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Why is a Retinopathy?
VOL. 68, NO. 3
OCULAR DEPOSITION OF COPPER
generation (Wilson's disease). Science 116:484, 19S2. 10. Beam, A. G. and Kunkel, H. G. : Abnormali ties of copper metabolism in Wilson's disease and their relationship to the aminoaciduria. J. Clin. In vest. 33:400, 1954. 11. Uzman, L. L., Iber, F. L., Chalmers, T. C. and Knowlton, M. : The mechanism of copper depo sition in the liver in hepatolenticular degeneration (Wilson's disease). Am. J. Med. Sci. 231:511, 1956. 12. Hrgovcic, M., Tessmer, C. F., Minckler, T. M., Mosier, B. and Taylor, G. H. : Serum copper levels in lymphoma and leukemia. Special reference to Hodgkin's disease. Cancer 21:743, 1968. 13. Gerhard, J. P. and Calme, P. : Le dosage cuivre dans l'humeur aqueuse humaine et ses varia tions pathologiques. Bull. Soc. Ophtal. France 64:929, 1964. 14. Gerhard, J. P. : Etude du cuivre de l'humeur aqueuse. Docum. Ophthal. 20:104, 1966. 15. Ashton, N. : Ocular changes in multiple myelomatosis. Arch. Ophth. 73:487, 1965. 16. Slansky, H. H., Bronstein, M. and Gartner,
427
S. : Ciliary body cysts in multiple myeloma. Their relation to urethane, hyperproteinemia and duration of the disease. Arch. Ophth. 76:686, 1966. 17. Sanders, T. E., Podos, S. M. and Rosenbaum, L. J. : Intraocular manifestations of multiple my eloma. Arch. Ophth. 77 :789, 1967. 18. Biirki, E. : Ueber Hornhautveränderungen bei einem Fall von multiplem Myelom (Pasmocytom). Ophthalmologica 135:565, 1958. 19. François, J. : Thésaurismose de la cornée dans le myélomatose multiple. Bull. Soc. Belge Ophtal. 142:494, 1966. 20. Clarke, E. : Ophthalmological complications of multiple myelomatosis. Brit. J. Ophth. 39:233, 1955. 21. Records, R. E., Claman, H. N. and Merrill, D. : Unpublished observations. 22. François, J. and Rabaey, M. : Microelectrophoresis on agar of normal and pathological aqueous humor. Arch. Ophth. 63 :836, 1960. 23. Hemmingsen, L. and 0ther, A. : Disc electrophoresis of aqueous humor. Acta Ophth. 45:359, 1967.
W H Y IS A R E T I N O P A T H Y ? P. J. LEINFELDER,
M.D.
Iowa City, Iowa
Since its inception, ophthalmoscopy has been oriented toward diagnostic specificity. Writings and investigations, especially in pa thology, have endeavored to substantiate the value of ophthalmoscopy in clinical diagnosis and prognosis ; this is illustrated by the elab oration of the Keith-Wagner classification of vascular disease. These dissertations em phasized the positive correlates of retinopathies with different diseases but ignored those situations in which retinal changes were absent in patients who apparently had as severe an involvement with a general dis ease. Furthermore, no consideration was given to circumstances in which specific changes were present but. diagnosis of the specific disease was not possible. From the Department of Ophthalmology, College of Medicine, University of Iowa. This paper is dedicated to Alson E. Braley, M.D. Reprint requests to P. J. Leinfelder, M.D., De partment of Ophthalmology, University Hospitals, Iowa City, Iowa 52240.
