VITREOUS FLUOROPHOTOMETRY IN ADULT-ONSET DIABETES MELLITUS S T E P H E N R. W A L T M A N , M.D., T H E O D O R E K R U P I N , M.D., C H A R L E S K I L O , M.D., AND B E R N A R D B E C K E R , M.D. St. Louis,
Vitreous f l u o r o p h o t o m e t r y d e m o n strates an early breakdown of the bloodretinal barrier in diabetes mellitus. 1 This occurs before angiographically demon strable retinopathy and clearly separates diabetic from control populations. 2 , 3 This sensitive, quantitative technique allows reproducible measurements of the degree of breakdown of this barrier. We used vitreous fluorophotometry to quantitate alteration of the blood-retinal barrier in adult-onset diabetes mellitus, and studied the effects of various forms of therapy, of hypertension, and of the pres ence of background retinopathy. S U B J E C T S AND M E T H O D S
Eighty-three adult-onset (after age 30 years) diabetic patients were investigated as outpatients. The subjects were in good general health and in a stable state metabolically. They were fully informed of the nature of the outpatient study before giv ing their consent. The first group consist ed of 52 insulin-dependent, adult-onset diabetic patients. They ranged in age from 39 to 77 years (mean, 55.9± 1.2 SEM). The duration of diabetes was three to 26 years (10.3 ± 0.8). The second group
Missouri
consisted of 31 adult-onset diabetics re ceiving oral hypoglycemic agents. They ranged in age from 43 to 82 years (61.9 ± 1.7) with a duration of three to 19 years (9.7 ± 0.8). The patients treated with oral agents were significantly older (P < .005) than the diabetics who required insulin, but the duration of disease was similar. All patients studied had best corrected visual acuities of 6/6 (20/20) and normal results of ocular examinations except for early background diabetic retinopathy in 31 of the 83 patients. This consisted of microaneurysms, hemorrhages, and exudates. None had proliferative retinopathy. After pupillary dilatation, color fundus photographs were taken and fluorescein angiography was performed using a weight-standardized dose of 7 mg/kg of body weight. One hour after the intrave nous fluorescein injection, a corneal con tact lens was placed and the vitreous fluorescein concentrations quantitated with a slit-lamp fluorophotometer, as pre viously described. 1,4 The results were re corded as the average of the mid-vitreous and posterior vitreous readings. Student's t-iest and chi-square analysis were used for statistical analysis. RESULTS
From the Departments of Ophthalmology (Drs. Waltman, Krupin, and Becker) and Internal Medi cine (Dr. Kilo), Washington University School of Medicine, St. Louis, Missouri. This study was sup ported in part by grant EY-02198 and Career and Research Development Award EY-00082 (Dr. Krupin) from the National Eye Institute, and by the Charles Kilo, M.D., Diabetes and Vascular Disease Research Foundation. Reprint requests to Stephen R. Waltman, M.D., Department of Ophthalmology - Box 8096, Wash ington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. 342
Vitreous fluorescein concentration in 52 insulin-dependent, adult-onset dia betic subjects, one hour following in travenous fluorescein administration, was 14.47 ± 0.57 ng/ml (mean ± SEM) (Table 1). The mean values in 31 patients given oral hypoglycemic agents was 14.87 ± 1.04. There was no difference between these two groups. In the insulin-dependent patients, vit-
AMERICAN JOURNAL O F OPHTHALMOLOGY 88:342-345, 1979
VOL. 88, NO. 3, PART I
