MBS Review
SULZBERGER ON ATOPIC DERMATITIS FRANCES PASCHER, M.D, From the Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, and ihe Department of Dermatology, New York University School of Medicine, New York, New York
neurodermatitis" and other atopic disorders. Atopic dermatitis is now the prevalent term in the United States and the United Kingdom. Some do prefer allergic eczema or atopic dermatitis and infantile eczema,"* and other clinicians' earlier terms continue to be used in France, Germany and Scandinavia.^
Marion Sulzberger has contributed to all aspects of the subject of atopic dermatitis from the coining of the name' to the formulation of a synthesis of the many diverse concepts of a disease that is still not entirely understood.^
Etiology and Pathogenesis Immunological Factors Immediate (urticarial) Skin Reactivity to Protein Allergens. On the basis of investigational procedures such as direct (scratch) and indirect (passive-transfer) tests, Sulzberger concluded that allergic skin hypersensitivity to foods in infants and to inhalants in young adults was an essential part of the producing mechanism of atopic dermatitis.''-8 Nevertheless, Sulzberger recognized that conclusive proof of the causal role of these proteins was lacking and "that it is evident that other important unknown determinants, so-called X-factors, are of varying significance."" Furthermore, he and his collaborators had been unable to produce the dermatosis by experimental exposure or to effect a cure by the removal of suspected substances. That "careful elimination of foods giving positive skin tests and the utmost possible reduction of exposure to environmental allergens eliciting wheal reactions, reputedly efficacious in the hands of some observers, have proved on the whole disappointing in my adult patients."^ This was in marked contrast to the overestimation of the value of skin testing with atopens in the 193O's and '4O's. Most
Nomenclature and Pathogenesis The designation atopic dermatitis was first proposed by Wise and Sulzberger' to replace a host of purely descriptive, morphologic terms such as neurodermatitis disseminatus (Brocq and Jacquet), prurigo diathesique (Besnier) and fruh und spat exudatives eczematoid (Rost), to cite but a few. Atopy, literally "strange" disease, had been coined by Coca and Cooke^ 10 years before for an allergic form of hypersensitiveness occurring in genetically susceptible individuals manifested by asthma, hay fever, eczema and certain varieties of food and drug idiosyncrasy. The term atopic dermatitis proved to have 3 purposes: it separated and removed this entity from a large group of eczemas, prurigos and lichens; it eliminated the Implication of a predominantly neurogenic or psychogenie causation suggested by neurodermatitis and it recognized the relationship between the principal form of infantile eczema and "disseminated Address for reprints: Frances Pascber, M,D,, 1715 Nottingham Road, Raleigb, NC 27607,
376
No. 5
ATOPIC DERMATITIS
dermatologists and pediatricians today are in agreement that skin responses to direct and indirect testing are of limited value, ln those cases in which foods do seem to play a role, whether or not an allergic mechanism is involved remains debatable. The disposition of atopic individuals to develop an anaphylactic-type of allergic sensitivity to penicillin, a feature emphasized by Sulzberger in the 194O's, has been verified by many observers.'^" Delayed Contact Reactivity. In contrast to the frequency of immediate reactions in atopies to direct and indirect testing, Sulzberger and coinvestigators^' 7. 12 found that in patients with atopic dermatitis there is usually a normal or less than normal incidence of typical eczematous reactions to patch tests.8' 12 As Sulzberger expressed it,*^ "not only are they less sensitive to patch tests than are patients with contact-type eczematous dermatitis, but what is more remarkable, our patients with atopic dermatitis have been in general perhaps a little less sensitive to patch tests than are "normal persons." Sulzberger also noted that there was no particular predisposition on the part of atopic persons to acquire eczematous contact dermatitis.^ This first intimation of impaired cellmediated immunity in atopic dermatitis was lost sight of for 2 decades. Sulzberger's observations have been confirmed by recent studies."-^^ Dermal (Tuberculin-Type) Sensitivity. Sulzberger and Witten'^ recognized that patients with atopic dermatitis were especially susceptible to cutaneous viral infection with herpes simplex, vaccinia and molloscum contagiosum. The dissemination of herpetic and vaccinia infections with the development of constitutional symptoms and a fatal outcome at times is now attributed largely to impaired T-cell immunity.'^