Definitive ophthalmoscopic diagnosis de pends upon the association of particular types of observable changes with a single disease. Certain vascular changes are consid ered typical of arteriosclerosis, other changes of hypertension, punctate hemorrhages and microaneurysms of diabetes. In many in stances in which a specific diagnosis is indi cated, alternate diagnoses are also possible; seemingly specific changes in the retina may occur in several unrelated diseases. Diseases which may be associated with retinopathies may exist in severe or mild form with or without retinopathy and, at times, in patients who are not particularly ill with their dis ease. Ophthalmoscopic changes have been cor related with the altered microscopic anat omy, resulting in an association of the late and often terminal stages of the disease with the ophthalmoscopically visible alterations in the tissue. This association has been of
428
AMERICAN JOURNAL OF OPHTHALMOLOGY
value, but it has led to neglect of the basic first event in disease—disturbed physiology. There are extensive reports on the patho logic changes in the retina, but there is so lit tle knowledge of basic physiology that a stri ate hemorrhage cannot be adequately ex plained. Satisfaction with the knowledge of retinal pathology and its created image of disease has resulted in stagnation of investi gation and general neglect of physiology and pathophysiology. Disturbed physiology is the basis of tissue alteration. However, knowledge in this area is extremely deficient. Do we really know why hemorrhages, edema or localized infil trates of various types occur ? What triggers retinopathy? What substances in the meta bolic or catabolic cycles induce retinal changes? Certainly vascular or circulatory changes alone are not responsible since se vere vascular alterations can occur without retinopathy. The disease itself is not always responsible yet certain correlates can be made (viscosity in blood-protein diseases, se vere renal complications in hypertension) but the associations are not constant. Why are there a number of distinct forms of diabetic retinopathy? Nothing is known of pathophysiologic differences that may be associated with the various forms. Some morphologic attributes may be described but basic physiologic disturbances are not under stood. The investigative challenge remains, and it seems certain that its solution contains explanations for a number of puzzling retinopathies and their diseases, for example, diabetes, leukemia, blood-protein diseases and vascular diseases. Specific relationships between various dis eases and recognizable retinal changes can no longer remain unchallenged. Cotton-wool areas, "micro"* aneurysms, white-centered hemorrhages and vascular changes are not indicative of single diseased states. Cotton* Newell points out that many microaneurysms would be invisible with the magnification of the ophthalmoscope. Macroaneurysm is a preferred term. (Ophthalmology. St. Louis, Mosby, 1965, p. 254.)
SEPTEMBER, 1969
wool areas occur in a number of diseases, in cluding collagen diseases, diabetes, multiple myeloma, extensive carcinoma of the lower gastrointestinal tract, blood dyscrasias, com plications of postoperative heart surgery, cirrhosis of the liver, renal disease and vas cular diseases. "Micro" aneurysms occur most frequently in diabetes but may also occur in obliterative vascular disease (other than retinal artery occlusion), after venous (venous-arterial) occlusion, in nonoblitera ti ve vascular disease (hypertension), sicklecell disease, Hodgkin's disease and multiple myeloma. White-centered hemorrhages, at one time considered pathognomonic of leukemia and aplastic anemia, are also seen after heart surgery, in multiple myeloma, iron-deficiency anemia, subacute bacterial endocarditis, rheumatic fever without subacute bacterial endocarditis, diabetes, collagen diseases, cyanosis retinae and others. The changes of the retinal arterioles usually de scribed may be observed in patients without evident hypertension or arteriosclerosis. Since disease and lesion specificity does not exist, other explanations must be sought. Toxins are frequently mentioned, but no specific disturbing poisons have been demon strated. At one time, nitrogen retention was thought to cause retinopathy in renal disease, but many exceptions exist, for example, ob structive uremia is not associated with fundus change. It seems obvious, however, that certain metabolic phenomena—enzymatic, nutritive, endocrine, autonomie or catabolic —are involved, but present knowledge is de ficient. Certain factors seem to be related to fundus changes, but other factors must exist in order to explain all circumstances. Those recognizable in disease are increased venous pressure, increased blood viscosity, capillary permeability changes and vascular occlusive phenomena. Capillary epithelium hypoxia has been suggested as a cause of retinal hemorrhages but it is difficult to accept that normal retinal function with hypoxia is suf ficient to cause hypoxia of capillary cells.
