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The Ophthalmoscopic Findings in C + S Disease
THE O P H T H A L M O S C O P I C FINDINGS IN C + ROBERT A. LEVINE, M.D.,
S DISEASE*
AN 3 ARNOLD M . KAPLAN,
Chicago,
Sickle-cell anemia is the best known ex ample of an inherited disease caused by an abnormal hemoglobin. The patient with classic sickle-cell anemia reflects a homozy gous ( S + S ) form of the disease and all the progeny resulting from his marriage to a person with normal hemoglobin ( A + A ) will carry sickle-cell trait ( A + S ) . Sicklecell trait, as in other heterozygous hemo globinopathies (C + S ) , reflects codominance of each moiety rather than the more common dominant-recessive relationship. Since the original work on sickle-cell he moglobin, many additional hemoglobins have been identified which have been given alpha betic names. One of these is hemoglobin C which is occasionally associated with sicklecell hemoglobin (hemoglobin S ) in a hetero zygous state. Hematologists have arbitrarily decided that the first letter should represent the hemoglobin having the higher blood con centration and so the cases represented here are classified as C + S disease. They would have been called sickle-cell hemoglobin C disease in the older terminology. Hemoglobin S occurs more frequently in Central and West Africa and less so in the central Mediterranean region, the Persian Gulf and India. Hemoglobin C is prevalent in West Africa and is rather uncommon in other parts of the world. Hemoglobin S oc curs in about 10 percent and hemoglobin C in about two percent of the American Negro population. Estimates are that 20,000 to 30,000 Negroes in the United States have the C + S hemoglobinopathy or disease. All types of study are valuable in under standing this entity, but most advances have been made in the biochemical, immunologic and genetic fields. The normal adult hemo* From the Department of Ophthalmology of the Michael Reese Hospital and Medical Center, Chicago, Illinois.
M.D.
Illinois
globin molecule (hemoglobin A ) is com posed of four peptide chains, two β, and two ß chains. The molecule is arranged in identical halves, each half containing an α and a ß chain. A change in an amino acid in one peptide chain is mirrored in its counter part. For this reason it is convenient to speak of hemoglobin in terms of half a mole cule containing 141 amino acids in the a peptide and 146 in the ß peptide. The α pep tide chain is identical in hemoglobin A , S and C but position number 6 of the ß pep tide chain carries glutamic acid, valine and lysine in hemoglobin A , S and C, respec tively. In all other respects the ß peptide chain is the same in the three hemoglobins. Therefore, in contrasting hemoglobins A , S and C it has been found that 286 of the 287 amino acids are identical in name and posi tion. 3
Electrophoretic mobility is based upon this chemical structure. Hemoglobins, like all proteins, will move as charged particles in an electric field. In the alkaline chromato graphic solvent all hemoglobins are nega tively charged and the rapidity with which they migrate to the anode is proportionate to their degree of negativity. Glutamic acid adds negative charge to the molecule, valine has no charge and lysine has a positive charge. Therefore, hemoglobin A has the greatest mobility, hemoglobin S less mobil ity and hemoglobin C the least mobility. Because hemoglobin C and S differ only in the sixth position of the ß polypeptide chain, the genes controlling the production of hemoglobin C and S are mutants and allelomorphic* Of clinical importance is that these allelic genes influence all red blood cells and that practically all red blood cells containing hemoglobin C + S will sickle if there is sufficient anoxia even in the hetero zygous state. In other words, if quantita-
38
ROBERT A. L E V I N E A N D ARNOLD Μ. K A P L A N disc and coursing superotemporally was a neovascularized gliotic membrane which extended into the vitreous. Just below the midline temporally lay a huge yellow globular vitreal mass seemingly at tached to the retina. The course of the disease was characterized by further deterioration of vision in the left eye, asso ciated with an extension of the preretinal hemor rhage into the vitreous. When last seen, no retinal details could be found in this eye. The right eye has remained clinically unchanged although serial fun dus photographs indicate some gliosis and shrinkage of the aneurysms. CASE 2
Fig. 1 (Levine and Kaplan). Typical glistening deposits ( A ) ; pigmented lesion ( B ) on a back ground of pigmentary atrophy.
live electrophoresis reveals equal amounts of hemoglobin C and S, this reflects the amount present in each red blood cell. As mentioned earlier, the C + S popula tion in the United States is, admittedly, a small one. However, the ophthalmic compli cations of this disease are common. After encountering one patient with such compli cations, we evaluated a group of patients with C + S hemoglobinopathy who were vi sually asymptomatic. Our findings in these 10 patients are as follows: RKI'UKT
OF
A five-year-old Negro girl had no ocular com plaints. The visual acuity in the right and left eye was 20/20. Ophthalmoscopically, the right eye showed iridescent, irregularly round, copper-colored lesions peripherally (fig. S ) . Gliotic areas were present in the inferior periphery and there was pronounced vascular tortuosity in the in ferotemporal periphery. The left eye showed similar iridescent copper-colored lesions and a large clump of tor tuous vessels was noted in the nasal periphery.
