Diffuse Lepra*

DIFFUSE LEPRA* M. E. OBERMAYER, M.D., S. C. BONAR, M.D. n R. ROSENQUIST, M.D.

Diffuse lepra, an unusual variety of the lepromatous type of the disease, was first described by the Mexican leprologist R. Lucio (1), in 1851, under the names

"spotted" or "Lazarine" lepra. However, Lucio's report was soon forgotten, and the disease escaped further observation until 1937, when it was again identi-

fied by F. Latapi and his co-workers. Further studies by these investigators added considerably to knowledge of the condition. One of us (M. E. 0.) became acquainted with diffuse lepra in 1944, when LatapI allowed him to observe patients with the disease in his clinic and leprosarium, and he subsequently prepared a brief account of the disease for inclusion in the revision of a dermatologic text (2). In 1947 it was learned that some members of the seasonal labor force annually imported from Mexico had been found to be suffering from diffuse lepra after their return home, although examinations by Mexican and American health authorities prior to their admission to the United States had disclosed no illness. Obermayer subsequently published a warning about diffuse lepra to the physicians of the southwestern states in the form of an illustrated article (3). These two publications are, to our knowledge, the only studies of this rare and bizarre form of lepra in the English language. LatapI (4) has expressed the belief that diffuse lepra is an exclusively Mexican disease. Even in Mexico it is regional, for it is encountered much more frequently in the state of Sinaloa, (where 60 to 70 per cent of the instances of lepromatous lepra are of the diffuse type) than in the other states (where an average of only 17 per cent of the patients with lepromatous lepra have the diffuse form). In view of the prevalent belief that the disease does not occur in countries other than Mexico, it is not surprising that we were unprepared to meet with diffuse lepra in the American-born patient who is the subject of this case report. Diffuse lepra has two special features: diffuse infiltration of the skin of the whole body and a peculiar type of lepra reaction called "Lucio's phenomenon," or erythema necroticans. The first manifestations of the disease, as in the ordinary lepromatous form, are frequently anidrosis, numbness of the extremities and slowly progressive loss

of the eyelashes and the eyebrows. Later all the hair of the body is affected; the brows and lashes disappear, and the alopecia may even manifest itself on the scalp, where the lesions sometimes resemble those of alopecia areata. Lepromatous nodules are not formed; instead, there is a diffuse inifitration of the skin of the entire body. The skin may appear normal on clinical inspection, but the

histamine test will elicit an abnormal response; and mycobacteria leprae can * From the

Birmingham Veterans Administration Hospital, Van Nuys, Calif. Published with the permission of the Chief Medical Director, Department of Medicine and Surgery, Veterans Administration, who assumes no responsibility for the opinions expressed or conclusions drawn by the authors. Received for publication December 9, 1948. 243

244

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

usually be obtained, by the scraped incision method, from any region of the skin. In some cases there is chronic, diffuse swelling of the face, hands or legs, and the

patient may have the "moon-faced" appearance so frequently encountered in myxedema. There are often widespread small telangiectases, which are particularly common on the face and trunk. About 3 or 4 years after the first manifestations of the disease, the unique lepra

reactions appear. In the beginning there are only a few lesions; later they are more numerous. The lesions, which are tender and painful, are erythematous, slightly infiltrated macules. They are irregularly shaped, often triangular, and average 0.5 to 1.0 cm. in diameter. They appear first on the legs and, to a lesser extent, the arms; much later the face and trunk are involved as well. The development and involution of the individual macules are uniform and rapid; the entire cycle takes about 2 weeks. The lesions soon darken and have become purpuric 3 or 4 days after they first appear; central necrosis develops, and an eschar forms and falls off in a few days, leaving a superficial, sharply circumscribed atrophic

scar. At times there is ulceration, usually on the legs, with a consequent delay in healing and the production of a deep residual scar. Since there are recurrent crops of the lepra reactions, scars and lesions in all stages of development may be present simultaneously. Many of the manifestations commonly encountered in the ordinary type of lepromatous lepra are also observed in diffuse lepra. For example, fever or disturbances of the gastrointestinal, pulmonary or circulatory systems may accompany the cutaneous reactions; hoarseness is common, and nasal involvement often results in the production of a saddle nose. Itis noteworthy that ocular involvement and the formation of cutaneous nodules, both regularly encountered in the ordinary lepromatous form of the disease, are not observed. There are progressive weakness, loss of weight and anemia, and without modern therapy the disease terminates fatally after an average duration of 8 years. The results of the Wassermann complement-fixation and Kahn precipitation tests are virtually always positive, and the sedimentation rate is extraordinarily high. The reaction to the conventional lepromin (Mitsuda) test is negative, as one

might expect in a lepromatous form of lepra. However, recent studies by Medina (5) indicate that there is an intense, short-lived intracutaneous reaction to lepromin which appears 4 to 6 hours after the test is performed. LatapI and