Pascher
377
Nonimmunologic Factors There is now increasing agreement on the importance of nonallergic factors in the pathogenesis of atopic dermatitis.^ They are: rapid fluctuations in ambient temperature, high temperatures with high humidity, sweat disturbances, seasonal factors, psychic stress, abnormal vascular responses and unknown determinants or X-factors. Sulzberger was aware of these factors^ and came to the conclusion that they may act in combination to trigger an overt attack or exacerbation of the disease. More importantly, he and his co-workers'^ 20 are to be credited with original work in the area of sweat and sebum secretion."-22 They demonstrated localized areas of hypoor anhidrosis in atopic patients with dry skin, the adverse effects of sweat retention, histoiogic plugging of the sweat pores and follicular orifices, qualitative alterations in sebum and a quantitative reduction in sebum output.^ Rajka, likewise,2' has found an appreciable reduction in the sebum secretion rate and among others an alteration in the ratio of various lipid components.22 Whether or not the dry skin of atopies is partly attributable to plugged pores and follicles is difficult to say. The histoiogic findings noted have either not been confirmed or have been overlooked or ignored in current standard textbooks on dermohistopathology. ln 1940,8 perhaps earlier, Sulzberger stressed the importance of hospitalization or some other change in environment in the management of difficult cases of atopic dermatitis. Without going into detail as to the operative factors (reduction of exposure to allergens, compliance with therapeutic measures, release from stress, etc.) in the benefit derived in refractory and persistent cases, it still holds true despite advances in management since 1940, that hospi-
378
INTERNATIONAL JOURNAL OF DERMATOLOGY
falizafion or a climatic change may be necessary. While Sulzberger accepts physical and emotional stress as one of the links in a chain of causes,^ his position on the role of psychogenic factors in 1955"^ was that "the burden of proof must lie on those who say that psychic mechanisms are primary or causal or essential in the production of clinical or other manifestations." The role of psychological factors in the causation of atopic dermatitis is by no means settled but there certainly is less emphasis today on the significance of psychogenic mediators than there was in the past. , Clinical Features and Differential Diagnosis In collaboration with HiII,23 Sulzberger traced the evolution of atopic dermatitis from the acute, vesicular eczema of infancy to the thickened, chronic lichenified dermatitis of early adult life. Three stages were clearly delineated: (1) infantile eczema of the atopic type, (2) atopic dermatitis of childhood (2-12 years); and (3) atopic dermatitis (disseminated neurodermatitis) of the adult. A few years later in the course of a discussion of the different clinical pictures at various stages of life, Sulzberger^ expressed a farreaching, serendipitous thought, namely that "the infant is not merely a small man; he is a different sort of small man. In many ways and in many diseases his reactions differ from the adult. . . . It is not strange, then, that atopic dermatitis is not similar in clinical appearance at different ages. It would be strange if it were similar." The relevancy of these observations were soon recognized by dermatologists and applauded by pediatricians. Sulzberger also pointed out that most cases of atopic dermatitis healed by the age of 30 or so years.^ The foregoing observations continue to hold true.
