SPECIAL ARTICLE
Historical Perspective: The Neurotrophic Theory of Skin Ulceration L
Jeffrey M.Levine, M D Though nearly forgotten, the neurotrophic theory was very much a part of mainstream medical thinking during the midnineteenth century. This theory stated that all bodily organs are maintained by special nutritional factors secreted by the central nervous system. Development of skin ulceration in the face of neurologic injury became a model for the theory, and controversy involved two great neurologists of the time, Jean Martin Charcot and Edouard Brown-SPquard. As the
neurotrophic theory fell into disfavor, interest in decubitus ulcers waned as well. Today, pressure sores remain a major epidemiologic problem for the growing population of frail elderly persons in both acute and long-term care settings. Because of the increased mortality, morbidity, and cost associated with these lesions, attention needs to be refocused on research and education concerning the decubitus ulcer. J Am Geriatr SOC40:1281-1283,1992
eveloped during the nineteenth century, the neurotrophic theory aimed to explain the effect of the central nervous system on maintenance of body organs through chemical substances. Forgotten for nearly a century, this hypothesis has been partially resurrected by modern medical science. Examination of the theory in its historical context is enlightening, because the decubitus ulcer was at one time a model for the trophic theory in action. Controversy over the theory resulted in some of the first experimental studies on skin ulceration, and involved two of the greatest names in the history of neurology, Jean Martin Charcot and Edouard Brown-Sequard. The neurotrophic theory stated that the central nervous system exerts influence on function and maintenance of all body parts and organs through special nutritional substances called neurotrophic factors. Acute skin ulceration following neurologic injury was, according to this theory, a result of cessation of production of these substances. Another manifestation of trophic disturbance was the muscle wasting accompanying paraplegia. The arthropathy that we refer to today as ”Charcot’s joint” was originally described in the context of the neurotrophic theory.’ Jean Martin Charcot was, in fact, one of the premier proponents of the neurotrophic theory. Born in 1825, Charcot spent most of his professional years as neurologist and neuropathologist in Paris at the SaltpOtriere, a sprawling public hospital housing 5,000 patients and composed of 45 buildings.2 These patients, mostly women, included prisoners, the mentally ill, and the aged. Here he reorganized the clinical service and established laboratories and teaching facilities. A charismatic lecturer and author, his weekly case presentations attracted large numbers of students and foreign physicians. Charcot is considered a key figure not
only in the development of neurology, but in the field of geriatrics as well (Figure l).3 The SaltpGtriere presented ample opportunity for Charcot to study the course and evolution of skin ulceration. The occurrence of decubiti in the setting of acute paraplegia was well known, and the neurotrophic theory proved a perfect hypothesis with which to suggest a cause-and-effect relationship. More problematic in the framework of the theory, however, was skin ulceration in patients not suffering from sudden neurologic damage, but who instead had slowly progressive conditions. During Charcot’s life, Alzheimer’s disease had not yet been described, and the first antibiotics were still years away. Many bedridden patients were simply old and infirm, while others carried the diagnosis of dementia paralytica, a condition we now know was tertiary syphilis. These debilitated patients suffered from decubiti that ran an indolent and subacute course and thus seemed to differ in natural history from quickly developing ulcers following acute neurologic injury. Charcot used the neurotrophic theory to explain such observations. He made a distinction between passive lesions resulting from functional inaction alone and trophic disorders following acute lesions of the nervous system. Skin ulcers were therefore divided into two categories. Decubitus chronicus was ulceration occurring over a longer period and associated with inactivity, and Recubitus acutus was described as ulceration resulting from interruption of trophic factors immediately following neurologic i n j ~ r y . ~ Drawing upon his background as a neurologist, Charcot further elaborated upon the Recubitus acutus by correlating localization of nerve damage with site of skin breakdown. This idea was advanced despite the fact that anatomic tracts carrying these factors were yet to be demonstrated. According to his precepts, injury to the spinal cord would cause ulceration in the midline over the sacrum, while damage to the cerebral hemispheres would result in Decubitus acutus over a peripheral area such as the buttocks (Figure 2).5
D
From Jewish Home and Hospital for Aged, Bronx, New York. Portrait of Jean Martin Charcot is courtesy of the New York Academy of Medicine. Address correspondence to Jeffrey M. Levine, MD, Jewish Home and Hospital for Aged, 100 W. Kingsbridge Rd., Bronx, N Y 10468.
