Erythromelalgia: studies on pathogenesis and therapy

Erythromelalgia (EM) is a rare condition characterized by red, hot and painful extremities. Local skin cooling provides relief. Warmth, exercise and dependency of the extremity intensify the discomfort. Shunt hypothesis: Clinical observations and pathophysiological findings are compatible with microvascular arteriovenous shunting of blood as a final common pathway of pathogenesis of erythromelalgia in affected skin. The hypothesis postulates that available blood is maldistributed. An insufficient proportion of blood is directed through nutritional capillaries, leading to skin hypoxia. while a large proportion of blood is shunted through microvascular anatomical or functional arteriovenous anastomoses. The skin hypoxia induces arteriolar dilatation and hyperemia, resulting in elevated skin temperature and accelerated metabolism. Because the hyperemic perfusion is still maldistributed, the hypoxia is not revealed. This vicious cycle may be triggered by different mechanisms related to hemorrheological problems, defects in prostaglandin metabolism, dysfunction of endothelial cells or the autonomic nervous system. Aim of the studies: The aim of this thesis was: to challenge the shunt hypothesis, to characterize the mechanisms underlying the vascular dysfunction in erythromelalgia, and to test if therapy, based on this understanding of the pathogenesis, would improve clinical and objective outcome measures in patients with erythromelalgia. Materials, methods and study design: Patients were selected from a database of EM patients built up over nearly 20 years (n=160). The patients were characterized by demographic and clinical parameters (cooling and pain scores, global assessment). Skin perfusion was assessed using laser Doppler flowmetry (LDF), laser Doppler perfusion imaging (LDPI) and computer assisted video microscopy (CAVM. LDPI assesses global (thermoregulatory and nutritive) skin perfusion; CAVM evaluates skin capillary morphology. Perfusion was assessed following vasoconstrictory and vasodilatory stimuli to characterize central and local neurogenic reflexes as well as vascular smooth muscle and vascular endothelial cell function and following central body heating to provoke EM symptoms in patients and healthy controls. In a double blind, crossover, placebo controlled clinical trial, EM patients were treated with misoprostol, a prostaglandin E 1 analogue with vasodilatory and thrombocyte inhibitory effects. Results: In EM patients, LDF assessed skin microvascular perfusion was significantly reduced during basal conditions. Vasoconstrictor responses involving central sympathetic reflexes were attenuated in affected skin. Central body heating induced a significant increase in LDPI-assessed perfusion and reduction in capillary density in affected EM skin containing many anatomical arteriovenous shunts, as compared to asymptomatic patients and controls. In areas with no or few shunts, the groups did not differ. We demonstrated beneficial clinical effects of misoprostol and redistribution in skin microcirculation in favor of nutritive perfusion. Conclusion: Increased thermoregulatory flow and decreased capillary density during EM attacks, as well as clinical improvement and redistribution of the skin microcirculation in favor of the nutritive perfusion after misoprostol treatment give support to the shunt hypothesis. Erythromelalgia was associated with neuropathy, which may be one underlying mechanism for the disturbance in the vascular dynamics. On the other hand vasculopathy with hypoxia may cause neuropathy. LIST OF PAPERS ASSOCIATED WITH THIS THESIS This thesis is based on the following papers, referred to in the text by their Roman numerals: I. Mørk C, Asker CL, Salerud EG, Kvernebo K: Microvascular shunting is a probable pathogenetic mechanism in erythromelalgia. Jlnvest Dermatol 114:643-646, 2000 II. Mørk C, Kvernebo K, Asker CL, Salerud EG: Reduced skin capillary density during attacks of erythromelalgia implies arteriovenous shunting as pathogenetic mechanism. Jlnvest Dermatol 119:949-953, 2002 III. Mørk C, Kalgaard OM, Kvernebo K: Impaired neurogenic control of skin perfusion in erythromelalgia. Jlnvest Dermatol 118:699-703, 2002 IV. Mørk C, Salerud EG, Asker CL, Kvernebo K: The prostaglandin E 1 analogue misoprostol reduces symptoms and microvascular arteriovenous shunting in patients with erythromelalgia. A