June 1977
Vol. 16
The differential diagnosis of atopic dermatitis from 2 other common eczematous eruptions — contact-type allergic dermatitis and seborrheic dermatitis — can be difficult at times. Sulzberger's classic table. Differential Diagnosis of ContactType Eczematous Dermatitis, Atopic Dermatitis and Seborrbeic Dermatitis,^ is valid today. Rajka in his comprehensive monograph on atopic dermatitis has reprinted the table.5 Management of Atopic Dermatitis Sulzberger has contributed greatly to the management of atopic dermatitis. He has devoted numerous chapters and papers to this aspect of the subject. Early and subsequent writings drew attention to the primary importance of local therapy: the value of coal tar and coal tar derivatives as antieczematous and antipruritic agents; the place of iodochlorhydroxyquin USP (Vioform), and the need not infrequently, for a combination of antipruritics. Among other guidelines, he also drew attention to the fact that some vehicles are tolerated better than others by atopies. For example, Sulzberger observed that atopies tolerated greases and "greasy" vehicles poorly; that pastes and "shake" lotions are generally preferable. Verification of Sulzberger's findings and pharmacological sophistication have given rise to lipid-free vehicles designed primarily for atopies. For atopic dermatitis, as for other symmetrically distributed eruptions, Sulzberger also advocated the use of the simultaneous paired comparison technique as a means of evaluating therapy. Sulzberger and Witten^''. 2S were the first to report on the beneficial effect of topically applied hydroeortisone in selected dermatoses including infantile eczema. In 1961'° they demonstrated the enhanced potency of this compound when covered by a thin plastic film. Sub-
No. 5
ATOPIC DERMATITIS
sequent experience has shown that hydrocortisone is the safest corticosteroid now available and the topical agent of choice for infants and for long-term use in the management of atopic dermatitis. Conclusions
Sulzberger's many-faceted contributions to the subject of atopic dermatitis are much greater than the sum of the contributions discussed. In addition to a large body of seminal work, there are his illuminating discussions of the work of others, the inoculation of ideas carried forward by students and colleagues and his own exemplary drive to explore and to understand. : References 1. Wise, F., and Sulzberger, M. B.: Year Book of Dermatology and Syphilology. Chicago, Year Book Publishers, 1933, p. 38. 2. Sulzberger, M. B.: Atopic Dermatitis—Part I & III. In Dermatology in General Medicine. Edited by Fitzpatrick, T., et al. New York, McGraw-Hill, 1971, pp. 680-684; 687-697. 3. Coca, A. F., and Cooke, R. A.: On the classification of the phenomena of hypersensitiveness. ). Immunol. 6:63, 1923. 4. Rostenberg, A., Jr., and Solomon, L. M.: Atopic Dermatitis and Infantile Fczema in Immunological Diseases. Edited by Samter, M., Boston, Little Brown, 1971, pp. 920-935. 5. Rajka, C : Atopic dermatitis. Maj. Probl. Dermatol. 1:2, 5, 109, 142, 143, 1975. 6. Sulzberger, M. B., Spain, W. C , Sammis, F., and Shahon, H. F.: Studies in hypersensitiveness in certain dermatoses. J. Allergy 3:423, 1932. 7. Sulzberger, M. B., and Coodman, ] . : The relative importance of specific hypersensitivity in adult atopic dermatitis. JAMA 106: 1000, 1936. 8. Sulzberger, M. B.: Dermatologic Allergy. Springfield, Charles C Thomas, 1940, pp. 96-99, 158-181. 9. Rajka, C , and Skog, E. Z.: On the relation between drug allergy and atopy. Acta Allergy 20:387, 1965. 10. Levine, B. B., Redmond, A. P., Fellner, et al.: Immune responses of man to benzylpenicillin and penicillin allergy. ). Clin. Invest. 45: 1895, 1966.
11. 12.
13.
14.
15.
16.
17. 18.
19.
Pascher
379
Miller, F. F.: History of drug sensitivity in atopic persons. J. Allergy 40:46, 1967. Rostenberg, A., Jr., and Sulzberger, M. B.: Some results of patch tests: compilation and discussion of cutaneous reactions to about 500 different substances as elicited by over 10,000 tests in approximately 1,000 patients. Arch. Dermatol. Syphilol. 35:433, 1937. Rajka, C : Prurigo Besnier (atopic dermatitis) with special reference to the role of allergic factors. II. Evaluation of skin reactions. Acta Derm. Venereol. 40:285, 1961. Cronin, F., Bandmann, H. J., Calnan, C. D., et al.: Contact dermatitis in the atopic. Acta Derm. Venereol. 50:183, 1970. Jones, H. E., Lewis, C. W., and McMarlin, S. L.: Allergic contact sensitivity in atopic dermatitis. Arch. Dermatol. 107:217, 1973. Sulzberger, M. B.: Atopic Dermatitis: Its clinical and histologic picture. In Atopic Dermatitis. Edited by Baer, R. L., Philadelphia, J. B. Lippincott Co., 1955, pp. 11-42. Maize, J. C : Atopic dermatitis. Int. |. Dermatol. 15:555, 1976. Sulzberger, M. B., Herrmann, F., and Lak, F. C.: Studies of sweating. I. Preliminary report with particular emphasis on the sweat retention syndrome. J. Invest. Dermatol. 9: 221, 1947. Sulzberger, M. B., and Herrmann, F.: The clinical significance of disturbances in the delivery of sweat. Springfield, Charles C Thomas, 1954, pp. 105, 113, 114.