CASKS
CASE 1
A 30-year-old Negro was hospitalized on Octo ber 27, 1962, with a five-day history of painless blurring of vision in the left eye. He admitted to a similar episode in the right eye two months pre viously. The visual acuity was 20/20 in the right eye and finger counting in the left. Cells were present in the vitreous of hotli eyes. Ophtlialmoscopically, the right eye showed scattered large pigmented lesions in the periphery. In the same area there were numerous copper-colored glistening deposits (figs. 1 and 2 ) . Dramatic peripheral aneurysmal changes were seen in the snperotemporal periphery (fig. 3 ) . Inferonasally, a glial membrane extended from the retina into the vitreous, accompanied by several tortuous vessels. White fluffy preretinal masses ob scured the lower one third of the fundus. The left eye showed a preretinal hemorrhage which obscured a view of the lower one-half of the fundus. Two discrete sausage-shaped preretinal hemorrhages were located nasally (fig. 4 ) . Beginning at the
Fig. 2 (Levine and Kaplan). Aggregates of glistening deposits ( A ) with numerous smaller deposits in background.
39
FINDINGS IN" C + S D I S E A S E TABLE 1 SYSTEMIC AND LABORATORY FEATURES OF CASE REPORTS
Case
Past History
6 7 8 9 10
Negative Out-patient care for abdominal pain Hospitalized for bronchopneumonia Hospitalized for back ana abdominal pain, salmonella osteomyelitis and serum hepatitis Hospitalized for abdominal pain and pneu monitis Hospitalized for back and abdominal pain Hospitalized for hematuria Hospitalized with crisis during pregnancy Noncontributory Noncontributory
Splenomegaly
Reticulocytosis
No No No data Marked
No Very mild No data Marked with crisis
Moderate Moderate No data Mild, moderate with crisis
Very mild
Very mild
Marked Mild Yes No No data
Marked with crisis Mild Marked with crisis Very mild Mild
Mild, moderate with crisis Moderate Moderate No data Mild Mild
CASE 3
This eight and one-half year-old Negro girl is and has been visually asymptomatic. Visual acuity: O.D., 20/20; O.S., 20/20. Ophthalmoscopic evalua tion was not remarkable. CASE 4
This 14-year-old Negro boy, a brother of the patient in Case 3, is and has been visually asymp tomatic. Visual acuity: O.D., 2 0 / 2 0 ; O S . , 20/25 and 20/20 with pinhole. Ophthalmoscopic evalua tion was not remarkable. CASE 5
This 17-year-old Negro youth, a brother of the patients in the two previous cases, is and has been visually asymptomatic. Visual acuity: O.D., 2 0 / 2 0 ; O.S., 20/20. Ophthalmoscopically, O.D. revealed neovascular arborizations in the superior temporal periphery. Discrete white lines in this area appeared to be fibrotic superficial retinal vessels. Scattered
Fig. 3 (Levine and Kaplan). Racemose aneurysm of the peripheral retina with bulbous vascular dilatations.
Anemia
throughout the peripheral fundus, particularly na sally, inferonasally, inferiorly and inferotemporally were numerous iridescent, copper-colored, conglom erates (fig. 6 ) . O.S. revealed similar but less numer ous copper-colored iridescent bodies scattered in the peripheral fundus. CASE 6
This 10-year-old Negro boy is and has been visually asymptomatic. Visual acuity: O.D., 20/20; O.S., 20/20. Ophthalmoscopically, O.D. revealed two solitary, round, reddish-brown lesions in the inferior periphery. In this area there were numer ous wispy white strands which were superficially placed so that they partially obscured the super ficial retinal vascular tree. Another area of these wispy white linear lesions was located superotemporally in the peripheral fundus. O.S. was not remarkable. CASE 7
This 18-year-old Negro youth is and has been visually asymptomatic. Visual acuity: O.D., 2 0 / 2 0 ; O.S., 20/20. Ophthalmoscopically, O.D. revealed a small, round circumscribed slate-gray lesion in the inferotemporal periphery. It clinically appeared to be a choroidal nevus. O.S. was not remarkable.
Fig. 4 (Levine and Kaplan). Preretinal hemorrhages ( A ) .
ROBERT A. LEVINE A N D ARNOLD Μ. K A P L A N
40
Fig. 6 (Levine and Kaplan). Glistening deposits encircled ( A ) ; artefact (b).
DISCUSSION
Fig. 5 (Levine and Kaplan)- Aggregate of glistening deposits.