JAGS 40:1281-1283, 1992 0 1992 by the Anterican Geriatrics Society
0002-8614192/$3.50
1282
LEVINE
IAGS-DECEMBER 1992-VOL. 40. NO.1 2
imized the role of local irritative factors in the genesis of ulceration: "The circumstances in which acute bed-sore of apoplectic patients develops, evidently do not permit us to refer to the intervention of pressure on the parts where it appears, as the only element in its production. . . Nor can the irritating contact of urine be given as the cause. In several cases, I have had this liquid drawn off hour by hour, day and night, during the whole time of the disease, in order to avoid as much as possible the irritation of the skin of the seat, and in spite of every care, the eschar was produced in accordance with the rules which I have indi~ated."~
FIGURE 1. lean Martin Charcot
One contemporary neurophysiologist, Edouard Brown-Sbquard, was a vocal opponent of the neurotrophic theory. Born on the island of Mauritius in 1817, his approach to scientific truth was through experimentation rather than clinical bedside study. An eccentric individual, Brown-Sbquard housed his animals and laboratory in his Paris apartment. We remember him today for his description of the syndrome of spinal cord hemisection, with ipsilateral motor function deficit and contralateral sensory loss. Using animals whose spinal cords he surgcally transected, Brown-Skquard investigated many aspects of physiologic function in the presence of paraplegia. In his experiments, he noted the importance of pressure and local irritation on both genesis and cure of skin ulceration, and concludes the erroneous nature of the neurotrophic theory. He writes in one of his physiological treatises: "On guinea-pigs, upon which the spinal cord was cut in the dorsal region, and on pigeons, upon which the spinal cord was destroyed from the fifth costal vertebra to its 'termination, I have found that no ulceration appeared when I took care to prevent any part of their bodies from being in a continued state of compression, and of washing them many times a day to remove the urine and feces. . . In cases where an ulceration had been produced, I have succeeded in curing it by washing and preventing compression. Therefore the ulcerations which appear, in cases of paraplegia, do not exist directly in consequence of the palsy; they can be avoided and in many cases they can be cured."6 Charcot, in defense of the neurotrophic theory, addressed the concerns raised by his colleague, but min-
There is an anecdate that Charcot once had inscribed above his door, "You will not find a clinic for dogs here."' If true, perhaps this reflected his feelings toward experiments which tended to refute his teachings. Discussion concerning the neurotrophic theory continued into the twentieth century, but demonstration of neurotrophic factors and the anatomic tracts which carried them never materialized. Charcot's suppositions correlating localization of decubiti with area of central nervous system damage proved erroneous. In addition, it appeared that the Decubitus acutus and Decubitus chronicus were one and the same lesion. Freeman, in his chapter on skin ulceration from a major surgical text published in 1909, reviews the trophic theory as proposed by Charcot and notes the lack of supporting evidence. He writes regarding decubitus formation: "In considering the causation of bedsores, it is customary to keep prominently in view their division into ordinary decubitus and that appearing in connection with nervous lesions, although it is doubtful if any real difference exists between them."' Munro, a Boston neurosurgeon, wrote extensively on bedsores associated with paraplegia. In 1940 he attempted to lay the trophic theory to rest. With respect to bedsore etiology, he asserts: "This process should be based, if possible, on known facts, and should eliminate such highly theoretical concepts as are suggested by the unexplainable terms 'trophic nerves' and 'trophic changes'."'' Kosiak, in his classic paper on the role of pressure in decubitus genesis, was kinder toward the neurotrophic theory's legacy." Though conceding its lack of validity, he points out the indirect role of neurologic damage, with loss of sensory and motor function, and possible involvement of vasomotor reflex arcs. Parish et a1," in their discussion of the decubitus in medical history, add an excellent perspective regarding Charcot's hypothesis. They state that the neurotrophic theory resulted in an era of therapeutic nihilism, when the pressure ulcer "was accepted . . . as a neurologic fact of life." The trophic theory remained hypothetical and unsubstantiated, and interest in it ultimately waned. Unfortunately, interest in decubiti dwindled as well. Never again would the bedsore attract the spotlight of
IAGS-DECEMBER 7992-VOL 40, NO 72
NEUROTROPHIC THEORY
1283
_--.--- -__ ----l
/---
FIGURE 2. Thes e illustrations, re produc e d from Charcot’s original textbook, depict h i s e r r o n e o u s t h e o r y of d e c u b i t u s localization c o r r e s p o n d ing t o area of C N S d a m a g e . The pa tie nt on t h e left s uffe re d from cerebral h e m o r r h a g e , a n d d e v e l o p e d a Decubitus a c u t u s on t h e buttocks. On t h e o t h e r h a n d , t h e p a tie nt on t h e right de ve lope d a lesion i n t h e midline, interpreted by C h a r c o t a s resulting from s p i n a l cord disease.
interest it possessed in Paris during the nineteenth century. Indeed, modern authors have demoaned the lack of concern for pressure ulcers expressed by the medical community.13,14 But the neurotrophic theory did not completely pass into oblivion. Today, 100 years later, progress in medical science has clearly demonstrated the existence of “trophic factors” secreted not only by nerves but from other tissues as well, although a direct relationship to the formation of decubitus ulcers has not been demonstrated. Biotechnology companies are now racing to find practical application for these compounds, raising hopes for alleviation of chronic neurodegenerative diseases, such as Alzheimer‘s and parkinsonism, and for accelerated healing of decubitus ulcers.’5,I‘ The annual market for wound care products alone is estimated at 1 billion dollars, and this financial stimulus combined with technologic advancement virtually assures us that further research on these products will occur.17 But scientific developments have yet to affect some common medical problems. Decubitus ulcers remain a huge dilemma in all facilities caring for the elderly, and changing demographics with a rapidly aging population will ensure a growing number of persons at risk.” Yet, we still lack essential information needed to guide us in cost-effective care. It is estimated, for example, that 80 percent of guidelines for pressure ulcer management have weak supporting scientific rationale.” Given the added cost, morbidity, and suffering which decubiti cause, we are faced with an imperative to institute sound principles of prevention and treatment based on thorough understanding of natural history. Continued efforts in research, education, and awareness will be necessary to come to grips with the pressure ulcer, a disease which one author has aptly described as ”a serious epidemic, but . . . a silent one, hidden under the sheets.””
ACKNOWLEDGMENT The author thanks Dr. Manuel Rodstein, Dr. Seymour Jacobson, and Dr. Benjamin Kropsky for reviewing the manuscript. REFERENCES 1. Charcot JM. Lectures on the Diseases of the Nervous System. London: The New Sydenham Society, 1877, p 22.