Chevez (6) confirmed this observation and obtained identical reactions to streptococcic and staphylococcic antigens. They have suggested that the reactions to both mycobacteria leprae and pyogenic organisms resemble the Shwartzman phenomenon rather than the conventional reaction to lepromin and that they may indicate a bacterial synergy. They read a preliminary report (7) on these reactions, which have such an important bearing on the immunologic aspects of the disease, before the 5th International Congress of Lepra and are continuing their investigations. Until the advent of the suffones the response to treatment was uniformly negative, but considerably better results have been reported with the use of promin

DIFFUSE LEPRA

245

(p.p.-diaminodiphenylsulfonate) and diasone (disodium formaldehyde sulfonylate diaminodipheaysuIfonate) (8). REPORT OF CASE

M. V., a 21 year old American man nf Mexican descent, entered the Birmingham Veterans'

Administration Hespital in December 1946, because of recurrent ulcers nf the extremities of more than 3 years' duration, lie had always been in good health until June 1943, when a tender red spot appeared on his right thigh; it later ulcerated and left a deep scar. Since then similar lesions have continued to appear almost without cessation on both the upper and the lower extremities. At about the time the first lesions developed the patient noticed that his beard and eyebrows were becoming less heavy. Since December 1943, when he entered an Army hospital, he has received almost continuous hospital care, in several in-

stitutions. In all of the hospitals, repeated, strongly positive reactions to the complement fixation and precipitation tests for syphilis were noted; even at the time of his induction into the Army, in January 1943, a doubtful reaction to the serologic examinations was recorded. However, since repeated examinations for treponema pallidum failed to reveal the micro-organism, microscopic study of specimens obtained from the ulcers showed

only the features of obliterative endarteritis and no other evidence of syphilitic infection was uncovered, no antisyphilitic therapy was ever instituted, a point which indicates rare discernment if not complete enlightment on the part of the many physicians who took care of 1dm.

Except for a 6 months' visit to the state of Sonoca, Mexico, where his parents were born, the patient had never left Southern California. At the Birmingham Veterans' Administration Hospital his disease went undiagnosed for several months. The bizarre, angular pattern of the numerous purpurie maeules and punched-out ulcerations and their sharply circumscribed atrophic residual sears did not seem to fit into any known dermatologie entity except dermatitis artefaeta. Because the patient's general health was good at that time, because his temperature was normal and the application of occlusive dressings seemed to aid the healing of the ulcers, this diagnosis was considered as a possibility for a while. In September 1947 the patient was discharged from the hospital, but he reentered the institution 2 weeks later because of fatigue, increasing weakness, progressive loss of weight and the development of more intensely inflammatory new lesions. He had attacks of nausea and vomiting, and his temperature began to show daily elevations to 1010 and 102° F. It was the alopecia of the eyebrows and eyelashes which at that time led to a consideration of the possibility that he had lepra. Once considered, the diagnosis was readily confirmed, and the hitherto inexplicable laboratory data became intelligible. The patient was presented at the meeting of the Los Angeles Dermatologieal Society in January 1948. At that time he was poorly nourished. His eyelashes were absent, and the lateral third of the eyebrows was sparse. The anterior portion of the nasal septum was perforated. There were several small telangieetases on his neck and trunk. Many atrophic, sharply demarcated, irregular sears of varying size, surrounded by zones of hyperpigmentation, were visible on both the upper and the lower extremities. On the legs there were a few angular, darkly erythematous, slightly raised maeules which did not pale on diaseopie

pressure. On the right arm and the right leg 2 ulcers with irregular contours could be seen; they had granulating bases and exuded a slight amount of serosanguinous fluid. The ulnar, median and common peroneal nerves were enlarged and could be palpated

without causing pain. There was hypaesthesia to pain, temperature and touch in the proximal portions and anesthesia in the distal parts of the extremities. All of the lymphnodes were enlarged, and the liver was palpable 2 cm. below the costal margin. Hoentgenologie examination of the chest, the long bones and the urinary tract disclosed no abnormalities. The reactions to lepromin (Mitsuda test) and eoeeidioidin were negative and that to

246

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

tuberculin was 2 plus in the first dilution. Intracutaneous injection of an aqueous solution of histamine, 1:5,000, failed to produce an erythematous flare on either the involved or the apparently normal skin. The results of quantitative Kahn tests ranged from 20 to 160 units. Urinalysis consistently demonstrated albumin (1 to 3 plus) and moderate numbers of white and red blood cells; there were no porphyrins or Ilenee-Jones protein. Tests for amyloid gave negative results. Examinations of the blood showed 5,000 to 10,000 white cells, 3,000,000 to 4,000,000 red cells and 9 to 12 Gm. of hemoglobin per hundred cubic centimeters; the differential count

was within normal limits. Fragility of the red blood cells was normal, and there was no evidence of Sickle cell anemia. The total serum protein content was 6.7 Gm. per hundred cubic centimeters, with an albumin-globulin ratio of 3.6:3.1. Tests of renal and hepatie function showed marked impairment. The basal metabolic rate was normal. Examination of spinal fluid revealed no abnormalities.