CASE 8
This 25-year-old Negro woman had poor vision in the left eye since childhood because of anisóme tropin. Corrected visual acuity: O.D., 2 0 / 2 0 ; O.S., 20/400. Ophthalmoscopically, O.D. revealed scat tered tiny white round lesions in the peripheral fundus, most numerous in the 5-o'clock periphery. O.S. revealed an accumulation of iridescent bodies in the 9-o'clock periphery, and in the peripheral fundus at the 5-o'clock position there was a small round white lesion from which radiated a pigment spicule. There was occasional peripheral vessel sheathing in both eyes. CASE 9
This 35-year-old Negro woman, mother of the patients described in Cases 3, 4 and 5, is and has been visually asvmptomatic. Visual acuitv: O.D., 2 0 / 2 0 ; O.S., 20/20. Ophthalmoscopically, O.D. re vealed numerous discrete white lesions scattered throughout the posterior pole. Clinically they ap peared drusenlike. O.S. was not remarkable. CASE 10
This 58-year-old Negro is and has been visually asvmptomatic. Visual acuitv: O.D., 20/200 and 20/30 with pinhole; O.S., 20/100 and 20/30 with pinhole. Ophthalmoscopically, O.D. revealed a cluster of radiating, white gliotic lesions located in the temporal peripheral fundus. O.S. revealed a gliotic vessel in the temporal periphery.
The association of C + S hemoglobinop athy with eye disease has been recognized only during the past 10 years. Prior to this time, these cases had been classified as cases of sickle-cell disease. The more careful use of electrophoresis made it apparent that a peculiarly high percent of Negroes with C + S hemoglobin experience eye complications, in contrast with those Negroes having the far more common S + S (sickle-cell ane mia) or A + S (sickle-cell t r a i t ) . The early case reports " of eye complica tions in C + S disease emphasized its most florid form: vitreous hemorrhage, fre quently with organization and retinal detach ment. Goodman, et al. and Munro and Walker placed greater emphasis on the ear lier more specific fundus features. Cells and clumps of cottony material were found in the vitreous, and were interpreted as reflect ing the residua of hemorrhage into the vit reous. The fundus lesions mainly were peripheral. Sheathing, arborizations, abnor mal anastomoses, bulbous dilatations and aneurysmal changes of the peripheral retinal vessels were found. Chalky white vessels and patches of retinitis proliferans also were seen. Occasionally they noted sharply out5
8
9
7
41
FINDINGS IN C + S D I S E A S E
lined red areas resembling retinal tears which on continued observation proved to be thin layers of preretinal hemorrhages. Discrete areas of depigmentation and hyperpigmentation resembling patches of healed focal chor ioretinitis also were observed. Of note is that Goodman, et al. also described chorioretinal scars surrounded by "glistening specks" in their only visually asymptomatic case. The ophthalmoscopic features of Case 1 described herein are therefore typical of those reported in the literature. Unlike Case 1 the remainder of the patients in this series with C + S hemoglobinopathy had no eye com plaints and warrant further comment. Seven of these other nine patients exhibited some fundus abnormality and, except in Case 9, all lesions were limited to the peripheral fundus. Although gliotic patches (Cases 2 and 1 0 ) , tortuous and arborizing vessels (Cases 2 and S ) , pigmented lesions (Cases 6, 7 and 8 ) and chalky white vessels (Cases 5 and 10) were seen, we feel the distinctive iridescent fundus lesions to be of greatest importance because they occurred in the younger patients where nonspecific degenerative changes and other associated diseases would be most unlikely. These copper-colored bodies were noted in Cases 2, 5 and 8 in which the patients were 5, 17, and 25 years of age respectively. They were also present in the fundus of the 30year-old patient described in Case 1. These glistening lesions may represent cholesterol deposits in the retina, a fairly common de generative phenomenon after hemorrhage or infarction. The preretinal wispy lesions seen in Case 6 may well represent the residua of blood in the vitreous. As a group, the 10 patients reported in this paper reflect most of the typical systemic manifestations of C + S hemoglobinop athy, including pain in the abdomen, chest, flank and extremities, hematuria, and malig nant anemia with a crisis during the third trimester of pregnancy. The commonly asso ciated findings of splenomegaly, shortened red blood cell survival time, reticulocytosis 7
and erythroid hyperplastic marrow reflect a hemopoetic system operating at maximum capacity at all times. In this situation anemia may become evident only during stress periods such as pregnancy or intercurrent infection. Target cells, found in the periph eral blood smear, are a far more diagnostic feature of the disease than anemia. The role of the target cell in the pathogenesis of the disease remains obscure. The pathologic changes seen in this disease are probably referable to the presence of S hemoglobin. All patients with C + S hemo globinopathy are found to have a positive rapid sickling test. Once sickled, the erythro cyte loses its flexibility and blood viscosity rises, resulting in spasm or stasis and even tuating in widespread capillary infarction and tissue necrosis. Kimmelstiel, in his study of the subject, concluded that thrombosis, per se, is not a significant feature of this ischemic infarctive process. Paton states that me chanical factors of blood flow are important in the pathogenesis of the comma-shaped vascular segments seen in the conjunctiva of patients with either C + S or S + S hemoglobinopathy. 10
11
Certain factors inherent to ophthalmic tissue may predispose to sickling. The high rate of glycolysis of the retina, which favors the rapid depletion of oxygen from the eryth rocyte, may well enhance the sickling ten dency. The end-arteriole system of the retinal vascular tree may add to the vulnerability of the retina to the sickling process. The retinal vascular shunt mechanism which burdens the peripheral retina with a great concentration of reduced hemoglobin S may partially explain the clinical finding that the ophthalmoscopic manifestations of the dis ease are found primarily in the peripheral fundus. Even more conjectural are the ex planations for the unusually high incidence of eye complications in patients with C + S hemoglobinopathy unlike those with either hemoglobin S + S or A + S. The role of hemoglobin C in this disease has yet to be fully clarified.