FLUOROPHOTOMETRY IN DIABETES
343
tients with and without systemic hyper tension, as evidenced by the need for antihypertensive medication. Of the dia betic patients who required insulin, 41 were normotensive. Their vitreous fluoroVitreous Fluorescein, photometry readings were not signifi Therapy Group No. ng/ml (mean ± SEM) cantly different from the 11 patients with Insulin 52 14.47 ± 0.57 high blood pressure (Table 3). In the Oral hypoglycemics 31 14.87 ± 1.04 group of patients receiving oral hypo glycemic agents, the 16 patients with high blood pressure had higher vitre reous fluorescein concentration was relat ous fluorophotometric readings than the 15 who were normotensive. However, ed to age (y = 2.235 + 0.22x; correlation the difference was also not significant coefficient 0.45; P < .001). There was no '(.10 > P > .05). In the combined groups relationship between vitreous fluorophothere was no difference between those tometric readings and duration of disease. with and without systemic hypertension. In those patients receiving oral hypoSignificantly more patients taking oral glycemic agents, the vitreous fluores hypoglycemic agents were receiving sys cein concentration was also age-related temic antihypertensive medication than (y = — 1.82 + 0.27x; correlation coefficient in the group requiring insulin (x2 = 8.21; 0.46; P < .001). The vitreous readings were poorly related to the duration of the P < .005). disease (y = 13.91 + O.lx; correlation DISCUSSION coefficient 0.08; P = NS). Vitreous fluo rescein concentrations were higher (but Our present study confirms the early not significantly) in those patients with breakdown of the blood-retinal barrier to background retinopathy in both the in fluorescein in adult-onset diabetes mellisulin and oral hypoglycemic groups tus. 2 Fluorescein accumulates in the vit (Table 2). reous in diabetics with and without de Retinopathy was present in 24 of the tectable background retinopathy and 52 insulin-dependent patients but in clearly separates these groups from nor 3 only seven of the 31 patients taking oral mal subjects. In the adult-onset patients hypoglycemic agents. This difference the vitreous accumulation of fluorescein proved statistically significant (x2 = 4.61; increases with age. The rate of increase with age is alrnost identical to that seen in P < .05). Both groups were separated into pa the juvenile-onset group; however, there TABLE 1
VITREOUS FLUORESCEIN CONCENTRATIONS O N E H O U R A F T E R INTRAVENOUS F L U O R E S C E I N ADMINISTRATION
TABLE 2 VITREOUS FLUORESCEIN CONCENTRATIONS IN DIABETES MELLITUS P A T I E N T S W I T H AND W I T H O U T R E T I N O P A T H Y *
Therapy Group (No.)
No Retinopathy, ng/ml (mean ± SEM)
Background Retinopathy, ng/ml (mean ± SEM)
P Value
Insulin (52) Oral hypoglycemics (31) Total (83)
14.20 ± 0.82 (28) 14.55 ± 1.24 (24) 14.35 ± 0.69 (52)
14.77 ± 0.85 (24) 16.10 ± 2.29 ( 7) 15.07 ± 0.81 (31)
NS NS NS
*Numbers in parentheses indicate number of patients; NS, not significant.
344
AMERICAN JOURNAL OF OPHTHALMOLOGY
SEPTEMBER, 1979
TABLE 3 VITREOUS FLUORESCEIN CONCENTRATIONS IN DIABETES MELLITUS PATIENTS W I T H AND W I T H O U T H Y P E R T E N S I O N *
Therapy Group
Normotensive, ng/ml (mean ± SEM)
Hypertensive, ng/ml (mean ± SEM)
P Value
Insulin Oral hypoglycemics Combined
14.68 ± 0.68 (41) 13.18 ± 0.98 (15) 14.27 ± 0.56 (56)
13.66 ± 1.03 (11) 16.46 ± 1.74 (16) 15.32 ± 1.13 (27)
NS NS NS
*Numbers in parentheses indicate number of patients; NS, not significant.