double-blind, crossover, placebo-compared study. Jlnvest Dermatol 122, 587-593, 2004 PART ONE: INTRODUCTION Erythromelalgia (EM) is a clinical syndrome characterized by heat, redness and pain. EM symptoms are commonly intermittent, though constant in some patients. The duration of episodes or "flare-ups" varies from minutes to hours. The attacks occur more frequently during evenings and nights. Doctors therefore rarely observe the episodes unless the patients are hospitalized. As many doctors are not familiar with the disease, most patients have symptoms for many years before they get a diagnosis. A short introduction to the present understanding of erythromelalgia is given in Appendix I (Mørk & Kvernebo, 2000a). 1.1 History and nomenclature Graves reported in 1834 a young lady who suffered from a "hot and painful" leg, and the associated increase in temperature was found to be "so disagreeable" (Graves, 1834). In 1878, Silas Weir Mitchell reported 16 cases with painful affections of the feet of various types and severity and introduced the term "erythromelalgia" by combining the three Greek words erythros (red), melos (extremities) and algos (pain) to illustrate the triad of presenting symptoms and signs of the condition (Mitchell, 1872; Mitchell, 1878). He also described erythromelalgia as a `vascular storm." Erythromelalgia has also been named Mitchell's or Weir Mitchell's disease. Little notice was taken of the condition for many years (Collier, 1898; Cassirer 1912; May & Hillemand, 1924). In the literature, there has been confusion and inconsistency regarding the nomenclature, classification, prevalence, and pathophysiology. In 1932, Brown proposed five criteria for the diagnosis of erythromelalgia: (1) Attacks of bilateral or symmetrical burning pain in the hands and/or feet, (2) During attacks, the affected parts are flushed and congested and exhibit increased local temperature, (3) The attacks are initiated or aggravated by standing, exercise or exposure to warmth (limb temperature >34 ° C), (4) Relief is obtained by elevation or exposure to cold, and (5) The condition is refractory to treatment (Brown & Giffin, 1930; Brown, 1932). The term "erythermalgia" was introduced by Smith and Allen to emphasize the rubor, calor, and dolor, and they proposed a subdivision into a primary group, with no associated disease, and a secondary group, particularly hyperviscosity syndromes (Smith & Allen, 1938). The term "erythralgia" has also been used (Lewis, 1933; Lewis & Hess, 1933). In German literature "erythroprosopalgia" (prosopon-face) describes the condition in the face (Regli, 1969). The term "erythermomelalgi" is a more complete description of the clinical features, but this unwieldy label is not in general use (Zoppi et al, 1985). Other less common terms are acromelalgia, erythrothermia, red neuralgia, vasomotor paralysis of the extremities and Gerhardt's syndrome (Gerhardt, 1892). Lazareth et al proposed three major criteria (paroxysmal pain, burning pain, redness of affected skin) and four minor criteria (typical precipitating factors (heat exposure, effort), typical relieving factors (cold, rest), elevated skin temperature in affected skin, response of symptoms to acetylsalicylic acid) and demanded three major and two minor criteria for the diagnosis (Lazareth et al, 1988). Erythromelalgia and erythermalgia have been used interchangeable for many years, but Michiels et al proposed to restrict the term erythromelalgia to aspirin-responsive disease associated with thrombocytosis related to myeloproliferative disorder, and used erythermalgia for aspirin-resistant idiopathic cases or conditions secondary to other diseases (Michiels et al, 1995). Some authors subgroup their patients into "early-onset" and "late-onset" cases irrespective of etiology (Kurzrock & Cohen, 1991; Kurzrock & Cohen, 1995). "Pediatric erythromelalgia" has also been subdivided into a primary form with early debut, often severe, resistance to treatment and sometimes with a family history, and a secondary form associated with hypertension (Finley et al, 1992; Drenth et al, 1995). The term "epidemic erythromelalgia" has been used for outbreaks in China (Zheng et al, 1988). Some authors use a combination of the above terms to sub-classify cases based on the underlying pathophysiology. A modified classification of erythromelalgia, type I erythromelalgia ("classical") and type Il erythromelalgia, lacking the burning nature of the pain, and lacking relief by cooling or limb elevation, has also been used (Littleford, 1997; Littleford et al, 1999a,b). Like most authors, we use the term erythromelalgia, and in our work we have used the following inclusion criteria for this clinical syndrome (Thompson et al, 1979; Mørk & Kvernebo, 2000a): • Burning extremity pain • Pain aggravated by warming • Pain relieved by cooling • Erythema of affected skin • Increased temperature of affected skin Each criterion is dependent on individual clinical judgment. 