42
ROBERT
Α. L E V I N E
AND
ARNOLD
Μ.
KAPLAN
3. The presence or degree of fundus pathology did not seem to be related to se verity of the systemic illness nor could it be correlated with the existence of splenomeg aly, anemia or reticulocytosis.
SUMMARY
The following inferences have been made: 1. A significant number of visually asymp tomatic patients with C + S hemoglobinop athy have peripheral fundus pathology and this may be found as early as the age of five years. 2. Although a variety of fundus lesions were seen in this visually asymptomatic group, the most common lesions were multi ple copper-colored iridescent deposits in the peripheral fundus.
Ill
North
Wabash
Avenue
(2).
ACKNOWLEDGMENT
W e wish to express our appreciation to Drs Michael Hogan and Daniel Snydacker for their helpful criticism of the paper.
REFERENCES 1. Chernoff, Α. Γ.: The human hemoglobins in health and disease. New England I. Med., 2 5 3 : 3 2 2 , 365, 416, 1955. 2. Myersoson, R. M., Harrison, E., and Lohmuller, H. \V.: Incidence and significance of ahnormal hemoglobins. Am. J . Med., 2 6 : 5 4 3 , 1959. 3. Ingram, V. M.: The Hemoglobins in Genetics and Evolution. New York, Columbia, 1963. 4. Alper, R. G, Cavanagh, D., and Jonson, U.: Sickle-cell hemoglobin C disease. Obst, it Gvnec, 1 3 : 319, 1959. 5. Hannon, J . F.: Vitreous hemorrhages associated with sickle-cell hemoglobin C disease. Am. I. Ophth, 4 2 : 7 0 7 , 1956. 6. Kennedv, I. T., and Cope, C. B.: Intraocular lesions associated with sickle-cell disease. A M A Arch. Ophth.. 5 8 :163," 1957. 7. Isbev, E. K., lr., Clifford, G. O., and Tanaka, K. R. : Vitreous hemorrhages associated with sicklecell C disease. Am. J . Ophth., 4 5 :870, 1958. 8. Goodman, G, von Sallmann, L., and Holland, M. C.: Ocular manifestations of sickle-cell disease. A M A Arch. Ophth., 5 8 :655, 1957. 9. Munro, S., and Walker, C.: Ocular complications in sickle-cell hemoglobin C disease. Brit. 1. Ophth., 44:1.1960. 10. Kimmelstiel, P.: Vascular occlusion and retinal infarction in sickle-cell anemia. Am. T. M. Sc., 216:11,1948. 11. Patón, D.: The conjunctival sign of sickle-cell disease. A M A Arch. Ophth., 6 8 : 6 2 7 , 1962.
FURTHER
CLINICAL EARI. Fort
MAXWKI-L, Worth,
Now that 5-iodo-2'-deoxyuridine ( I D U ) is commercially available it may be of inter est to review the accumulated results of a clinical evaluation and compare the early data with that obtained later in the study. One pharmaceutical manufacturing com pany* in May, 1962, made this drug avail able to all qualified investigators who would furnish the information required by the Food and Drug Administration and sign the * From Alcon Laboratories, Inc.
EVALUATION
OF
IDU*
M.D.