is no correlation between the disease du ration and increasing vitreous fluorescein accumulation. This may be partly be cause of the difficulty in ascertaining the exact duration of diabetes in adult-onset patients compared to juvenile-onset pa tients. As in the juvenile-onset group, there is no difference between those pa tients with and without early background retinopathy as detected by fluorescein angiography. Patients with more florid, ad vanced background retinopathy or proliferative disease have an increased accu mulation of fluorescein in the vitreous compared to those with minimal or no background retinopathy. 2 Vitreous fluorophotometry measure ments are similar in those adult diabetics who required insulin and those main tained with oral hypoglycemic agents. Significantly more patients taking insulin had detectable background retinopathy, however, when compared to those receiv ing oral agents, despite a similar duration of diabetes for both groups. Because the presence of early background diabetic retinopathy does not influence the vitre ous fluorophotometry measurements in either group, this suggests that our meth ods for detecting morphologic changes are not sufficiently sensitive or that differ ent elements are involved in the physio logic breakdown of the barrier and the morphologic changes of microaneurysms. Physiologic breakdown of the
blood-retinal barrier occurs much earli er than presently detectable anatomic changes and does not appear to be influ enced by the addition of early morpho logic changes. Systemic hypertension may contribute to the increased vitreous fluorescein val ues in the group maintained with oral agents. This is worthy of further study, because severe hypertension can cause significant retinal vascular abnormali ties with exudation and breakdown of the permeability barrier of the retinal blood vessels. More patients taking oral hypo glycemic agents require the use of sys temic antihypertensive medicine than the adult diabetic patients maintained with insulin or than normal subjects. Patients in the oral hypoglycemic group are slight ly older than those taking insulin, but the duration of diabetes is almost identical. SUMMARY
We studied the breakdown of the blood-retinal barrier in 83 patients with adult-onset diabetes mellitus, by using vitreous fluorophotometry. The patients were in good stable metabolic control and were receiving injectible insulin or oral hypoglycemic agents. Vitreous fluoro photometry readings were abnormally high but similar in both groups of pa tients, and no significant differences were found between those with and those without early background diabetic reti-
VOL. 88, NO. 3, PART I
FLUOROPHOTOMETRY IN DIABETES
nopathy. Significantly more patients tak ing oral agents were hypertensive, and significantly fewer of these patients had background retinopathy.
REFERENCES 1. Krupin, T., Waltman, S. R., Oestrich, C , Santi ago, J., Ratzan, S., Kilo, C , and Becker, B.: Vitreous
345
fluorophotometry in juvenile-onset diabetes mellitus. Arch. Ophthalmol. 96:812, 1978. 2. Cunha-Vaz, J., Abreu, J. F., Campos, A. J., and Figo, G. M.: Early breakdown of the blood-retinal barrier in diabetes. Br. J. Ophthalmol. 59:649,1975. 3. Cunha-Vaz, J. C , Fonseca, J. R., Abreu, J. F., and Ruas, M. A.: A follow-up study by vitreous fluorophotometry of early retinal involvement in diabetes. Am. J. Ophthalmol. 86:467, 1978. 4. Waltman, S. R., and Kaufman, H. E.: A new objective slit lamp fluorophotometer. Invest. Ophthalmol. 9:247, 1970.
Vitreous f l u o r o p h o t o m e t r y d e m o n strates an early breakdown of the bloodretinal barrier in diabetes mellitus. 1 This occurs before angiographically demon strable retinopathy and clearly separates diabetic from control populations. 2 , 3 This sensitive, quantitative technique allows reproducible measurements of the degree of breakdown of this barrier. We used vitreous fluorophotometry to quantitate alteration of the blood-retinal barrier in adult-onset diabetes mellitus, and studied the effects of various forms of therapy, of hypertension, and of the pres ence of background retinopathy. S U B J E C T S AND M E T H O D S
Eighty-three adult-onset (after age 30 years) diabetic patients were investigated as outpatients. The subjects were in good general health and in a stable state metabolically. They were fully informed of the nature of the outpatient study before giv ing their consent. The first group consist ed of 52 insulin-dependent, adult-onset diabetic patients. They ranged in age from 39 to 77 years (mean, 55.9± 1.2 SEM). The duration of diabetes was three to 26 years (10.3 ± 0.8). The second group
Missouri