1.2 Erythromelalgia in Norway Einar Hval (1901-1958) at the Department of Dermatology, Rikshospitalet, reported the first case of erythromelalgia in Norway (Hval, 1928). A renewed interest for erythromelalgia in Norway started in 1983 when a patient with a medical history typical for erythromelalgia was referred to Knut Kvernebo. Kvernebo was then working at the Department of Surgery, Aker University Hospital in Oslo with a vascular laboratory for examination of arterial and venous extremity blood flow as well as skin microvascular perfusion. The patient had cooled her feet in a bucket of iced water for up to 20 hours a day over 16 years. Together with Egil Seem, Kvernebo investigated the microvascular hemodynamics in the affected EM skin. Her situation was mentioned in a national radio program (Asa Rytter Evensen, "Saran er livet", NRK, Oslo), resulting in contact with a large number of frustrated patients with similar symptoms. 39 patients (50% of the respondents) suffered from erythromelalgia. Hemodynamic studies were performed in 1984-89, and a more thorough understanding of the pathophysiological and thereby pathogenetic mechanisms was obtained, resulting in the hypothesis that erythromelalgia is a condition caused by microvascular arteriovenous (AV) shunting. This work was rewarded with the King Olav V's Gold Medal in 1990. Kvernebo's work is presented in a monography (Kvernebo, 1998). Kvernebo contacted the Department of Dermatology, Rikshospitalet University Hospital, and presented his work, resulting in initiation of the scientific work presented in this thesis. An Erythromelalgia Study Group (ESG) was established with focus on epidemiology, pathogenesis and therapy. ESG is organized as a research network, so far involving the following seven units: Department of Biomedical Engineering, University Hospital, Linkopings Universitet, Sweden; Department of Cardiothoracic Surgery, Ullevaal University Hospital; Rikshospitalet University Hospital with the following departments: Institute of Laboratorium of Clinical Neurophysiology, Department of Neurology, Department of Psychosomatic Medicine, Department of Pathology, and Department of Dermatology; and The Erythromelalgia Association (TEA; www.erythromelaliga.org). Patients have continuously been referred to Department of Dermatology, Rikshospitalet University Hospital, and we have over a period of almost 20 years established a database of 160 patients, probably the largest EM cohort in the western world. All patients have been examined by one of three physicians in the group (Kvernebo, Kalgaard, Mork). Patients from Norway, Sweden, Denmark, UK, and USA were included. 1.3 Clinical features The EM diagnosis is based on the medical history and findings, and no objective laboratory criteria are available. Erythromelalgia is heterogeneous with regard to severity, localization, age at onset, etiology and prognosis. 1.3.1 Symptoms Before erythromelalgia is diagnosed, heat intolerance and symptomatic relief from cooling should be demonstrated. These features are hallmarks of erythromelalgia. The patients report major adjustments to their lifestyle to avoid precipitation of an EM attack. A prickling or itching sensation may herald the pain. All patients find self-induced measures to control their burning pain or deep aching. Patients typically seek relief by cooling of affected skin on cold floors, wet sand, wet towels, immersion in cold water, or by applying cold objects. The patients frequently sleep with the affected extremities outside the bed cover. Partial relief can be obtained by elevation of the affected extremity. Some patients show peculiar behavior, like walking barefoot in the snow, sleeping with the feet out of a window, putting the feet into a refrigerator or continuously living with a bucket with iced water at their side day and night. Cold and immersion may induce tissue damage, like immersion feet, infections, reactive