20. Sulzberger, M. B., Herrmann, F., Morill, S. D., et al.: Studies of sweat, lipids and histopathology in children with dry skin (xerosis). Int. Arch. Allergy AppI. Immunol. 14:129, 1959. 21. Wheatley, V. R.: Secretions of the skin in eczema. |. Ped. 66/2:200, 1965. 22. Mustakallio, K. K., Kustalla, U., Piha, J., and Nieminen, E.: Epidermal lipids in Besnier's prutigo (atopic eczema). Ann. Med. Exper. Biol. Fennial 45:323, 1967. 23. Hill, L. W., and Sulzberger, M. B.: Evolution of atopic dermatitis. Arch. Dermatol. Syphilol. 32:451, 1935. 24. Sulzberger, M. B., and Witten, V. H.: The effects of topically applied compound F. in selected dermatoses. J. Invest. Dermatol. 19:2, 1952. 25. Witten, V. H., Amier, A. B., Sulzberger, M. B., and DeSanctis, A. C : Hydrocortisone ointment in the treatment of infantile eczema. Am. I. Dis. Child. 87:298, 1954. 26. Sulzberger, M. B., and Witten, V. H.: Thin plastic films in topical dermatologic therapy. Arch. Dermatol. 84:1027, 1961.
SULZBERGER ON ATOPIC DERMATITIS FRANCES PASCHER, M.D, From the Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, and ihe Department of Dermatology, New York University School of Medicine, New York, New York
neurodermatitis" and other atopic disorders. Atopic dermatitis is now the prevalent term in the United States and the United Kingdom. Some do prefer allergic eczema or atopic dermatitis and infantile eczema,"* and other clinicians' earlier terms continue to be used in France, Germany and Scandinavia.^
Marion Sulzberger has contributed to all aspects of the subject of atopic dermatitis from the coining of the name' to the formulation of a synthesis of the many diverse concepts of a disease that is still not entirely understood.^
Etiology and Pathogenesis Immunological Factors Immediate (urticarial) Skin Reactivity to Protein Allergens. On the basis of investigational procedures such as direct (scratch) and indirect (passive-transfer) tests, Sulzberger concluded that allergic skin hypersensitivity to foods in infants and to inhalants in young adults was an essential part of the producing mechanism of atopic dermatitis.''-8 Nevertheless, Sulzberger recognized that conclusive proof of the causal role of these proteins was lacking and "that it is evident that other important unknown determinants, so-called X-factors, are of varying significance."" Furthermore, he and his collaborators had been unable to produce the dermatosis by experimental exposure or to effect a cure by the removal of suspected substances. That "careful elimination of foods giving positive skin tests and the utmost possible reduction of exposure to environmental allergens eliciting wheal reactions, reputedly efficacious in the hands of some observers, have proved on the whole disappointing in my adult patients."^ This was in marked contrast to the overestimation of the value of skin testing with atopens in the 193O's and '4O's. Most
Nomenclature and Pathogenesis The designation atopic dermatitis was first proposed by Wise and Sulzberger' to replace a host of purely descriptive, morphologic terms such as neurodermatitis disseminatus (Brocq and Jacquet), prurigo diathesique (Besnier) and fruh und spat exudatives eczematoid (Rost), to cite but a few. Atopy, literally "strange" disease, had been coined by Coca and Cooke^ 10 years before for an allergic form of hypersensitiveness occurring in genetically susceptible individuals manifested by asthma, hay fever, eczema and certain varieties of food and drug idiosyncrasy. The term atopic dermatitis proved to have 3 purposes: it separated and removed this entity from a large group of eczemas, prurigos and lichens; it eliminated the Implication of a predominantly neurogenic or psychogenie causation suggested by neurodermatitis and it recognized the relationship between the principal form of infantile eczema and "disseminated Address for reprints: Frances Pascber, M,D,, 1715 Nottingham Road, Raleigb, NC 27607,
376
No. 5
ATOPIC DERMATITIS