Texas
proper form. In the ensuing year over 2,000 ophthalmologists requested and were sent this experimental drug. Kaufman's original work and subsequent papers " gave the necessary incentive to amass a large series of clinical cases to evaluate the safety and effectiveness of this promising new drug. It is true that a doubleblind study seemed appropriate; however, any individual clinic had so few cases that a significant series was exceedingly slow to evolve. Double-blind studies performed on 1
2
4
S DISEASE*
AN 3 ARNOLD M . KAPLAN,
Chicago,
Sickle-cell anemia is the best known ex ample of an inherited disease caused by an abnormal hemoglobin. The patient with classic sickle-cell anemia reflects a homozy gous ( S + S ) form of the disease and all the progeny resulting from his marriage to a person with normal hemoglobin ( A + A ) will carry sickle-cell trait ( A + S ) . Sicklecell trait, as in other heterozygous hemo globinopathies (C + S ) , reflects codominance of each moiety rather than the more common dominant-recessive relationship. Since the original work on sickle-cell he moglobin, many additional hemoglobins have been identified which have been given alpha betic names. One of these is hemoglobin C which is occasionally associated with sicklecell hemoglobin (hemoglobin S ) in a hetero zygous state. Hematologists have arbitrarily decided that the first letter should represent the hemoglobin having the higher blood con centration and so the cases represented here are classified as C + S disease. They would have been called sickle-cell hemoglobin C disease in the older terminology. Hemoglobin S occurs more frequently in Central and West Africa and less so in the central Mediterranean region, the Persian Gulf and India. Hemoglobin C is prevalent in West Africa and is rather uncommon in other parts of the world. Hemoglobin S oc curs in about 10 percent and hemoglobin C in about two percent of the American Negro population. Estimates are that 20,000 to 30,000 Negroes in the United States have the C + S hemoglobinopathy or disease. All types of study are valuable in under standing this entity, but most advances have been made in the biochemical, immunologic and genetic fields. The normal adult hemo* From the Department of Ophthalmology of the Michael Reese Hospital and Medical Center, Chicago, Illinois.
M.D.
Illinois
globin molecule (hemoglobin A ) is com posed of four peptide chains, two β, and two ß chains. The molecule is arranged in identical halves, each half containing an α and a ß chain. A change in an amino acid in one peptide chain is mirrored in its counter part. For this reason it is convenient to speak of hemoglobin in terms of half a mole cule containing 141 amino acids in the a peptide and 146 in the ß peptide. The α pep tide chain is identical in hemoglobin A , S and C but position number 6 of the ß pep tide chain carries glutamic acid, valine and lysine in hemoglobin A , S and C, respec tively. In all other respects the ß peptide chain is the same in the three hemoglobins. Therefore, in contrasting hemoglobins A , S and C it has been found that 286 of the 287 amino acids are identical in name and posi tion. 3
Electrophoretic mobility is based upon this chemical structure. Hemoglobins, like all proteins, will move as charged particles in an electric field. In the alkaline chromato graphic solvent all hemoglobins are nega tively charged and the rapidity with which they migrate to the anode is proportionate to their degree of negativity. Glutamic acid adds negative charge to the molecule, valine has no charge and lysine has a positive charge. Therefore, hemoglobin A has the greatest mobility, hemoglobin S less mobil ity and hemoglobin C the least mobility. Because hemoglobin C and S differ only in the sixth position of the ß polypeptide chain, the genes controlling the production of hemoglobin C and S are mutants and allelomorphic* Of clinical importance is that these allelic genes influence all red blood cells and that practically all red blood cells containing hemoglobin C + S will sickle if there is sufficient anoxia even in the hetero zygous state. In other words, if quantita-
38
ROBERT A. L E V I N E A N D ARNOLD Μ. K A P L A N disc and coursing superotemporally was a neovascularized gliotic membrane which extended into the vitreous. Just below the midline temporally lay a huge yellow globular vitreal mass seemingly at tached to the retina. The course of the disease was characterized by further deterioration of vision in the left eye, asso ciated with an extension of the preretinal hemor rhage into the vitreous. When last seen, no retinal details could be found in this eye. The right eye has remained clinically unchanged although serial fun dus photographs indicate some gliosis and shrinkage of the aneurysms. CASE 2
Fig. 1 (Levine and Kaplan). Typical glistening deposits ( A ) ; pigmented lesion ( B ) on a back ground of pigmentary atrophy.
live electrophoresis reveals equal amounts of hemoglobin C and S, this reflects the amount present in each red blood cell. As mentioned earlier, the C + S popula tion in the United States is, admittedly, a small one. However, the ophthalmic compli cations of this disease are common. After encountering one patient with such compli cations, we evaluated a group of patients with C + S hemoglobinopathy who were vi sually asymptomatic. Our findings in these 10 patients are as follows: RKI'UKT
OF
A five-year-old Negro girl had no ocular com plaints. The visual acuity in the right and left eye was 20/20. Ophthalmoscopically, the right eye showed iridescent, irregularly round, copper-colored lesions peripherally (fig. S ) . Gliotic areas were present in the inferior periphery and there was pronounced vascular tortuosity in the in ferotemporal periphery. The left eye showed similar iridescent copper-colored lesions and a large clump of tor tuous vessels was noted in the nasal periphery.
