Clinical r e v i e w Erythermalgia with vasculitis: A review John L. Ratz, M.D., Wilma F. Bergfeld, M.D., and Willard D. Steck, M,D. Cleveland, OH Erythermalgia is a condition of the extremities characterized by redness, increased temperature, and burning pain. A case of erytherrnalgia and coincident vasculitis of the feet is reported. The literature on the subject is reviewed, and a possible mechanism of pathogenesis is discussed. (J AM ACAD [)ERMATOL 1:443-450, 1979.)

Erythermalgia is a disorder of lower and/or upper extremities characterized by redness, heat, and pain. It may occur alone or in association with a number of other diseases. A case of erythermalgia with lymphocytic vasculitis, panniculitis, and hypertension is reported. The concmrence of the disorders may show an association or may be the result of therapeutic misadventure on the part of the patient (i.e., vasculitis due to soaking his feet in ice water). The presentation is followed by a discussion of erythermalgia, with a review of the literature and various theories on the pathogenesis of this process. Utilizing the data available, we propose that an additional mechanism may be functioning in the pathogenesis of erythermalgia, one which might explain the results of documented therapeutic trials recorded to date for both the primary and secondary forms. CASE PRESENTATION

A 70-year-old retired male chemistry teacher came to the Cleveland Clinic in mid-March, 1977, with a 3-month history of swelling, redness, and burning of the feet. The problem occurred daily and was worse at night and early morning. Ice water soaks and leg elevation relieved the discomfort. A diagnosis of erythermalgia had been made by his family physician, and numerous medicaFrom the Department of Dermatology, The Cleveland Clinic Foundation. Reprint requests to: Dr. John L. Ratz, Department of Dermatology, The Cleveland Clinic, Cleveland, OH 44106/216-444-5722. 0190-9622/79/050443+08500.80/0 © 1979 Am Acad Dermatol

tions had been tried without success. These included indomethacin, propranolol hydrochloride, methysergide maleate, probenecid, hydrochlorothiazide, and acetylsalicylic acid (ASA) (up to 8 tablets per day). Symptoms worsened during a short course of prednisone. The patient had been in good health prior to the onset of his problems, and he had no history o f hypertension, diabetes mellitus, connective tissue disease, gout, or myeloproliferative disease. Review of symptoms was unremarkable with the exception of occasional mild dysuria. Physical examination, including peripheral pulses, was entirely normal; however, his feet became noticeably red and hot to palpation by late in the afternoon (Fig. 1). The erythema was most marked distally, and the temperature elevation did not extend proximally beyond the ankles. The results of the following laboratory studies were normal or negative: electrocardiogram, chest x-ray, urogram, barium enema and upper gastrointestinal x-rays, calcium, inorganic phosphorus, glucose, uric acid, cholesterol, total protein, albumin, total bilirubin, alkaline phosphatase, lactic dehydrogenase (LDH), serum glutamic oxaloacetic transaminase (SGOT), serum protein electrophoresis, complete thyroid evaluation, serology, acid phosphatase, and erythrocyte sedimentation rate. The white blood cell count was 5,100. Hemoglobin and hematocrit were normal, as were red cell indices and platelet count. Serum electrolytes were normal; however, the blood urea nitrogen (BUN) was mildly elevated at 30 mU/ml, and there were many white blood cells in the 443

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Fig. 1. Appearance of patient's feet during severe symptoms. Fig. 2. Vasculitis lesions appeared acrally on patient's feet. Fig. 3. Lymphocytic vasculitis with underlying panniculitis. (HematoxyIin-eosin stain; original magnification, x 66.)

urine. The urine culture grew more than 100,000 enterococcus organisms. An electromyeiogram revealed mild to moderate 1° axonal neuropathy, interpreted as being insignificant. Trial 1

The urinary tract infection was successfully treated with ampicillin, and repeat culture was negative. A trial of ergotamine tartrate with caffeine (Cafergot) was begun for the erythermalgia. The patient was advised to continue ice water soaks for relief of burning distress. By the end of April no appreciable difference in the erythermalgia was noted, and, in addition, painful red papules developed on the digits of his left foot (Fig. 2). These lesions varied in size from 2 to 4 ram, were bright red to inspection with a smxounding erythema, were acraIly located, and were quite tender to palpation. Histologically, they were characterized by a dense infiltrate of mononuclear cells within the dermis, the dermal arterioles, and the subcutaneous fat and its vessels. In addition, fibrinoid degeneration was noted in many of the affected vessels. The picture was that of lymphocytic vasculitis and septal panniculitis (Fig. 3).

