intermittently and then became more frequent and prolonged until they were continuous. In the series of 168 patients,⁸ symptoms were intermittent in 163 patients (97%) and continuous in 5 (3%).

The specific precipitant for erythromelalgia varies from person to person, but the most frequent precipitant is an increase in temperature of the affected acral area. This may be caused by an increase in ambient temperature, and patients may experience increases in severity and frequency of attacks during the summer. Erythromelalgia affecting the feet is often precipitated by an increase in local temperature from aerobic exercise. Symptoms can also be precipitated or intensified by lowering the affected part. Common aggravating factors include warm rooms, floors, or water; placing the extremity near heating appliances; sleeping under bedcovers; and wearing shoes and gloves. Walking, exercise, sitting, dependency of the extremities, and application of skin pressure may intensify symptoms. Some patients relate that episodes of erythromelalgia occur spontaneously without clear precipitating factors.

Aspirin may dramatically relieve symptoms in a subset of patients with underlying myeloproliferative disease, but otherwise aspirin is rarely effective. Other agents that have been reported to relieve symptoms are presented later in the section on treatment. Many patients report that plunging their feet into ice water during an episode relieves their symptoms. Patients frequently report that the affected extremities must be exposed to cold surfaces or air-conditioned rooms or be immersed in buckets of cool or ice water to relieve their symptoms. A decrease in local temperature may decrease the severity of erythromelalgia or even abort an episode. Some patients sleep with their extremities outside the bedcovers, and some engage in unusual behaviors such as sleeping with their feet out a window, putting their feet in a refrigerator, walking barefoot in the snow, or storing shoes in a freezer. Kvernebo¹⁰ described a patient who, for almost 25 years day and night, lived with a bucket of ice water at her side, immersing her feet intermittently for 15 to 30 minutes an hour. Thus, in what superficially appears to be the antithesis of Raynaud’s phenomenon, patients seek relief by cooling the affected extremity.

Symptoms of erythromelalgia are intermittent, and the clinical examination is often normal. If the patient is examined during an episode of erythromelalgia, the affected extremity is tender, erythematous, and objectively hot. In up to two thirds of patients, affected extremities are discolored (blue/cyanotic, red, or mottled) and cool or cold to the touch, with varying degrees of discomfort between episodes. Raynaud’s phenomenon is not uncommon between episodes, occurring in 15% of one series.³¹

The syndrome of erythromelalgia is frequently worsened when patients try to relieve their symptoms. For example, patients soak their feet in water and ice, which can lead to immersion irritant contact dermatitis or even frostbite. Allergic contact dermatitis due to substances that have been applied to the affected feet can occur. Other common vascular problems in the lower extremities such as edema, venous insufficiency, and lymphedema can be worsened by erythromelalgia. Patients may have high requirements for pain medications and become addicted to or dependent on narcotic analgesics. Psychiatric problems such as depression and obsessive-compulsive behaviors to avoid episodes of erythromelalgia can occur. The syndrome can be socially disabling if patients avoid exercising, walking, participating in sports, or leaving their homes, which leads to a sense of disablement, isolation, and loneliness. The syndrome frequently affects performance in the workplace (especially with manual work or jobs that entail standing) and at home.

Erythromelalgia predominantly affects individuals who are white and of any age. In the largest published series,⁸ all 168 patients were white, the female-to-male ratio was approximately 3:1, and the mean age was 55.8 years (range, 5-91 years). Symptoms had been present since childhood in seven patients (4.2%), and six patients (3.6%) had a first-degree relative with erythromelalgia.

Erythromelalgia can also occur in the pediatric age group. In the largest pediatric series reported—32 patients (girls, 22 [69%]) seen at the Mayo Clinic³²—mean age was 14.1 years (range, 5-18 years), and the diagnosis was delayed; mean time to diagnosis was 5.2 years. Seven patients (22%) had a first-degree relative with erythromelalgia; four were from the same family. Physical activity was limited in 21 patients (66%), and school attendance was affected in 11 patients (34%). Hypertension was not a feature of these patients. In contrast, Drenth et al.³³ described nine children in whom erythromelalgia was transient (seven girls and two boys, mean age 11.6 years); in seven, hypertension was directly related to the symptoms, and treatment of the hypertension with intravenous (IV) sodium nitroprusside relieved symptoms.

Diagnosis

Making the diagnosis is often a problem because objective findings may not be present during the physical examination, so the diagnosis may rest on history alone. However, because the differential diagnosis includes many possibilities, it is best to have evidence to support the diagnosis. The following may help:

Classification

Most authors agree on the fundamentals of the diagnosis of erythromelalgia, but there are many described criteria for diagnosis and many subclassifications of erythromelalgia. Use of these subclassifications may depend on whether one is a “lumper” or “splitter.”^28,29,34 The most popular classification of erythromelalgia is into primary and secondary forms.

Incidence

In a population-based study from Olmsted County, Minnesota, the overall age- and sex-adjusted incidence rate (95% confidence interval [95% CI]) was calculated to be 1.3 (0.8-1.7) per 100,000 persons 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 persons per year, respectively.⁸⁹ The incidence was noted to have increased over the past 3 decades. This incidence was approximately five times higher than that reported from Norway, where the incidence was calculated to be 2.5 to 3.3 per 1 million inhabitants per year in the Norwegian population, with a corresponding annual prevalence of 18 to 20 per 1 million.¹⁰ Cases of borderline erythromelalgia were not included in these figures.^9,10

Pathophysiology

The pathophysiology of erythromelalgia is not clearly understood. Part of the difficulty in understanding this disorder has been the heterogeneity of the affected population.⁹⁰ The underlying pathological mechanisms most likely involve a complex dysregulation of cutaneous blood flow that ultimately results in microvascular ischemia. Determining the nature of this dysfunction has also been challenging because control of cutaneous blood flow depends on an intricate interplay of systemic and local signals and is not completely understood.⁹⁰ A small-fiber neuropathy likely contributes to this dysregulation.^91,92