CASKS
CASE 1
A 30-year-old Negro was hospitalized on Octo ber 27, 1962, with a five-day history of painless blurring of vision in the left eye. He admitted to a similar episode in the right eye two months pre viously. The visual acuity was 20/20 in the right eye and finger counting in the left. Cells were present in the vitreous of hotli eyes. Ophtlialmoscopically, the right eye showed scattered large pigmented lesions in the periphery. In the same area there were numerous copper-colored glistening deposits (figs. 1 and 2 ) . Dramatic peripheral aneurysmal changes were seen in the snperotemporal periphery (fig. 3 ) . Inferonasally, a glial membrane extended from the retina into the vitreous, accompanied by several tortuous vessels. White fluffy preretinal masses ob scured the lower one third of the fundus. The left eye showed a preretinal hemorrhage which obscured a view of the lower one-half of the fundus. Two discrete sausage-shaped preretinal hemorrhages were located nasally (fig. 4 ) . Beginning at the
Fig. 2 (Levine and Kaplan). Aggregates of glistening deposits ( A ) with numerous smaller deposits in background.
39
FINDINGS IN" C + S D I S E A S E TABLE 1 SYSTEMIC AND LABORATORY FEATURES OF CASE REPORTS
Case
Past History
6 7 8 9 10
Negative Out-patient care for abdominal pain Hospitalized for bronchopneumonia Hospitalized for back ana abdominal pain, salmonella osteomyelitis and serum hepatitis Hospitalized for abdominal pain and pneu monitis Hospitalized for back and abdominal pain Hospitalized for hematuria Hospitalized with crisis during pregnancy Noncontributory Noncontributory
Splenomegaly
Reticulocytosis
No No No data Marked
No Very mild No data Marked with crisis
Moderate Moderate No data Mild, moderate with crisis
Very mild
Very mild
Marked Mild Yes No No data
Marked with crisis Mild Marked with crisis Very mild Mild
Mild, moderate with crisis Moderate Moderate No data Mild Mild
CASE 3
This eight and one-half year-old Negro girl is and has been visually asymptomatic. Visual acuity: O.D., 20/20; O.S., 20/20. Ophthalmoscopic evalua tion was not remarkable. CASE 4
This 14-year-old Negro boy, a brother of the patient in Case 3, is and has been visually asymp tomatic. Visual acuity: O.D., 2 0 / 2 0 ; O S . , 20/25 and 20/20 with pinhole. Ophthalmoscopic evalua tion was not remarkable. CASE 5
This 17-year-old Negro youth, a brother of the patients in the two previous cases, is and has been visually asymptomatic. Visual acuity: O.D., 2 0 / 2 0 ; O.S., 20/20. Ophthalmoscopically, O.D. revealed neovascular arborizations in the superior temporal periphery. Discrete white lines in this area appeared to be fibrotic superficial retinal vessels. Scattered
Fig. 3 (Levine and Kaplan). Racemose aneurysm of the peripheral retina with bulbous vascular dilatations.
Anemia
throughout the peripheral fundus, particularly na sally, inferonasally, inferiorly and inferotemporally were numerous iridescent, copper-colored, conglom erates (fig. 6 ) . O.S. revealed similar but less numer ous copper-colored iridescent bodies scattered in the peripheral fundus. CASE 6
This 10-year-old Negro boy is and has been visually asymptomatic. Visual acuity: O.D., 20/20; O.S., 20/20. Ophthalmoscopically, O.D. revealed two solitary, round, reddish-brown lesions in the inferior periphery. In this area there were numer ous wispy white strands which were superficially placed so that they partially obscured the super ficial retinal vascular tree. Another area of these wispy white linear lesions was located superotemporally in the peripheral fundus. O.S. was not remarkable. CASE 7
This 18-year-old Negro youth is and has been visually asymptomatic. Visual acuity: O.D., 2 0 / 2 0 ; O.S., 20/20. Ophthalmoscopically, O.D. revealed a small, round circumscribed slate-gray lesion in the inferotemporal periphery. It clinically appeared to be a choroidal nevus. O.S. was not remarkable.
Fig. 4 (Levine and Kaplan). Preretinal hemorrhages ( A ) .
ROBERT A. LEVINE A N D ARNOLD Μ. K A P L A N
40
Fig. 6 (Levine and Kaplan). Glistening deposits encircled ( A ) ; artefact (b).
DISCUSSION
Fig. 5 (Levine and Kaplan)- Aggregate of glistening deposits.