Trial 2

The ergot preparation was discontinued, and prednisone, 60 mg daily, was given for 5 days. However, the vasculitic lesions continued to develop in increased numbers acrally on both feet, and the erythermalgia was unaffected. Trial 3

Biofeedback was then attempted but was unsuccessful in controlling either condition. This was repeated at a later date, again without success. Trial 4

It was believed that the vasculitic lesions may have been secondary to chronic cold exposure, and the ice water soaks were discontinued. In addition, ASA, 650 mg every 4 hours, and phenoxybenzamine hydrochloride, 10 mg daily for 1 week and 20 mg daily thereafter, were begun. The patient noticed not only cessation in the formation of vasculitic lesions but also a decrease in the symptoms of erythermalgia. Further laboratory studies at this time, which were either negative or normal, included: cryoglobulins, lupus erythematosus prepmation (LE prep), antinuclear factor, rheumatoid factor, he-

Volume 1 Nmnber 5 November, 1979 patitis-associated antigen (HAA), serum magnesium, urine and blood lead, urine mercury, serum and urine electrophoresis, creatinine and creatinine clearance, platelets, prothrombin time, and partial thromboplastic time. BUN was still slightly elevated at 30 mU/ml, serum IgM was normal, serum [gA was slightly increased at 380 rag%, and serum IgG was slightly decreased (850 mg%). These slight deviations were not considered significant. Platelet function studies were normal except for a slight increase in the Hardesty test of factor 1II availability. Again, this was not considered significant. The phenoxybenzamine was increased to 30 mg daily, and the patient began to notice longer pain-free intervals. However, because of unpleasant side effects, he asked that the medication be stopped in July, 1977. ASA was continued. By September, he began to complain of an increase in burning pain, and a second trial of methysergide maleate was begun without success. Phenoxybenzamine hydrochloride was restarted by October when the patient began to notice new lesions of vasculitis acrally. This was totally without benefit as it had been earlier, and was discontinued after 6 weeks. Trial 5

A course of dapsone (Avlosulfon), 200 mg daily for 6 weeks, was unsuccessful, and (Trial 6) betamethasone (NF), 6 mg daily for 2 weeks, was without benefit. Trial 7

All medications were discontinued in December, 1977, and the patient was admitted for a course of intravenous low-molecular weight dextran (LMWD). Results of laboratory studies were as before; however, the urine contained less than 1 mg/dl IgG. Myeloma typing was negative, and repeat urinalysis was normal. Roentgenograms of the feet were normal. A second course of LMWD and another trial of biofeedback were unsuccessful as the patient's symptoms continued. Trial 8

Topical 2% nitroglycerin ointment gave no relief, and new crops of vasculitic lesions began to

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develop. Findings of another biopsy were identical with those of the earlier biopsy. In addition, direct immunofluorescence revealed granular deposits of IgM and C3 in the dermal arterioles. Serum Clq assay and total hemolytic complement assay were within normal limits. Trial 9

A 3-month course of a combination drug containing isometheptene mucate, dichloralphenazone, and acetaminophen (Midrin) was attempted because of its benefit in vascular headaches. When it failed (Trial 10), phenylbutazone was begun for its anti-inflammatory action, but it was discontinued as well when it proved to be ineffectual. In April, 1978, he was again admitted to the hospital, and his blood pressure was found to be 170/100 mm Hg. His stools were black and positive for occult blood. An upper gastrointestinal series revealed three active duodenal ulcer craters. Results of laboratory studies were essentially unchanged, and, in addition, serum salicylate levels were normal, as were the serum gastrin, Clq, C3, cryoglobulins, and cryofibrinogen. Cold agglutinins were positive on one occasion at a titer of 1: 4, but a repeat study was negative. All medications were discontinued. Antacid therapy was begun for the ulcer disease, and hydrochlorothiazide was started for the hypertension. Trial 11

In September, 1978, the ulcer disease had stabilized, and, because of severe discomfort, azathioprine, 50 mg every day, and betamethasone (NF), 6 mg every day, were prescribed for the vasculitis. The patient noticed a gradual cessation in the formation of vasculitic lesions; however, the erythermalgia remained active and unchanged. Both of these medications were later tapered and stopped because of unpleasant side effects, and the vasculitic lesions began to reappear. Since that time, the patient has had additional trials of numerous medications, all of which have been unsuccessful in controlling the erythermalgia and vasculitis. The drugs used included hydroxychloroquine sulfate, 200 mg every day, and the combination of ephedrine sulfate, 50 mg three times daily, and methysergide maleate, 2 nag three

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Table I. Summary of results*

Parameter No. cases Age Asymmetry Sites most often affected Associated disease Male: female

I

Primary 30 All age groups 2 cases Legs No 2:1

I Secondary 21 Only >40 6 cases Legs Yes 1: 1

Since Babb's paper, four patients younger than the age of 40 have been reported, 5 *Data from Babb RR, et al: Circulation 29: 136-141, 1964.