Fm. 1. Microscopic view of a lesion of erythema necrotieans. The dilated dermal vessels nre surrounded by inflamnmatory elements. (X 300).

In November 1947 material for microscopic study was obtained from the nasal septum, a lesion of erythema neerotieans on the forearm, an area of apparently normal skin and an ulcer on the leg. Section of the nasal septum revealed that beneath a squamous surface epithelium the connective tissue was evenly and heavily infiltrated with histiocytes, plasma cells and other mononuclear elements; only a few polyniorphonuclear leukocytes were evident. There were dilated vascular channels, particularly close to the surface. In one area, where there were edema and separation at the dermo-epidermal junction, the lumens of several small vessels were occluded by thrombi. Acid-fast rods were scattered in abundance through-

out the tissue. There were packets of mycobaeteria in many histiocytcs, and the presence of microorganisms in the vascular endothelium was strikingly apparent. Microscopic examination of the lesion of erythema neeroticans showed cellular aggregates about the smaller vessels near the surface (fig. 1) and the larger vessels in the deeper plexus composed of mononuclear elements and extravasated red cells. There were similar collections about nerves and appendages. In some small vessels there was homogenization of the walls, and others showed thrombotie plugs. Acid-fast organisms could be seen in the perivascular inflammatory elements, and some appeared in the muscular layer of the vessels.

247

DIFFUSE LEPRA

Histologic study of a section of "normal" skin disclosed perivascular granulomas, composed chiefly of lustiocytes. Larger infiltrates were present in the deeper subcutaneous

tissue and fat (fig. 2). Many cells of the infiltrate were vacuolated but could not be identified.

NI

.s-• F.

-

S.

1• -

.

:,Y'

N': Fig. 2. Section of apparently normal skin. Granulomas resembling miliary lepromatous nodules are evident in the dermis and subcutaneous fat. (X 25).

Fig. 3. Low-power photomicrograph of ulcer. A mass of inflamed granulation tissue pro-

trudes above the surface of the skin. (X 70).

The section of an exophytic ulcer (fig. 3) showed a protruding mass of granulation tissue

covered by a necrotic membrane and infiltrated by a variety of inflammatory elements, including eosinophiles. In the deeper layers were masses of lymphocytes and plasma cells in dense fibrous tissue. The dermis beneath the intact epidermis alongside the ulcer showed scarring and excessive vascularization.

TIlE JOURNAL OF INVESTIGATIVE DERMATOLOGY

248

The patient was released to the Los Angeles County General Hospital, preparatory tn transfer to the National Leprosarium, at Carville, La., to which institution ho was finally admitted. COMMENT

The identification of diffuse lepra in an American-born patient is evidence against the belief, which LatapI has expressed, that the occurrence of this variety of lepra is confined to certain regions of Mexico. We should like to suggest that it is the bizarre and unconventional features of diffuse lepra, so different from the characteristics of other forms of the disease, which have impeded its recognition in other countries, even those in which lepra is endemic. It is of grave importance

that physicians realize that diffuse lepra does occur in the United States and elsewhere, because patients with the disease may appear healthy on superficial inspection even though they are the bearers of a highly infectious type of lepromatous lepra. REFERENCES 1. Lvcro, H. AND ALVANADO, I.: Opusculo sobre el Mal do San Lazaro o elefaneiasis do

los Criegos. M. Murguia y Cia, Mexico, 1852. 2. BECKER, S. W. AND OBERMAYER, M. E.: Modern Dermatology and Syphilology, Second

Edition. J. B. Lippincott Company, Philadelphia, 1947. 3. OBERaJAYER, M. E.: Diffuse Lepra. Annals of Western Medicine and Surgery, Vol. 1, No. 6, August, 1947.

4. LATAPI, F.: Lepra, Prensa Medica Mexioana, Jan. 1946, Mexico. 5. Personal Communication to the Authors hy Dr. Fernando Latapi, Professor and Chairman of the Department of Dermatology, National Univorsity, Mexico. 6. LATAPI, F. AND CUEVEZ, A.: La Lepra "manehada" de Lueio; ostudio clinico y histopatologico inicial, V International Congress of Lepra, La Hahana, Cuba, April 1948. In process of publication. 7. LATAPI, F. AND CIIEVEZ, A.: Interpretaeion actual do la lepra do Lueio, V International Congress of Lepra, La Habana, Cuba, April 1948. In process of publication. S. Personal Communication to the Authors by Dr. Fernando Latapi, Professor and Chairman of the Department of Dermatology, National University, Mexico.