dermatologists and pediatricians today are in agreement that skin responses to direct and indirect testing are of limited value, ln those cases in which foods do seem to play a role, whether or not an allergic mechanism is involved remains debatable. The disposition of atopic individuals to develop an anaphylactic-type of allergic sensitivity to penicillin, a feature emphasized by Sulzberger in the 194O's, has been verified by many observers.'^" Delayed Contact Reactivity. In contrast to the frequency of immediate reactions in atopies to direct and indirect testing, Sulzberger and coinvestigators^' 7. 12 found that in patients with atopic dermatitis there is usually a normal or less than normal incidence of typical eczematous reactions to patch tests.8' 12 As Sulzberger expressed it,*^ "not only are they less sensitive to patch tests than are patients with contact-type eczematous dermatitis, but what is more remarkable, our patients with atopic dermatitis have been in general perhaps a little less sensitive to patch tests than are "normal persons." Sulzberger also noted that there was no particular predisposition on the part of atopic persons to acquire eczematous contact dermatitis.^ This first intimation of impaired cellmediated immunity in atopic dermatitis was lost sight of for 2 decades. Sulzberger's observations have been confirmed by recent studies."-^^ Dermal (Tuberculin-Type) Sensitivity. Sulzberger and Witten'^ recognized that patients with atopic dermatitis were especially susceptible to cutaneous viral infection with herpes simplex, vaccinia and molloscum contagiosum. The dissemination of herpetic and vaccinia infections with the development of constitutional symptoms and a fatal outcome at times is now attributed largely to impaired T-cell immunity.'^
Pascher
377
Nonimmunologic Factors There is now increasing agreement on the importance of nonallergic factors in the pathogenesis of atopic dermatitis.^ They are: rapid fluctuations in ambient temperature, high temperatures with high humidity, sweat disturbances, seasonal factors, psychic stress, abnormal vascular responses and unknown determinants or X-factors. Sulzberger was aware of these factors^ and came to the conclusion that they may act in combination to trigger an overt attack or exacerbation of the disease. More importantly, he and his co-workers'^ 20 are to be credited with original work in the area of sweat and sebum secretion."-22 They demonstrated localized areas of hypoor anhidrosis in atopic patients with dry skin, the adverse effects of sweat retention, histoiogic plugging of the sweat pores and follicular orifices, qualitative alterations in sebum and a quantitative reduction in sebum output.^ Rajka, likewise,2' has found an appreciable reduction in the sebum secretion rate and among others an alteration in the ratio of various lipid components.22 Whether or not the dry skin of atopies is partly attributable to plugged pores and follicles is difficult to say. The histoiogic findings noted have either not been confirmed or have been overlooked or ignored in current standard textbooks on dermohistopathology. ln 1940,8 perhaps earlier, Sulzberger stressed the importance of hospitalization or some other change in environment in the management of difficult cases of atopic dermatitis. Without going into detail as to the operative factors (reduction of exposure to allergens, compliance with therapeutic measures, release from stress, etc.) in the benefit derived in refractory and persistent cases, it still holds true despite advances in management since 1940, that hospi-
378
INTERNATIONAL JOURNAL OF DERMATOLOGY
falizafion or a climatic change may be necessary. While Sulzberger accepts physical and emotional stress as one of the links in a chain of causes,^ his position on the role of psychogenic factors in 1955"^ was that "the burden of proof must lie on those who say that psychic mechanisms are primary or causal or essential in the production of clinical or other manifestations." The role of psychological factors in the causation of atopic dermatitis is by no means settled but there certainly is less emphasis today on the significance of psychogenic mediators than there was in the past. , Clinical Features and Differential Diagnosis In collaboration with HiII,23 Sulzberger traced the evolution of atopic dermatitis from the acute, vesicular eczema of infancy to the thickened, chronic lichenified dermatitis of early adult life. Three stages were clearly delineated: (1) infantile eczema of the atopic type, (2) atopic dermatitis of childhood (2-12 years); and (3) atopic dermatitis (disseminated neurodermatitis) of the adult. A few years later in the course of a discussion of the different clinical pictures at various stages of life, Sulzberger^ expressed a farreaching, serendipitous thought, namely that "the infant is not merely a small man; he is a different sort of small man. In many ways and in many diseases his reactions differ from the adult. . . . It is not strange, then, that atopic dermatitis is not similar in clinical appearance at different ages. It would be strange if it were similar." The relevancy of these observations were soon recognized by dermatologists and applauded by pediatricians. Sulzberger also pointed out that most cases of atopic dermatitis healed by the age of 30 or so years.^ The foregoing observations continue to hold true.