Table lI. Distribution of patients according to associated disease

Disease Polycythemia Polycythemia alone Polycythemiaand hypertension Polycythemia and gout Polycythemia and hypertension and vasculitis Thrombocythemia Myeloid metaplasia Hypertension Hypertension and vasculitis Hypertension and venous insufficiency Venous insufficiency (postphlebitic) Diabetes melIitus Systemic LE Rheumatoid arthritis LSA Total

I Babb*I Expanded 9

9

1 3

5 1 3

3 4 1 1

--

]

3

3

1

1

2 1

2 6

1

1

21

1 33

*Data from Babb RR, et al: Circulation 29" 136-141, 1964.

times daily. The patient is currently taking only a diuretic. Further therapeutic trials, including possible plasmapheresis, are anticipated in hopes of alleviating the severe heat and pain as well as the continuing vasculitis that have been so incapacitating to him. DISCUSSION

"Erythromelalgia" was first described by MitchelP in 1878 and later renamed erythermalgia by Smith and Allen." These authors also divided the condition into primary and secondary forms, depending on the absence or presence, respectively, of associated disease.

In an extensive review of fifty-one patients from the Mayo Clinic, Babb et al a further characterized the two forms of the disease. A critical temperature of 32 to 36 C was found necessary to activate both forms of the disease,which could also be induced by exercise and dependence. A summary of their findings can be seen in Tables 1 and II. A further study of eight of the twenty-one patients with secondary erythermalgia showed that an associated condition could precede the erythermalgia by as long as 16 years.4 The number of patients with secondary erythermalgia was then expanded by Alarcon-Segovia et aP to include five patients with systemic lupus erythematosus. All of these patients were women; four were younger than 40, and all responded to adequate treatment of their lupus with prednisone. Two female patients with essential thrombocythemia were described by Redding, ~ and three more (two men and one woman) with thrombocytosis were described by Boneu et al.r Hammar 8 then added one patient with lesions of lichen sclerosis et atrophicus (LSA) occurring on the feet in association with erythermalgia. If one includes our patient as having hypertension and vasculitis, the number of patients with secondary erythermalgia becomes thiz~ty-three (Table II). It is interesting that our patient, as well as three others reported, a' 8 had peptic ulcer disease in addition to erythermalgia and associated condition. Two of these 4 had lupus and another had LSA. The number of reported cases of primary erythermalgia has also increased; '~-1l four were added to the number originally reported by Babb. In the report of Babb et al, a the various treatment modalities used in erythermalgia were reviewed. These included aspirin, Kutapressin, epinephrine, heat desensitization, vaccines, sublingual isoproterenol hydrochloride (Isuprel), nitroglycerin ointment, phenoxybenzamine hydrochloride, lumbar ganglionectomy, and peripheral nerve block or section. Also suggested as being helpful are prednisone, 5 phlebotomy, 4 methysergide maleate, 1~ and propranolol, la Jelinek 9 further listed tobacco, ephedrine, ergotamine tartrate, and antihistamines. In addition, he had the opportunity to study in his laboratory the effects of various medications on a patient with