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

94

linolenic acid extract. Arch. This pdf is a scanned copy UV of irradiated a printed document.

24. Wynn, C. H. and Iqbal, M.: Isolation of rat

skin lysosomes and a comparison with liver Path., 80: 91, 1965. and spleen lysosomes. Biochem. J., 98: lOP, 37. Nicolaides, N.: Lipids, membranes, and the 1966.

human epidermis, p. 511, The Epidermis

Eds., Montagna, W. and Lobitz, W. C. Acascopic localization of acid phosphatase in demic Press, New York. human epidermis. J. Invest. Derm., 46: 431, 38. Wills, E. D. and Wilkinson, A. E.: Release of 1966. enzymes from lysosomes by irradiation and 26. Rowden, C.: Ultrastructural studies of kerathe relation of lipid peroxide formation to tinized epithelia of the mouse. I. Combined enzyme release. Biochem. J., 99: 657, 1966. electron microscope and cytochemical study 39. Lane, N. I. and Novikoff, A. B.: Effects of of lysosomes in mouse epidermis and esoarginine deprivation, ultraviolet radiation and X-radiation on cultured KB cells. J. phageal epithelium. J. Invest. Derm., 49: 181, 25. Olson, R. L. and Nordquist, R. E.: Ultramicro-

No warranty is given about the accuracy of the copy.

Users should refer to the original published dermal cells. Nature, 216: 1031, 1967. version of1965. the material. vest. Derm., 45: 448, 28. Hall, J. H., Smith, J. G., Jr. and Burnett, S. 41. Daniels, F., Jr. and Johnson, B. E.: In prepa1967.

Cell Biol., 27: 603, 1965.

27. Prose, P. H., Sedlis, E. and Bigelow, M.: The 40. Fukuyama, K., Epstein, W. L. and Epstein, demonstration of lysosomes in the diseased J. H.: Effect of ultraviolet light on RNA skin of infants with infantile eczema. J. Inand protein synthesis in differentiated epi-

C.: The lysosome in contact dermatitis: A ration. histochemical study. J. Invest. Derm., 49: 42. Ito, M.: Histochemical investigations of Unna's oxygen and reduction areas by means of 590, 1967. 29. Pearse, A. C. E.: p. 882, Histochemistry Theoultraviolet irradiation, Studies on Melanin, retical and Applied, 2nd ed., Churchill, London, 1960.

30. Pearse, A. C. E.: p. 910, Histacheini.stry Thearetscal and Applied, 2nd ed., Churchill, London, 1960.

31. Daniels, F., Jr., Brophy, D. and Lobitz, W. C.: Histochemical responses of human skin fol-

lowing ultraviolet irradiation. J. Invest. Derm.,37: 351, 1961.

32. Bitensky, L.: The demonstration of lysosomes by the controlled temperature freezing section method. Quart. J. Micr. Sci., 103: 205, 1952.

33. Diengdoh, J. V.: The demonstration of lysosomes in mouse skin. Quart. J. Micr. Sci., 105: 73, 1964.

34. Jarret, A., Spearman, R. I. C. and Hardy, J. A.:

Tohoku, J. Exp. Med., 65: Supplement V, 10, 1957.

43. Bitcnsky, L.: Lysosomes in normal and pathological cells, pp. 362—375, Lysasames Eds., de Reuck, A. V. S. and Cameron, M. Churchill, London, 1953.

44. Janoff, A. and Zweifach, B. W.: Production of inflammatory changes in the microcirculation by cationic proteins extracted from lysosomes. J. Exp. Med., 120: 747, 1964.

45. Herion, J. C., Spitznagel, J. K., Walker, R. I. and Zeya, H. I.: Pyrogenicity of granulocyte lysosomes. Amer. J. Physiol., 211: 693, 1966.

46. Baden, H. P. and Pearlman, C.: The effect of ultraviolet light on protein and nucleic acid synthesis in the epidermis. J. Invest. Derm.,

Histochemistry of keratinization. Brit. J. 43: 71, 1964. Derm., 71: 277, 1959. 35. De Duve, C. and Wattiaux, R.: Functions of 47. Bullough, W. S. and Laurence, E. B.: Mitotic control by internal secretion: the role of lysosomes. Ann. Rev. Physiol., 28: 435, 1966. the chalone-adrenalin complex. Exp. Cell. 36. Waravdekar, V. S., Saclaw, L. D., Jones, W. A. and Kuhns, J. C.: Skin changes induced by

Res., 33: 176, 1964.