flaring, and severe ulcers that can take many months to heal. Beneficial effects of aspirin is rarely seen, except for cases secondary to myeloproliferative conditions. Analgesics have limited effect. Warm environments make the EM symptoms more severe. Aggravating or inducing factors often reported are warm rooms, floors, water, heating appliances, bed covers, shoes, and gloves. Walking, physical activity, placing the limb in a dependent position (hanging down), and application of skin pressure may also intensify or precipitate the symptoms. Many patients report an increase in severity and frequency of erythromelalgia in the summer period. In addition, some patients have found that foods, beverages (particularly alcohol), spices (monosodium glutamate), and some drugs aggravate EM symptoms. Some doctors may find the patients' stories bizarre and may not believe that the patient is suffering from a genuine somatic condition. Some of the patients have significant complaints without objective signs when seeing the doctors. 1.3.2 Signs Affected skin in erythromelalgia is red to purple in color and may be warm or hot on touching compared to the adjoining asymptomatic skin. After anemisation of affected skin by diascopy, there is a short refilling time. Initially, the patients do not always notice this redness and local heat. Skin temperature and color are often normal at the time of physical examination, as the patients frequently are asymptomatic at the time of examination. The skin may even be white/pale or blue/cyanotic, which is suggestive of low basal skin blood flow in the asymptomatic skin. The patients should be instructed to look for changes in skin temperature and color during EM symptoms. Photography and measurements of skin temperature with and without EM symptoms may be of help in assessing changes in skin color and temperature. The affected limb can occasionally be oedematous. Trophic skin changes of affected skin areas have been described (Belch, 1996). Nail dystrophy and slow-healing skin ulcers of the feet without obvious signs of trauma or infection has been observed in severely affected patients (Kvernebo, 1998). Biopsies from affected skin may also heal slowly. Gangrene of the affected extremity, in spite of open limb arteries, has also been observed. 1.3.3 Impact on quality of life Erythromelalgia may have a severe impact on normal life. Diminished scores in quality of life questionnaires have been reported, primarily due to the pain associated with erythromelalgia (Davis et al, 2000a). Disabilities described in this study from USA include inability to walk long distances (50%), stand for long periods (49%), having to give up a job (12.5%), inability to drive (12.5%), use of wheel chair (3%), and being bed bound (2%). Patients avoid warm weather and limit their activities to cool or air conditioned locations. Some have to move to cooler climates. They cannot wear socks or closed shoes even in winter. Work and social functioning may be disrupted. Sometimes the patients avoid leaving their homes, leading to disablement and isolation. Restless sleeping patterns affects family functioning. Over a third of a large cohort have reported clinical depression or "depressed" states (Littleford, 1997). Like most chronic pain conditions, psychological mechanisms probably play an important part in the experience and coping of pain in many EM cases. Compared with an ageand sex-matched population, an increased mortality rate, including suicide, has been found (Davis et al, 2000a). No specific psychological profile has been found in the EM patients compared to patients with other chronic disorders (Kalgaard et al, in manuscript). Contact with The Erythromelalgia Association (TEA; www.erythromelalgia.org) may be helpful for frustrated EM patients "shopping" from treatment to treatment and from doctor to doctor in an effort to get answers and help for their problems. 1.3.4 Clinical classification The severity of the symptoms varies widely, from mild discomfort to erythromelalgia with gangrene that require amputation of the affected limb. In daily clinical work the terms mild, moderate and severe may be used. Erythromelalgia can be regarded as the antithesis to Raynaud's phenomenon representing an extreme condition on a continuous spectrum from cold to warm hands and feet (Fig 1). A severity score scale has been introduced based on the needs to cool the affected skin. 1. Feeling uncomfortably warm in periods. No active cooling. 