Volume 1 Number 5 November, 1979

primary erythermalgia. These drugs included antazoline, ergotamine, isoproterenol, norepinephfine, carbachol, trinitrin, nicotine, methysergide, dipyramidole, and phenoxybenzamine. Jelinek found that none of these medications alone could control the patient's symptoms but that the combination of ephedrine, 60 mg three times daily, and methysergide maleate, 2 mg three times daily, brought about prompt relief. The symptoms could not be induced by strenuous exercise but could be induced by heating the patient's feet with an electric blanket. The symptoms, however, were adequately controlled on a daily basis. This relief was sustained for 9 months, at which point the methysergide maleate was tapered and stopped. Although his patient's symptoms returned to some degree, JeIinek found that these could be controlled by increasing the dose of ephedrine without restarting the methysergide. Little is actually known regarding the mechanisms causing erythermalgia; however, various theories have been proposed. A few of these are discussed by Babb et al a and include the ideas that such patients suffer from an unusual sensitivity to warmth, that distress might be due to increased blood pressure in the minute skin vessels, and that vasodilation is the direct cause of the burning distress, but that increased blood flow is not. This is evidenced by the fact that distress is not altered by use of a proximal blood pressure cuff. This finding was repeated by Mandell et al, 1° who suggested that, due to increased tone in the precapillary arterioles, blood is diverted to deep dermal and subdermal arteriovenous shunts. Blood flow, they theorize, may therefore be deficient distally, and the products of ischemia may further stimulate blood flow, as may be the case in dependent rubor. Boneu et al r found that aspirin in the presence of epinephrine suppressed platelet aggregation, suggesting a mode by which aspirin may function to benefit some patients. The results of platelet aggregation studies carried out by Boneu et al suggested that hyperaggregability might be due to increased numbers of platelets. Redding 6 suggested that such platelet aggregates are probably responsible for the release of vasoactive mediator substances. Jelinek° felt that mediators which may be

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responsible for the symptoms of erythermalgia might be linked to the kinin system. Pepper's 12 report implicated serotonin as a possible mediator, based on the fact that methysergide maleate, which is often beneficial in treating this disease, functions as an antiserotonin/vasoconstrictor, and despite the fact that normal serum serotonin levels have been found in such patients. An excellent study by JOrgensen and S~ndergaard 11 demonstrated the probable role of prostaglandins, particularly PGE, in the pathogenesis of erythermalgia. They demonstrated increased amounts of prostaglandins in perfusion studies of the skin of such patients, as well as abnormal responses to intradermally injected PGE,, PGE2, and PGF,,. In these patients, similar testing with other possible mediators was normal. All of the preceding studies suggest various mechanisms by which erythermalgia may be manifested. Any or all of these mechanisms may be working in any given patient. A solitary mechanism is suggested by the striking similarity of the symptoms in all patients with this disease. Different mechanisms, on the other hand, might better explain the effectiveness of one type drug (e.g., vasodilator) in some patients, while an opposite (e.g., vasoconstrictor) or unrelated drug (e.g., corticosteroids) may be the only beneficial therapy in other patients. Even though various mechanisms of action may be functioning, we propose a possible mechanism of action, based on observed arteriole damage or abnormality and findings reviewed previously in this report, that could conceivably be working in all cases of erythermalgia. We also point out how and why various drugs may or may not work in any given situation. Of the diseases associated with erythermalgia, systemic lupus erythematosus (as well as other collagen vascular disease), hypertension, and diabetes mellitus are all known to affect the peripheral vasculature adversely. In addition, polycythemia vera (PCV) has also been reported to be associated with peripheral vascular pathology. ,4 It is possible that such vascular damage may be the key to the pathogenesis of erythermalgia. It is tempting to suggest that vascular pathology, either primary or secondary, is present in all patients with erythermalgia because the associated

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R a t z et a/

MECHANICSOF ERYTHERMALGIA ARTERIOLE ?

bl°odf,o.

VENULE STIMULATE ~'f'~

~

°ge,..go,io.t )~EO.ATO.S =.d ~latelet [

OPEN SHUNT.

~

"~OPEN VENULES

andolhelial swolling narrowing o| lumon

Fig. 4. Proposed mechanism for erythermalgia. diseases all adversely affect the vasculature. Even though biopsy data are lacking in erythermalgia, based on our biopsy findings and those of others, 6 we would like to suggest that vascular abnormality or abnormal vascular response is present in patients with erythermalgia, and that this abnormality may be manifested as endothelial swelling in the cutaneous arteriolar vasculature. Such swelling then may effectively reduce the diameter of the vessel lumen and present an abnormal endothelial surface from which further pathologic responses can be generated. If such endothelial swelling is present, it must be enhanced or potentiated by ambient increases in temperature, exercise, or limb dependence, and reversed to some degree by the opposite actions. Such enhancement may then effectively reduce lumen diameter even further, setting the stage for sludging of blood flow and eventually platelet aggregation, 7 or even thrombus formation t° proximal to this constricted area, and relative vascular insufficiency distal to it. Platelet aggregates of this nature and/or perhaps damaged endothelium may then be responsible for the release of potent mediator substances, the nature of which is not fully understood at this time, but the identity of which has been alluded to earlier in this report. The primary action of such mediators is to attempt to restore circulation in the affected area. This can be done in two ways. One is to short-circuit the normal circulation by opening arteriovenous shunts as suggested earlier, 1° and the other is to stimulate some amount of vascular relaxation or dilatation on the postcapillary