CASE 8
This 25-year-old Negro woman had poor vision in the left eye since childhood because of anisóme tropin. Corrected visual acuity: O.D., 2 0 / 2 0 ; O.S., 20/400. Ophthalmoscopically, O.D. revealed scat tered tiny white round lesions in the peripheral fundus, most numerous in the 5-o'clock periphery. O.S. revealed an accumulation of iridescent bodies in the 9-o'clock periphery, and in the peripheral fundus at the 5-o'clock position there was a small round white lesion from which radiated a pigment spicule. There was occasional peripheral vessel sheathing in both eyes. CASE 9
This 35-year-old Negro woman, mother of the patients described in Cases 3, 4 and 5, is and has been visually asvmptomatic. Visual acuitv: O.D., 2 0 / 2 0 ; O.S., 20/20. Ophthalmoscopically, O.D. re vealed numerous discrete white lesions scattered throughout the posterior pole. Clinically they ap peared drusenlike. O.S. was not remarkable. CASE 10
This 58-year-old Negro is and has been visually asvmptomatic. Visual acuitv: O.D., 20/200 and 20/30 with pinhole; O.S., 20/100 and 20/30 with pinhole. Ophthalmoscopically, O.D. revealed a cluster of radiating, white gliotic lesions located in the temporal peripheral fundus. O.S. revealed a gliotic vessel in the temporal periphery.
The association of C + S hemoglobinop athy with eye disease has been recognized only during the past 10 years. Prior to this time, these cases had been classified as cases of sickle-cell disease. The more careful use of electrophoresis made it apparent that a peculiarly high percent of Negroes with C + S hemoglobin experience eye complications, in contrast with those Negroes having the far more common S + S (sickle-cell ane mia) or A + S (sickle-cell t r a i t ) . The early case reports " of eye complica tions in C + S disease emphasized its most florid form: vitreous hemorrhage, fre quently with organization and retinal detach ment. Goodman, et al. and Munro and Walker placed greater emphasis on the ear lier more specific fundus features. Cells and clumps of cottony material were found in the vitreous, and were interpreted as reflect ing the residua of hemorrhage into the vit reous. The fundus lesions mainly were peripheral. Sheathing, arborizations, abnor mal anastomoses, bulbous dilatations and aneurysmal changes of the peripheral retinal vessels were found. Chalky white vessels and patches of retinitis proliferans also were seen. Occasionally they noted sharply out5
8
9
7
41
FINDINGS IN C + S D I S E A S E
lined red areas resembling retinal tears which on continued observation proved to be thin layers of preretinal hemorrhages. Discrete areas of depigmentation and hyperpigmentation resembling patches of healed focal chor ioretinitis also were observed. Of note is that Goodman, et al. also described chorioretinal scars surrounded by "glistening specks" in their only visually asymptomatic case. The ophthalmoscopic features of Case 1 described herein are therefore typical of those reported in the literature. Unlike Case 1 the remainder of the patients in this series with C + S hemoglobinopathy had no eye com plaints and warrant further comment. Seven of these other nine patients exhibited some fundus abnormality and, except in Case 9, all lesions were limited to the peripheral fundus. Although gliotic patches (Cases 2 and 1 0 ) , tortuous and arborizing vessels (Cases 2 and S ) , pigmented lesions (Cases 6, 7 and 8 ) and chalky white vessels (Cases 5 and 10) were seen, we feel the distinctive iridescent fundus lesions to be of greatest importance because they occurred in the younger patients where nonspecific degenerative changes and other associated diseases would be most unlikely. These copper-colored bodies were noted in Cases 2, 5 and 8 in which the patients were 5, 17, and 25 years of age respectively. They were also present in the fundus of the 30year-old patient described in Case 1. These glistening lesions may represent cholesterol deposits in the retina, a fairly common de generative phenomenon after hemorrhage or infarction. The preretinal wispy lesions seen in Case 6 may well represent the residua of blood in the vitreous. As a group, the 10 patients reported in this paper reflect most of the typical systemic manifestations of C + S hemoglobinop athy, including pain in the abdomen, chest, flank and extremities, hematuria, and malig nant anemia with a crisis during the third trimester of pregnancy. The commonly asso ciated findings of splenomegaly, shortened red blood cell survival time, reticulocytosis 7
and erythroid hyperplastic marrow reflect a hemopoetic system operating at maximum capacity at all times. In this situation anemia may become evident only during stress periods such as pregnancy or intercurrent infection. Target cells, found in the periph eral blood smear, are a far more diagnostic feature of the disease than anemia. The role of the target cell in the pathogenesis of the disease remains obscure. The pathologic changes seen in this disease are probably referable to the presence of S hemoglobin. All patients with C + S hemo globinopathy are found to have a positive rapid sickling test. Once sickled, the erythro cyte loses its flexibility and blood viscosity rises, resulting in spasm or stasis and even tuating in widespread capillary infarction and tissue necrosis. Kimmelstiel, in his study of the subject, concluded that thrombosis, per se, is not a significant feature of this ischemic infarctive process. Paton states that me chanical factors of blood flow are important in the pathogenesis of the comma-shaped vascular segments seen in the conjunctiva of patients with either C + S or S + S hemoglobinopathy. 10
11
Certain factors inherent to ophthalmic tissue may predispose to sickling. The high rate of glycolysis of the retina, which favors the rapid depletion of oxygen from the eryth rocyte, may well enhance the sickling ten dency. The end-arteriole system of the retinal vascular tree may add to the vulnerability of the retina to the sickling process. The retinal vascular shunt mechanism which burdens the peripheral retina with a great concentration of reduced hemoglobin S may partially explain the clinical finding that the ophthalmoscopic manifestations of the dis ease are found primarily in the peripheral fundus. Even more conjectural are the ex planations for the unusually high incidence of eye complications in patients with C + S hemoglobinopathy unlike those with either hemoglobin S + S or A + S. The role of hemoglobin C in this disease has yet to be fully clarified.