June 1977
Vol. 16
The differential diagnosis of atopic dermatitis from 2 other common eczematous eruptions — contact-type allergic dermatitis and seborrheic dermatitis — can be difficult at times. Sulzberger's classic table. Differential Diagnosis of ContactType Eczematous Dermatitis, Atopic Dermatitis and Seborrbeic Dermatitis,^ is valid today. Rajka in his comprehensive monograph on atopic dermatitis has reprinted the table.5 Management of Atopic Dermatitis Sulzberger has contributed greatly to the management of atopic dermatitis. He has devoted numerous chapters and papers to this aspect of the subject. Early and subsequent writings drew attention to the primary importance of local therapy: the value of coal tar and coal tar derivatives as antieczematous and antipruritic agents; the place of iodochlorhydroxyquin USP (Vioform), and the need not infrequently, for a combination of antipruritics. Among other guidelines, he also drew attention to the fact that some vehicles are tolerated better than others by atopies. For example, Sulzberger observed that atopies tolerated greases and "greasy" vehicles poorly; that pastes and "shake" lotions are generally preferable. Verification of Sulzberger's findings and pharmacological sophistication have given rise to lipid-free vehicles designed primarily for atopies. For atopic dermatitis, as for other symmetrically distributed eruptions, Sulzberger also advocated the use of the simultaneous paired comparison technique as a means of evaluating therapy. Sulzberger and Witten^''. 2S were the first to report on the beneficial effect of topically applied hydroeortisone in selected dermatoses including infantile eczema. In 1961'° they demonstrated the enhanced potency of this compound when covered by a thin plastic film. Sub-
No. 5
ATOPIC DERMATITIS
sequent experience has shown that hydrocortisone is the safest corticosteroid now available and the topical agent of choice for infants and for long-term use in the management of atopic dermatitis. Conclusions
Sulzberger's many-faceted contributions to the subject of atopic dermatitis are much greater than the sum of the contributions discussed. In addition to a large body of seminal work, there are his illuminating discussions of the work of others, the inoculation of ideas carried forward by students and colleagues and his own exemplary drive to explore and to understand. : References 1. Wise, F., and Sulzberger, M. B.: Year Book of Dermatology and Syphilology. Chicago, Year Book Publishers, 1933, p. 38. 2. Sulzberger, M. B.: Atopic Dermatitis—Part I & III. In Dermatology in General Medicine. Edited by Fitzpatrick, T., et al. New York, McGraw-Hill, 1971, pp. 680-684; 687-697. 3. Coca, A. F., and Cooke, R. A.: On the classification of the phenomena of hypersensitiveness. ). Immunol. 6:63, 1923. 4. Rostenberg, A., Jr., and Solomon, L. M.: Atopic Dermatitis and Infantile Fczema in Immunological Diseases. Edited by Samter, M., Boston, Little Brown, 1971, pp. 920-935. 5. Rajka, C : Atopic dermatitis. Maj. Probl. Dermatol. 1:2, 5, 109, 142, 143, 1975. 6. Sulzberger, M. B., Spain, W. C , Sammis, F., and Shahon, H. F.: Studies in hypersensitiveness in certain dermatoses. J. Allergy 3:423, 1932. 7. Sulzberger, M. B., and Coodman, ] . : The relative importance of specific hypersensitivity in adult atopic dermatitis. JAMA 106: 1000, 1936. 8. Sulzberger, M. B.: Dermatologic Allergy. Springfield, Charles C Thomas, 1940, pp. 96-99, 158-181. 9. Rajka, C , and Skog, E. Z.: On the relation between drug allergy and atopy. Acta Allergy 20:387, 1965. 10. Levine, B. B., Redmond, A. P., Fellner, et al.: Immune responses of man to benzylpenicillin and penicillin allergy. ). Clin. Invest. 45: 1895, 1966.