vasculature. The end result would be a continuous surge of blood flow through arteriovenous shunts into the venous circulation, which completely bypasses the narrowed or occluded sites. Such increased local blood flow would be manifested clinically as erythema and an objective increase in the temperature of the affected area (Fig. 4). However, this action of the mediators alone could not account for the sensation of exquisite burning pain experienced by patients with erythermalgia. These or perhaps other mediators then must also stimulate local sensory nerve receptors to illicit this characteristic pain. Relief of this pain and of the other symptoms of erythermalgia, if this pathogenetic scheme is correct, might then be achieved by directing therapy at any of a number of targets or structures involved in promoting the response. Success or failure of a given modality will now be discussed by general mode of action of therapies utilized, rather than discussing this for separate drugs.

Vasoconstrieting agents Vasoconstricting agents, particularly methysergide maleate and ergot preparations, have been especially useful in controlling the symptoms of many patients with erythermalgia. In others, however, there has been no change or symptoms have worsened, as in our patient. This may be possible because, by constricting the already narrowed lumen of the cutaneous arterioles, such drugs promote the aggregation of platelets and the cascade of events that follows. However, in those cases in which such drags are beneficial in relieving symptoms, they may do so by closing or constricting the arteriovenous shunts that had been opened and perhaps also by bringing about some constriction of the postcapillary vasculature. This "closing off" of the postarteriole blood flow would effectively reverse clinical erythema and warmth. In addition to this action, such compounds may have a direct antimediator action, as has already been discussed for methysergide maleate. This type of action, if sufficient, should be able to negate the vascular response secondary to the mediators, and also to block stimulation of pain receptors responsible for the characteristic burning sensation. When this does not occur, and

Volume 1 Number 5 November, 1979 the pain and symptoms persist, mediator release may be in excess for the vasoconstricting agent to act effectively.

Vasodilating agents For a number of patients, various vasodilating drugs have appeared to be paradoxically effective. This beneficial response, however, may not be a paradox. Vasodilatation from any of these agents would occur in the arteriole circulation. Since this is the "take off" point of the erythermalgic response, opening or widening of the lumen here would eliminate sludging, decrease or halt platelet aggregation, and, therefore, inhibit mediator formation and release. Such agents could also keep the already formed arteriovenous shunts open, allow a more rapid clearing of lingering mediator substances, and establish a blood flow free of sludging. If arteriolar swelling and damage are particularly severe, however, these vessels may be unresponsive to the dilating compounds. When this occurs symptoms should persist and, in fact, erythema and warmth may even be aggravated by the action of such agents on the arteriovenous shunts and perhaps also the postarteriole circulation.

Anti-inflammatory agents Some drugs included in this broad category could be discussed individually. If only anti-inflammatory action is considered, these agents might be beneficial by reducing endothelial swelling, in such a way indirectly opening up the affected vascular lumen. The failure of such agents should not be surprising, however, because such action would in all probability be negligible. Also, platelet aggregation and thrombus formation may persist and with them the symptoms of erythermalgia. In this group of drugs, aspirin has long been advocated as being beneficial in the treatment of this condition. Aspirin, in addition to its antiinflammatory action, is also known to be adverse to platelet aggregation, 7 which may be enough to account for its efficacy. It is an analgesic and may also function as an inhibitor of mediator action, particularly if the mediator is a prostaglandin. 11 The failure of aspirin or any other drug to alleviate

Erythermatgia 449 symptoms in this condition could easily be due either to overwhelming vascular damage or to insufficient therapeutic action on the part of the drug. Also in this group of drugs, and meriting individual discussion, are the corticosteroids. If asyet-undefined autoimmune mechanisms play a role in the pathogenesis of this disease, then steroids would function by curtailing such mechanisms. It is likely that such mechanisms leading to vascular damage are functioning in the patients with systemic lupus erythematosus, and that the use of steroids is effective in these patients because the autoimmune machinery is shut down. In patients in whom this type of mechanism is not functioning and in whom steroids will be working only as anti-inflammatory agents, steroids should be, and probably have been, of very little use in controlling symptoms.