VOL. 68, NO. 3
RETINOPATHY
Increased venous pressure is best exem plified by occlusion of the central vein, but it is also the essential factor in branch vein oc clusions, choked disc, cyanosis retinae due to cardiac insufficiency and mediastinal neo plasm. Although venous occlusion is invari ably associated with hemorrhages, other factors seem to be involved, for example, cyanosis retinae in which there may be hypoxia, increased venous pressure and hypercapnia but no hemorrhages or edema. Increase of blood viscosity is important in the retinopathy of multiple myeloma, macroglobulinemia and cirrhosis of the liver; it may also be a factor in polycythemia vera, leukemia and diabetes. In patients with mul tiple myeloma and macroglobulinemia, im provement of the retinopathy occurs with re duction of the increased blood viscosity ; this indicates some direct relationship. Permeability alterations of the capillaries cause tissue changes and have been consid ered of some importance in diabetic retinop athy. However, a proven association is lack ing and, at the present time, must only be considered as a potential in the physiopathology of retinopathies. Arterial occlusive phenomena occur with or without accompanying retinal change. Edema is the early manifestation in the ret ina; later, after reduction of edema, the af fected arterioles may be normal or abnormal. Functional and morphologic integrity of the retina is not always proportional to observed apparent vascular damage. Sufficient evi dence exists to associate the cytoid body in the retina with endarteriolar occlusive phe nomena. This is often the cause of cotton wool areas, but it is doubtful whether every cotton-wool-like area is caused by an arteriolar occlusion. Does this explain the occur rence of cotton-wool areas in diabetes, leuke mia, pernicious anemia, malignant tumor of
429
the gastrointestinal tract, multiple myeloma, cirrhosis of the liver and peptic ulcer ? It is possible that all cotton-wool spots are not areas of so-called cytoid degeneration. Metabolic deficiencies unquestionably play an important etiologic role in retinopathies but, at present, it is almost impossible to as cribe any specific cause to any of the retinal phenomena except those due to vascular oc clusion. What explanation is there for a flame-shaped hemorrhage other than the ana tomic ? Why the white-centered hemorrhage ? It is not enough to say that the central por tion is devoid of blood ; that there is an asso ciated cotton-wool area; that it is an accu mulation of plasma in the hemorrhage; or that (rarely) it is an accumulation of leuko cytes. The status of the blood vessels, partic ularly the arteries, offers little explanation. Fluorescein angiography and electron mi croscopy can contribute basic knowledge if they are utilized as physiologic tools rather than as demonstrators of morphologic changes. A new approach which ignores the bias and misconceptions of the past is needed. It is hoped that awareness of this need will result in the development of new approaches and tools to solve this important problem. SUMMARY
The etiology of retinopathy is unknown. Histopathologic studies have described the late stages of disease but have not discovered the basic cause. The premise that retinopa thies are specific is fallacious ; the causes of hemorrhages and infiltrative areas are un known. Knowledge of vegetative physiology is so deficient that none of the phenomena of a retinopathy can be adequately explained. A new approach to the physiology and pathophysiology of the retina must begin with the development of new tools and meth ods of investigation.
OCULAR DEPOSITION OF COPPER
generation (Wilson's disease). Science 116:484, 19S2. 10. Beam, A. G. and Kunkel, H. G. : Abnormali ties of copper metabolism in Wilson's disease and their relationship to the aminoaciduria. J. Clin. In vest. 33:400, 1954. 11. Uzman, L. L., Iber, F. L., Chalmers, T. C. and Knowlton, M. : The mechanism of copper depo sition in the liver in hepatolenticular degeneration (Wilson's disease). Am. J. Med. Sci. 231:511, 1956. 12. Hrgovcic, M., Tessmer, C. F., Minckler, T. M., Mosier, B. and Taylor, G. H. : Serum copper levels in lymphoma and leukemia. Special reference to Hodgkin's disease. Cancer 21:743, 1968. 13. Gerhard, J. P. and Calme, P. : Le dosage cuivre dans l'humeur aqueuse humaine et ses varia tions pathologiques. Bull. Soc. Ophtal. France 64:929, 1964. 14. Gerhard, J. P. : Etude du cuivre de l'humeur aqueuse. Docum. Ophthal. 20:104, 1966. 15. Ashton, N. : Ocular changes in multiple myelomatosis. Arch. Ophth. 73:487, 1965. 16. Slansky, H. H., Bronstein, M. and Gartner,
427
S. : Ciliary body cysts in multiple myeloma. Their relation to urethane, hyperproteinemia and duration of the disease. Arch. Ophth. 76:686, 1966. 17. Sanders, T. E., Podos, S. M. and Rosenbaum, L. J. : Intraocular manifestations of multiple my eloma. Arch. Ophth. 77 :789, 1967. 18. Biirki, E. : Ueber Hornhautveränderungen bei einem Fall von multiplem Myelom (Pasmocytom). Ophthalmologica 135:565, 1958. 19. François, J. : Thésaurismose de la cornée dans le myélomatose multiple. Bull. Soc. Belge Ophtal. 142:494, 1966. 20. Clarke, E. : Ophthalmological complications of multiple myelomatosis. Brit. J. Ophth. 39:233, 1955. 21. Records, R. E., Claman, H. N. and Merrill, D. : Unpublished observations. 22. François, J. and Rabaey, M. : Microelectrophoresis on agar of normal and pathological aqueous humor. Arch. Ophth. 63 :836, 1960. 23. Hemmingsen, L. and 0ther, A. : Disc electrophoresis of aqueous humor. Acta Ophth. 45:359, 1967.