11. 12.
13.
14.
15.
16.
17. 18.
19.
Pascher
379
Miller, F. F.: History of drug sensitivity in atopic persons. J. Allergy 40:46, 1967. Rostenberg, A., Jr., and Sulzberger, M. B.: Some results of patch tests: compilation and discussion of cutaneous reactions to about 500 different substances as elicited by over 10,000 tests in approximately 1,000 patients. Arch. Dermatol. Syphilol. 35:433, 1937. Rajka, C : Prurigo Besnier (atopic dermatitis) with special reference to the role of allergic factors. II. Evaluation of skin reactions. Acta Derm. Venereol. 40:285, 1961. Cronin, F., Bandmann, H. J., Calnan, C. D., et al.: Contact dermatitis in the atopic. Acta Derm. Venereol. 50:183, 1970. Jones, H. E., Lewis, C. W., and McMarlin, S. L.: Allergic contact sensitivity in atopic dermatitis. Arch. Dermatol. 107:217, 1973. Sulzberger, M. B.: Atopic Dermatitis: Its clinical and histologic picture. In Atopic Dermatitis. Edited by Baer, R. L., Philadelphia, J. B. Lippincott Co., 1955, pp. 11-42. Maize, J. C : Atopic dermatitis. Int. |. Dermatol. 15:555, 1976. Sulzberger, M. B., Herrmann, F., and Lak, F. C.: Studies of sweating. I. Preliminary report with particular emphasis on the sweat retention syndrome. J. Invest. Dermatol. 9: 221, 1947. Sulzberger, M. B., and Herrmann, F.: The clinical significance of disturbances in the delivery of sweat. Springfield, Charles C Thomas, 1954, pp. 105, 113, 114.
20. Sulzberger, M. B., Herrmann, F., Morill, S. D., et al.: Studies of sweat, lipids and histopathology in children with dry skin (xerosis). Int. Arch. Allergy AppI. Immunol. 14:129, 1959. 21. Wheatley, V. R.: Secretions of the skin in eczema. |. Ped. 66/2:200, 1965. 22. Mustakallio, K. K., Kustalla, U., Piha, J., and Nieminen, E.: Epidermal lipids in Besnier's prutigo (atopic eczema). Ann. Med. Exper. Biol. Fennial 45:323, 1967. 23. Hill, L. W., and Sulzberger, M. B.: Evolution of atopic dermatitis. Arch. Dermatol. Syphilol. 32:451, 1935. 24. Sulzberger, M. B., and Witten, V. H.: The effects of topically applied compound F. in selected dermatoses. J. Invest. Dermatol. 19:2, 1952. 25. Witten, V. H., Amier, A. B., Sulzberger, M. B., and DeSanctis, A. C : Hydrocortisone ointment in the treatment of infantile eczema. Am. I. Dis. Child. 87:298, 1954. 26. Sulzberger, M. B., and Witten, V. H.: Thin plastic films in topical dermatologic therapy. Arch. Dermatol. 84:1027, 1961.