Other modalities A few other therapeutic modalities have been reported as being useful. Among these is phlebotomy. When this has been used successfully, it has been in patients with polycythemia. Its effectiveness is undoubtedly due to decreasing numbers of red blood cells and platelets, thereby reducing the opportunity for sludging and platelet aggregation. But just as phlebotomy does not always control PCV and its sequelae, it cannot be expected always to control erythermalgia, particularly if vascular damage is extensive. Sympathectomy, autonomic blockade, and biofeedback have also been proposed for treatment of erythermalgia. These may be viewed as surgical, neural, and "self-conscious" vascular control, respectively. If successful, it is because the resulting vascular reaction is sufficient to alleviate symptoms. The vascular mechanisms would be similar to those discussed for vasoactive agents in this report. CONCLUSION We have reported a case of erythermalgia with vasculitis. In addition, we have reviewed the literature and attempted to organize a theory of pathogenesis based on available data. We feel that erythermalgia is a complicated and disabling dis-

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ease in which the role of vasoactive mediators cap a b l e o f sensory nerve stimulation is of paramount i m p o r t a n c e . However, we feel that arteriolar damage and endothelial swelling are the essential and n e c e s s a r y features of the disease. Such vascular p a t h o l o g y results in a cascade o f events that includes platelet aggregation and possible thrombus f o r m a t i o n . Mediator release from here then results in stimulation of the cutaneous vasculature and p a i n receptors, resulting in the characteristic s y m p t o m complex of erythermalgia. W e h a v e also discussed the m o d e of action of a n u m b e r of drugs used in the treatment of eryt h e r m a l g i a and have suggested h o w and why they m a y or may not work based on our proposed mechanism. Erythermalgia by itself is not a malignant disease, Its symptoms, h o w e v e r , can be incapacitating and quite destructive to a patient's ability to function normally on a day-to-day basis. Because of this effect in our patient, we have offered him multiple trials of various medications, but without lasting effect. Because of the reported association with myeloproliferative disease, w e h a v e followed h i m closely for any sign of such a condition. It is our h o p e to offer him some relief f r o m his eryt h e r m a l g i a so that he m a y resume a m o r e normal daily life. Unfortunately, our attempts to date have b e e n thwarted.

REFERENCES

1. Mitchell SW: On a rare vasomotor neurosis of the extremities and on the maladies with which it may be confounded. Am J Med Sci 76:17-36, 1878. 2. Smith LA, Allen EV: Erythermalgia of the extremities: A syndrome characterized by redness, heat and pain. Am Heart J 16: 175-188, 1938. 3. Babb RR, Alarcon-Segovia A, Fairbairn JF: Erythermalgia, review of 51 cases. Circulation 29:I36-141, 1964.

4. Alarcon-Segovia D, Babb RR, Fairbaixn JF, Hagedorn AB: Erythermalgia. Arch Intern Med 117:511-515, 1966. 5. Alarcon-Segovia D, Diaz-Jouanen E: Erythermalgia in systemic lupus erythematosus. Am J Med Sci 266:149151, 1973. 6. Redding K: Thrombocythemia as a cause of erythermalgia. Arch Dermatol 113:468-471, 1977. 7. Boneu B, Pfis J, et al: Abnormalities of platelet aggregation during essential thrombopenia--effects of aspirin on erythromelalgia. Nouv Presse Med 14:2382-2388, 1972. 8. Hammar H: Plantar lesions of lichen sclerosis et atrophicus accompanied by erythermalgia. Acta Derm Venereol (Stockh) 58:91-92, 1978. 9. Jelinek VMJ: A study in erythromelalgia. Aust Ann Med 19:139-144, 1970. 10. Mandell F, Folkman J, Matsumoto S: Erythromelalgia. Pediatrics 59:45-48, 1977. 11. JCrgensen HP, Scndergaard J: Pathogenesis of erythromelalgia. Arch Dermatol 114:112-I 14, 1978. 12. Pepper H: Primary erythermalgia, report of a patient treated with methysergide maleate. JAMA 203:10661067, 1968. 13. Bada JL: Treatment of erythromelalgia with propranolol. Lancet 2:412, 1977. (Letter.) 14. Edwards EA, Cooley MH: Peripheral vascular symptoms as the initial manifestation of polycythemia vera. JAMA 214:1463-1467, 1970.

Erythermalgia with vasculitis: a review.

Clinical r e v i e w Erythermalgia with vasculitis: A review John L. Ratz, M.D., Wilma F. Bergfeld, M.D., and Willard D. Steck, M,D. Cleveland, OH Ery...
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