2 McHenry LC. Garrison’s History of Neurology. Springfield: Charles C. Thomas, 1969, p 284. 3. Zeman, F. D. Life’s Later Years: Studies in the Medical History of Old Age. Part XI, the Nineteenth Century. Repnnted in: Roots of Modern Gerontology and Geriatrics. G. J. Gruman, ed. New York: Arno Press, 1979, p 308. 4. Charcot JM. Lectures on the Diseases of the Nervous System. London: The New Sydenham Society, 1877, p 69. 5 . Charcot J M . Lectures on the Diseases of the Nervous System. London: The New Sydenham Society, 1877, p. 76. 6 . Brown-SPquard E. Experimental Researches Applied to Physiology and Pathology. New York: H. Bailliere, 1853, p 16. 7. Charcot JM. Lectures on the Diseases of the Nervous System. London: The New Sydenham Society, 1877, p 78. 8. Haymaker W. The Founders of Neurology, 2nd Ed. Springfield: Thomas, 1970, p 423. 9 . Freeman L. Ulceration and Ulcers. In: WW Keen, ed. Surgery: Its Principles and Practices, Vol 1, Philadelphia: Saunders, 1909, p 295. 10. Munro D. Care of the back following spinal cord injuries: A consideration of bedsores. N Engl J Med 1940;223:391-398. 1 1 . Kosiak M. Etiology and pathology of ischemic ulcers. Arch Phys Med Rehab 1959;40:62-69. 12. Parish LC, Witkowski, Crissey JA. The Decubitus Ulcer. New York Masson, 1983, p 8. 13. Mulholland JH, Tui CO, Wright AM, Vinci V, Shafiroff B. Protein metabolism and bedsores. Ann Surg 1943;118:1015-1023. 14. Editorial. Pressure Sore Prevention. Lancet 1990;335:1311-1312. 15. Medical News & Perspectives. Brain researchers bullish on prospects for preserving mental functioning in elderly. JAMA 1991;2672154-2156. 16. Robson MC, Phillips LG, Thomason A, et al. Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet 1992;339: 23-25. 17. Hunt TK, LaVan FB. Enhancement of wound healing by growth factors. N Engl J Med 1989;321:111-112, 18. Allman RM. Epidemiology of pressure sores in different populations. Decubitus 1989;2:30-33. 19. Lucas MD. Research implications of the pressure ulcer guidelines. Decubitus 1991;4:52-58. 20. Hibbs 1’. The economics of pressure ulcer prevention. Decubitus 1988;l: 32-38.
Historical Perspective: The Neurotrophic Theory of Skin Ulceration L
Jeffrey M.Levine, M D Though nearly forgotten, the neurotrophic theory was very much a part of mainstream medical thinking during the midnineteenth century. This theory stated that all bodily organs are maintained by special nutritional factors secreted by the central nervous system. Development of skin ulceration in the face of neurologic injury became a model for the theory, and controversy involved two great neurologists of the time, Jean Martin Charcot and Edouard Brown-SPquard. As the
neurotrophic theory fell into disfavor, interest in decubitus ulcers waned as well. Today, pressure sores remain a major epidemiologic problem for the growing population of frail elderly persons in both acute and long-term care settings. Because of the increased mortality, morbidity, and cost associated with these lesions, attention needs to be refocused on research and education concerning the decubitus ulcer. J Am Geriatr SOC40:1281-1283,1992
eveloped during the nineteenth century, the neurotrophic theory aimed to explain the effect of the central nervous system on maintenance of body organs through chemical substances. Forgotten for nearly a century, this hypothesis has been partially resurrected by modern medical science. Examination of the theory in its historical context is enlightening, because the decubitus ulcer was at one time a model for the trophic theory in action. Controversy over the theory resulted in some of the first experimental studies on skin ulceration, and involved two of the greatest names in the history of neurology, Jean Martin Charcot and Edouard Brown-Sequard. The neurotrophic theory stated that the central nervous system exerts influence on function and maintenance of all body parts and organs through special nutritional substances called neurotrophic factors. Acute skin ulceration following neurologic injury was, according to this theory, a result of cessation of production of these substances. Another manifestation of trophic disturbance was the muscle wasting accompanying paraplegia. The arthropathy that we refer to today as ”Charcot’s joint” was originally described in the context of the neurotrophic theory.’ Jean Martin Charcot was, in fact, one of the premier proponents of the neurotrophic theory. Born in 1825, Charcot spent most of his professional years as neurologist and neuropathologist in Paris at the SaltpOtriere, a sprawling public hospital housing 5,000 patients and composed of 45 buildings.2 These patients, mostly women, included prisoners, the mentally ill, and the aged. Here he reorganized the clinical service and established laboratories and teaching facilities. A charismatic lecturer and author, his weekly case presentations attracted large numbers of students and foreign physicians. Charcot is considered a key figure not
only in the development of neurology, but in the field of geriatrics as well (Figure l).3 The SaltpGtriere presented ample opportunity for Charcot to study the course and evolution of skin ulceration. The occurrence of decubiti in the setting of acute paraplegia was well known, and the neurotrophic theory proved a perfect hypothesis with which to suggest a cause-and-effect relationship. More problematic in the framework of the theory, however, was skin ulceration in patients not suffering from sudden neurologic damage, but who instead had slowly progressive conditions. During Charcot’s life, Alzheimer’s disease had not yet been described, and the first antibiotics were still years away. Many bedridden patients were simply old and infirm, while others carried the diagnosis of dementia paralytica, a condition we now know was tertiary syphilis. These debilitated patients suffered from decubiti that ran an indolent and subacute course and thus seemed to differ in natural history from quickly developing ulcers following acute neurologic injury. Charcot used the neurotrophic theory to explain such observations. He made a distinction between passive lesions resulting from functional inaction alone and trophic disorders following acute lesions of the nervous system. Skin ulcers were therefore divided into two categories. Decubitus chronicus was ulceration occurring over a longer period and associated with inactivity, and Recubitus acutus was described as ulceration resulting from interruption of trophic factors immediately following neurologic i n j ~ r y . ~ Drawing upon his background as a neurologist, Charcot further elaborated upon the Recubitus acutus by correlating localization of nerve damage with site of skin breakdown. This idea was advanced despite the fact that anatomic tracts carrying these factors were yet to be demonstrated. According to his precepts, injury to the spinal cord would cause ulceration in the midline over the sacrum, while damage to the cerebral hemispheres would result in Decubitus acutus over a peripheral area such as the buttocks (Figure 2).5
D
From Jewish Home and Hospital for Aged, Bronx, New York. Portrait of Jean Martin Charcot is courtesy of the New York Academy of Medicine. Address correspondence to Jeffrey M. Levine, MD, Jewish Home and Hospital for Aged, 100 W. Kingsbridge Rd., Bronx, N Y 10468.
JAGS 40:1281-1283, 1992 0 1992 by the Anterican Geriatrics Society
0002-8614192/$3.50
1282
LEVINE
IAGS-DECEMBER 1992-VOL. 40. NO.1 2
imized the role of local irritative factors in the genesis of ulceration: "The circumstances in which acute bed-sore of apoplectic patients develops, evidently do not permit us to refer to the intervention of pressure on the parts where it appears, as the only element in its production. . . Nor can the irritating contact of urine be given as the cause. In several cases, I have had this liquid drawn off hour by hour, day and night, during the whole time of the disease, in order to avoid as much as possible the irritation of the skin of the seat, and in spite of every care, the eschar was produced in accordance with the rules which I have indi~ated."~
FIGURE 1. lean Martin Charcot