42
ROBERT
Α. L E V I N E
AND
ARNOLD
Μ.
KAPLAN
3. The presence or degree of fundus pathology did not seem to be related to se verity of the systemic illness nor could it be correlated with the existence of splenomeg aly, anemia or reticulocytosis.
SUMMARY
The following inferences have been made: 1. A significant number of visually asymp tomatic patients with C + S hemoglobinop athy have peripheral fundus pathology and this may be found as early as the age of five years. 2. Although a variety of fundus lesions were seen in this visually asymptomatic group, the most common lesions were multi ple copper-colored iridescent deposits in the peripheral fundus.
Ill
North
Wabash
Avenue
(2).
ACKNOWLEDGMENT
W e wish to express our appreciation to Drs Michael Hogan and Daniel Snydacker for their helpful criticism of the paper.
REFERENCES 1. Chernoff, Α. Γ.: The human hemoglobins in health and disease. New England I. Med., 2 5 3 : 3 2 2 , 365, 416, 1955. 2. Myersoson, R. M., Harrison, E., and Lohmuller, H. \V.: Incidence and significance of ahnormal hemoglobins. Am. J . Med., 2 6 : 5 4 3 , 1959. 3. Ingram, V. M.: The Hemoglobins in Genetics and Evolution. New York, Columbia, 1963. 4. Alper, R. G, Cavanagh, D., and Jonson, U.: Sickle-cell hemoglobin C disease. Obst, it Gvnec, 1 3 : 319, 1959. 5. Hannon, J . F.: Vitreous hemorrhages associated with sickle-cell hemoglobin C disease. Am. I. Ophth, 4 2 : 7 0 7 , 1956. 6. Kennedv, I. T., and Cope, C. B.: Intraocular lesions associated with sickle-cell disease. A M A Arch. Ophth.. 5 8 :163," 1957. 7. Isbev, E. K., lr., Clifford, G. O., and Tanaka, K. R. : Vitreous hemorrhages associated with sicklecell C disease. Am. J . Ophth., 4 5 :870, 1958. 8. Goodman, G, von Sallmann, L., and Holland, M. C.: Ocular manifestations of sickle-cell disease. A M A Arch. Ophth., 5 8 :655, 1957. 9. Munro, S., and Walker, C.: Ocular complications in sickle-cell hemoglobin C disease. Brit. 1. Ophth., 44:1.1960. 10. Kimmelstiel, P.: Vascular occlusion and retinal infarction in sickle-cell anemia. Am. T. M. Sc., 216:11,1948. 11. Patón, D.: The conjunctival sign of sickle-cell disease. A M A Arch. Ophth., 6 8 : 6 2 7 , 1962.
FURTHER
CLINICAL EARI. Fort
MAXWKI-L, Worth,
Now that 5-iodo-2'-deoxyuridine ( I D U ) is commercially available it may be of inter est to review the accumulated results of a clinical evaluation and compare the early data with that obtained later in the study. One pharmaceutical manufacturing com pany* in May, 1962, made this drug avail able to all qualified investigators who would furnish the information required by the Food and Drug Administration and sign the * From Alcon Laboratories, Inc.
EVALUATION
OF
IDU*
M.D.
Texas
proper form. In the ensuing year over 2,000 ophthalmologists requested and were sent this experimental drug. Kaufman's original work and subsequent papers " gave the necessary incentive to amass a large series of clinical cases to evaluate the safety and effectiveness of this promising new drug. It is true that a doubleblind study seemed appropriate; however, any individual clinic had so few cases that a significant series was exceedingly slow to evolve. Double-blind studies performed on 1
2
4