W H Y IS A R E T I N O P A T H Y ? P. J. LEINFELDER,
M.D.
Iowa City, Iowa
Since its inception, ophthalmoscopy has been oriented toward diagnostic specificity. Writings and investigations, especially in pa thology, have endeavored to substantiate the value of ophthalmoscopy in clinical diagnosis and prognosis ; this is illustrated by the elab oration of the Keith-Wagner classification of vascular disease. These dissertations em phasized the positive correlates of retinopathies with different diseases but ignored those situations in which retinal changes were absent in patients who apparently had as severe an involvement with a general dis ease. Furthermore, no consideration was given to circumstances in which specific changes were present but. diagnosis of the specific disease was not possible. From the Department of Ophthalmology, College of Medicine, University of Iowa. This paper is dedicated to Alson E. Braley, M.D. Reprint requests to P. J. Leinfelder, M.D., De partment of Ophthalmology, University Hospitals, Iowa City, Iowa 52240.
Definitive ophthalmoscopic diagnosis de pends upon the association of particular types of observable changes with a single disease. Certain vascular changes are consid ered typical of arteriosclerosis, other changes of hypertension, punctate hemorrhages and microaneurysms of diabetes. In many in stances in which a specific diagnosis is indi cated, alternate diagnoses are also possible; seemingly specific changes in the retina may occur in several unrelated diseases. Diseases which may be associated with retinopathies may exist in severe or mild form with or without retinopathy and, at times, in patients who are not particularly ill with their dis ease. Ophthalmoscopic changes have been cor related with the altered microscopic anat omy, resulting in an association of the late and often terminal stages of the disease with the ophthalmoscopically visible alterations in the tissue. This association has been of
428
AMERICAN JOURNAL OF OPHTHALMOLOGY
value, but it has led to neglect of the basic first event in disease—disturbed physiology. There are extensive reports on the patho logic changes in the retina, but there is so lit tle knowledge of basic physiology that a stri ate hemorrhage cannot be adequately ex plained. Satisfaction with the knowledge of retinal pathology and its created image of disease has resulted in stagnation of investi gation and general neglect of physiology and pathophysiology. Disturbed physiology is the basis of tissue alteration. However, knowledge in this area is extremely deficient. Do we really know why hemorrhages, edema or localized infil trates of various types occur ? What triggers retinopathy? What substances in the meta bolic or catabolic cycles induce retinal changes? Certainly vascular or circulatory changes alone are not responsible since se vere vascular alterations can occur without retinopathy. The disease itself is not always responsible yet certain correlates can be made (viscosity in blood-protein diseases, se vere renal complications in hypertension) but the associations are not constant. Why are there a number of distinct forms of diabetic retinopathy? Nothing is known of pathophysiologic differences that may be associated with the various forms. Some morphologic attributes may be described but basic physiologic disturbances are not under stood. The investigative challenge remains, and it seems certain that its solution contains explanations for a number of puzzling retinopathies and their diseases, for example, diabetes, leukemia, blood-protein diseases and vascular diseases. Specific relationships between various dis eases and recognizable retinal changes can no longer remain unchallenged. Cotton-wool areas, "micro"* aneurysms, white-centered hemorrhages and vascular changes are not indicative of single diseased states. Cotton* Newell points out that many microaneurysms would be invisible with the magnification of the ophthalmoscope. Macroaneurysm is a preferred term. (Ophthalmology. St. Louis, Mosby, 1965, p. 254.)