One contemporary neurophysiologist, Edouard Brown-Sbquard, was a vocal opponent of the neurotrophic theory. Born on the island of Mauritius in 1817, his approach to scientific truth was through experimentation rather than clinical bedside study. An eccentric individual, Brown-Sbquard housed his animals and laboratory in his Paris apartment. We remember him today for his description of the syndrome of spinal cord hemisection, with ipsilateral motor function deficit and contralateral sensory loss. Using animals whose spinal cords he surgcally transected, Brown-Skquard investigated many aspects of physiologic function in the presence of paraplegia. In his experiments, he noted the importance of pressure and local irritation on both genesis and cure of skin ulceration, and concludes the erroneous nature of the neurotrophic theory. He writes in one of his physiological treatises: "On guinea-pigs, upon which the spinal cord was cut in the dorsal region, and on pigeons, upon which the spinal cord was destroyed from the fifth costal vertebra to its 'termination, I have found that no ulceration appeared when I took care to prevent any part of their bodies from being in a continued state of compression, and of washing them many times a day to remove the urine and feces. . . In cases where an ulceration had been produced, I have succeeded in curing it by washing and preventing compression. Therefore the ulcerations which appear, in cases of paraplegia, do not exist directly in consequence of the palsy; they can be avoided and in many cases they can be cured."6 Charcot, in defense of the neurotrophic theory, addressed the concerns raised by his colleague, but min-
There is an anecdate that Charcot once had inscribed above his door, "You will not find a clinic for dogs here."' If true, perhaps this reflected his feelings toward experiments which tended to refute his teachings. Discussion concerning the neurotrophic theory continued into the twentieth century, but demonstration of neurotrophic factors and the anatomic tracts which carried them never materialized. Charcot's suppositions correlating localization of decubiti with area of central nervous system damage proved erroneous. In addition, it appeared that the Decubitus acutus and Decubitus chronicus were one and the same lesion. Freeman, in his chapter on skin ulceration from a major surgical text published in 1909, reviews the trophic theory as proposed by Charcot and notes the lack of supporting evidence. He writes regarding decubitus formation: "In considering the causation of bedsores, it is customary to keep prominently in view their division into ordinary decubitus and that appearing in connection with nervous lesions, although it is doubtful if any real difference exists between them."' Munro, a Boston neurosurgeon, wrote extensively on bedsores associated with paraplegia. In 1940 he attempted to lay the trophic theory to rest. With respect to bedsore etiology, he asserts: "This process should be based, if possible, on known facts, and should eliminate such highly theoretical concepts as are suggested by the unexplainable terms 'trophic nerves' and 'trophic changes'."'' Kosiak, in his classic paper on the role of pressure in decubitus genesis, was kinder toward the neurotrophic theory's legacy." Though conceding its lack of validity, he points out the indirect role of neurologic damage, with loss of sensory and motor function, and possible involvement of vasomotor reflex arcs. Parish et a1," in their discussion of the decubitus in medical history, add an excellent perspective regarding Charcot's hypothesis. They state that the neurotrophic theory resulted in an era of therapeutic nihilism, when the pressure ulcer "was accepted . . . as a neurologic fact of life." The trophic theory remained hypothetical and unsubstantiated, and interest in it ultimately waned. Unfortunately, interest in decubiti dwindled as well. Never again would the bedsore attract the spotlight of
IAGS-DECEMBER 7992-VOL 40, NO 72
NEUROTROPHIC THEORY
1283
_--.--- -__ ----l
/---
FIGURE 2. Thes e illustrations, re produc e d from Charcot’s original textbook, depict h i s e r r o n e o u s t h e o r y of d e c u b i t u s localization c o r r e s p o n d ing t o area of C N S d a m a g e . The pa tie nt on t h e left s uffe re d from cerebral h e m o r r h a g e , a n d d e v e l o p e d a Decubitus a c u t u s on t h e buttocks. On t h e o t h e r h a n d , t h e p a tie nt on t h e right de ve lope d a lesion i n t h e midline, interpreted by C h a r c o t a s resulting from s p i n a l cord disease.