2. Feeling uncomfortably warm in periods. Walking barefoot on cold floors etc. 3. Feeling burning pain in periods. Immersion in cold water <1 hour/d 4. Feeling burning pain in periods. Immersion in cold water 1-3 hours/d, 5. Feeling burning pain in periods. Immersion in cold water 3-6 hours/d, 6. Feeling strong burning pain. Immersion in cold water 6-12 hours/d 7. Feeling very strong burning pain. Immersion in cold water >12 hours/d 8. Feeling very strong burning pain continually. Continuous need for cooling or plexus/epidural anesthesia Based on clinical findings and etiology a classification has been proposed to characterize the wide spectrum of erythromelalgia (Fig 2). The term "erythromelalgia syndrome" is used when there is a family history of erythromelalgia, and when the symptoms start during childhood or adolescence and gradually increase in intensity. The disturbances are associated with structural changes in the microvascular architecture of the skin. The term "erythromelalgia (Kvernebo, 1998) phenomenon" is used for all other cases. Erythromelalgia may be primary (idiopathic) or secondary when considered to be caused by a primary disease or condition. The term "acute" is used when the symptoms increase and reach maximum severity within one month. Cases with persistent symptoms over long periods are termed "chronic." Prognosis depends on the clinical subgroup: erythromelalgia syndrome gradually gets worse, acute erythromelalgia gets better, while chronic erythromelalgia seems to remain stable (Kalgaard et a1, 1997). In all new cases, underlying causes should be looked for, and a variety of etiological factors may be involved in secondary erythromelalgia. Cases initially classified as primary should be reclassified when an underlying condition has been diagnosed. Several hematological, metabolic, neurologic, connective tissue, musculoskeletal, cardiovascular, and infectious disorders as well as pharmacological substances have been described associated with erythromelalgia (Table 1). When erythromelalgia coexist with another disease or condition, the question arises whether the relationship is a coincidental or causal. A high incidence of co-occurrence, parallel and synchronous course of both conditions, remission of erythromelalgia after treatment of the underlying condition, and pathogenetic or etiological evidence of causality are all indications of a causal relationship. Due to the low prevalence of erythromelalgia, statistical or epidemiological evidence for a causal relationship is difficult to prove. A beneficial effect on the EM symptoms after successful treatment of the primary condition indicates a causal relationship. An understanding of the pathogenetic mechanisms in the primary condition as in myeloproliferative diseases may indicate a cause-and-effect linkage between the conditions. Many of the accompanying conditions reported in erythromelalgia may produce physiological disturbances in the vessel wall (blood/tissue diffusion barrier), in the composition of the blood (hemorrheological properties), or in blood flow (microvascular maldistribution), which seems to be important pathogenetic or etiological evidence for a linkage. The temporal relationship between erythromelalgia and an underlying disease varies. Since secondary erythromelalgia is caused by an underlying disease, the primary condition by definition must precede the development of erythromelalgia, but the primary disease may be undiagnosed for many years. The symptoms and signs of erythromelalgia usually affect the extremities, most frequently the lower extremities, and usually bilaterally and symmetrically. Most frequently the acral parts of hands and/or feet are involved but more proximal parts of the extremities may also be affected Rarely, Fig. 2: Clinical classification of erythromelalgia (Kvernebo, 1998) erythromelalgia may appear in the face and ears. Primary erythromelalgia is localized to skin areas distal to the ankle or wrist areas, where anatomical AV anastomoses have been described. In secondary erythromelalgia and in erythromelalgia syndrome, symptoms may occur in other skin areas. Based on the follow-up of 112 patients from our EM cohort, the clinical and demographic characteristics are presented in figure 3 and tables I-III. Twelve patients had a family history of erythromelalgia. Four legs in three patients are amputated, in spite of