SEPTEMBER, 1969
wool areas occur in a number of diseases, in cluding collagen diseases, diabetes, multiple myeloma, extensive carcinoma of the lower gastrointestinal tract, blood dyscrasias, com plications of postoperative heart surgery, cirrhosis of the liver, renal disease and vas cular diseases. "Micro" aneurysms occur most frequently in diabetes but may also occur in obliterative vascular disease (other than retinal artery occlusion), after venous (venous-arterial) occlusion, in nonoblitera ti ve vascular disease (hypertension), sicklecell disease, Hodgkin's disease and multiple myeloma. White-centered hemorrhages, at one time considered pathognomonic of leukemia and aplastic anemia, are also seen after heart surgery, in multiple myeloma, iron-deficiency anemia, subacute bacterial endocarditis, rheumatic fever without subacute bacterial endocarditis, diabetes, collagen diseases, cyanosis retinae and others. The changes of the retinal arterioles usually de scribed may be observed in patients without evident hypertension or arteriosclerosis. Since disease and lesion specificity does not exist, other explanations must be sought. Toxins are frequently mentioned, but no specific disturbing poisons have been demon strated. At one time, nitrogen retention was thought to cause retinopathy in renal disease, but many exceptions exist, for example, ob structive uremia is not associated with fundus change. It seems obvious, however, that certain metabolic phenomena—enzymatic, nutritive, endocrine, autonomie or catabolic —are involved, but present knowledge is de ficient. Certain factors seem to be related to fundus changes, but other factors must exist in order to explain all circumstances. Those recognizable in disease are increased venous pressure, increased blood viscosity, capillary permeability changes and vascular occlusive phenomena. Capillary epithelium hypoxia has been suggested as a cause of retinal hemorrhages but it is difficult to accept that normal retinal function with hypoxia is suf ficient to cause hypoxia of capillary cells.
VOL. 68, NO. 3
RETINOPATHY
Increased venous pressure is best exem plified by occlusion of the central vein, but it is also the essential factor in branch vein oc clusions, choked disc, cyanosis retinae due to cardiac insufficiency and mediastinal neo plasm. Although venous occlusion is invari ably associated with hemorrhages, other factors seem to be involved, for example, cyanosis retinae in which there may be hypoxia, increased venous pressure and hypercapnia but no hemorrhages or edema. Increase of blood viscosity is important in the retinopathy of multiple myeloma, macroglobulinemia and cirrhosis of the liver; it may also be a factor in polycythemia vera, leukemia and diabetes. In patients with mul tiple myeloma and macroglobulinemia, im provement of the retinopathy occurs with re duction of the increased blood viscosity ; this indicates some direct relationship. Permeability alterations of the capillaries cause tissue changes and have been consid ered of some importance in diabetic retinop athy. However, a proven association is lack ing and, at the present time, must only be considered as a potential in the physiopathology of retinopathies. Arterial occlusive phenomena occur with or without accompanying retinal change. Edema is the early manifestation in the ret ina; later, after reduction of edema, the af fected arterioles may be normal or abnormal. Functional and morphologic integrity of the retina is not always proportional to observed apparent vascular damage. Sufficient evi dence exists to associate the cytoid body in the retina with endarteriolar occlusive phe nomena. This is often the cause of cotton wool areas, but it is doubtful whether every cotton-wool-like area is caused by an arteriolar occlusion. Does this explain the occur rence of cotton-wool areas in diabetes, leuke mia, pernicious anemia, malignant tumor of
429
the gastrointestinal tract, multiple myeloma, cirrhosis of the liver and peptic ulcer ? It is possible that all cotton-wool spots are not areas of so-called cytoid degeneration. Metabolic deficiencies unquestionably play an important etiologic role in retinopathies but, at present, it is almost impossible to as cribe any specific cause to any of the retinal phenomena except those due to vascular oc clusion. What explanation is there for a flame-shaped hemorrhage other than the ana tomic ? Why the white-centered hemorrhage ? It is not enough to say that the central por tion is devoid of blood ; that there is an asso ciated cotton-wool area; that it is an accu mulation of plasma in the hemorrhage; or that (rarely) it is an accumulation of leuko cytes. The status of the blood vessels, partic ularly the arteries, offers little explanation. Fluorescein angiography and electron mi croscopy can contribute basic knowledge if they are utilized as physiologic tools rather than as demonstrators of morphologic changes. A new approach which ignores the bias and misconceptions of the past is needed. It is hoped that awareness of this need will result in the development of new approaches and tools to solve this important problem. SUMMARY
The etiology of retinopathy is unknown. Histopathologic studies have described the late stages of disease but have not discovered the basic cause. The premise that retinopa thies are specific is fallacious ; the causes of hemorrhages and infiltrative areas are un known. Knowledge of vegetative physiology is so deficient that none of the phenomena of a retinopathy can be adequately explained. A new approach to the physiology and pathophysiology of the retina must begin with the development of new tools and meth ods of investigation.