interest it possessed in Paris during the nineteenth century. Indeed, modern authors have demoaned the lack of concern for pressure ulcers expressed by the medical community.13,14 But the neurotrophic theory did not completely pass into oblivion. Today, 100 years later, progress in medical science has clearly demonstrated the existence of “trophic factors” secreted not only by nerves but from other tissues as well, although a direct relationship to the formation of decubitus ulcers has not been demonstrated. Biotechnology companies are now racing to find practical application for these compounds, raising hopes for alleviation of chronic neurodegenerative diseases, such as Alzheimer‘s and parkinsonism, and for accelerated healing of decubitus ulcers.’5,I‘ The annual market for wound care products alone is estimated at 1 billion dollars, and this financial stimulus combined with technologic advancement virtually assures us that further research on these products will occur.17 But scientific developments have yet to affect some common medical problems. Decubitus ulcers remain a huge dilemma in all facilities caring for the elderly, and changing demographics with a rapidly aging population will ensure a growing number of persons at risk.” Yet, we still lack essential information needed to guide us in cost-effective care. It is estimated, for example, that 80 percent of guidelines for pressure ulcer management have weak supporting scientific rationale.” Given the added cost, morbidity, and suffering which decubiti cause, we are faced with an imperative to institute sound principles of prevention and treatment based on thorough understanding of natural history. Continued efforts in research, education, and awareness will be necessary to come to grips with the pressure ulcer, a disease which one author has aptly described as ”a serious epidemic, but . . . a silent one, hidden under the sheets.””
ACKNOWLEDGMENT The author thanks Dr. Manuel Rodstein, Dr. Seymour Jacobson, and Dr. Benjamin Kropsky for reviewing the manuscript. REFERENCES 1. Charcot JM. Lectures on the Diseases of the Nervous System. London: The New Sydenham Society, 1877, p 22.
2 McHenry LC. Garrison’s History of Neurology. Springfield: Charles C. Thomas, 1969, p 284. 3. Zeman, F. D. Life’s Later Years: Studies in the Medical History of Old Age. Part XI, the Nineteenth Century. Repnnted in: Roots of Modern Gerontology and Geriatrics. G. J. Gruman, ed. New York: Arno Press, 1979, p 308. 4. Charcot JM. Lectures on the Diseases of the Nervous System. London: The New Sydenham Society, 1877, p 69. 5 . Charcot J M . Lectures on the Diseases of the Nervous System. London: The New Sydenham Society, 1877, p. 76. 6 . Brown-SPquard E. Experimental Researches Applied to Physiology and Pathology. New York: H. Bailliere, 1853, p 16. 7. Charcot JM. Lectures on the Diseases of the Nervous System. London: The New Sydenham Society, 1877, p 78. 8. Haymaker W. The Founders of Neurology, 2nd Ed. Springfield: Thomas, 1970, p 423. 9 . Freeman L. Ulceration and Ulcers. In: WW Keen, ed. Surgery: Its Principles and Practices, Vol 1, Philadelphia: Saunders, 1909, p 295. 10. Munro D. Care of the back following spinal cord injuries: A consideration of bedsores. N Engl J Med 1940;223:391-398. 1 1 . Kosiak M. Etiology and pathology of ischemic ulcers. Arch Phys Med Rehab 1959;40:62-69. 12. Parish LC, Witkowski, Crissey JA. The Decubitus Ulcer. New York Masson, 1983, p 8. 13. Mulholland JH, Tui CO, Wright AM, Vinci V, Shafiroff B. Protein metabolism and bedsores. Ann Surg 1943;118:1015-1023. 14. Editorial. Pressure Sore Prevention. Lancet 1990;335:1311-1312. 15. Medical News & Perspectives. Brain researchers bullish on prospects for preserving mental functioning in elderly. JAMA 1991;2672154-2156. 16. Robson MC, Phillips LG, Thomason A, et al. Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet 1992;339: 23-25. 17. Hunt TK, LaVan FB. Enhancement of wound healing by growth factors. N Engl J Med 1989;321:111-112, 18. Allman RM. Epidemiology of pressure sores in different populations. Decubitus 1989;2:30-33. 19. Lucas MD. Research implications of the pressure ulcer guidelines. Decubitus 1991;4:52-58. 20. Hibbs 1’. The economics of pressure ulcer prevention. Decubitus 1988;l: 32-38.