consisted of 31 adult-onset diabetics re ceiving oral hypoglycemic agents. They ranged in age from 43 to 82 years (61.9 ± 1.7) with a duration of three to 19 years (9.7 ± 0.8). The patients treated with oral agents were significantly older (P < .005) than the diabetics who required insulin, but the duration of disease was similar. All patients studied had best corrected visual acuities of 6/6 (20/20) and normal results of ocular examinations except for early background diabetic retinopathy in 31 of the 83 patients. This consisted of microaneurysms, hemorrhages, and exudates. None had proliferative retinopathy. After pupillary dilatation, color fundus photographs were taken and fluorescein angiography was performed using a weight-standardized dose of 7 mg/kg of body weight. One hour after the intrave nous fluorescein injection, a corneal con tact lens was placed and the vitreous fluorescein concentrations quantitated with a slit-lamp fluorophotometer, as pre viously described. 1,4 The results were re corded as the average of the mid-vitreous and posterior vitreous readings. Student's t-iest and chi-square analysis were used for statistical analysis. RESULTS
From the Departments of Ophthalmology (Drs. Waltman, Krupin, and Becker) and Internal Medi cine (Dr. Kilo), Washington University School of Medicine, St. Louis, Missouri. This study was sup ported in part by grant EY-02198 and Career and Research Development Award EY-00082 (Dr. Krupin) from the National Eye Institute, and by the Charles Kilo, M.D., Diabetes and Vascular Disease Research Foundation. Reprint requests to Stephen R. Waltman, M.D., Department of Ophthalmology - Box 8096, Wash ington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. 342
Vitreous fluorescein concentration in 52 insulin-dependent, adult-onset dia betic subjects, one hour following in travenous fluorescein administration, was 14.47 ± 0.57 ng/ml (mean ± SEM) (Table 1). The mean values in 31 patients given oral hypoglycemic agents was 14.87 ± 1.04. There was no difference between these two groups. In the insulin-dependent patients, vit-
AMERICAN JOURNAL O F OPHTHALMOLOGY 88:342-345, 1979
VOL. 88, NO. 3, PART I
FLUOROPHOTOMETRY IN DIABETES
343
tients with and without systemic hyper tension, as evidenced by the need for antihypertensive medication. Of the dia betic patients who required insulin, 41 were normotensive. Their vitreous fluoroVitreous Fluorescein, photometry readings were not signifi Therapy Group No. ng/ml (mean ± SEM) cantly different from the 11 patients with Insulin 52 14.47 ± 0.57 high blood pressure (Table 3). In the Oral hypoglycemics 31 14.87 ± 1.04 group of patients receiving oral hypo glycemic agents, the 16 patients with high blood pressure had higher vitre reous fluorescein concentration was relat ous fluorophotometric readings than the 15 who were normotensive. However, ed to age (y = 2.235 + 0.22x; correlation the difference was also not significant coefficient 0.45; P < .001). There was no '(.10 > P > .05). In the combined groups relationship between vitreous fluorophothere was no difference between those tometric readings and duration of disease. with and without systemic hypertension. In those patients receiving oral hypoSignificantly more patients taking oral glycemic agents, the vitreous fluores hypoglycemic agents were receiving sys cein concentration was also age-related temic antihypertensive medication than (y = — 1.82 + 0.27x; correlation coefficient in the group requiring insulin (x2 = 8.21; 0.46; P < .001). The vitreous readings were poorly related to the duration of the P < .005). disease (y = 13.91 + O.lx; correlation DISCUSSION coefficient 0.08; P = NS). Vitreous fluo rescein concentrations were higher (but Our present study confirms the early not significantly) in those patients with breakdown of the blood-retinal barrier to background retinopathy in both the in fluorescein in adult-onset diabetes mellisulin and oral hypoglycemic groups tus. 2 Fluorescein accumulates in the vit (Table 2). reous in diabetics with and without de Retinopathy was present in 24 of the tectable background retinopathy and 52 insulin-dependent patients but in clearly separates these groups from nor 3 only seven of the 31 patients taking oral mal subjects. In the adult-onset patients hypoglycemic agents. This difference the vitreous accumulation of fluorescein proved statistically significant (x2 = 4.61; increases with age. The rate of increase with age is alrnost identical to that seen in P < .05). Both groups were separated into pa the juvenile-onset group; however, there TABLE 1
VITREOUS FLUORESCEIN CONCENTRATIONS O N E H O U R A F T E R INTRAVENOUS F L U O R E S C E I N ADMINISTRATION
TABLE 2 VITREOUS FLUORESCEIN CONCENTRATIONS IN DIABETES MELLITUS P A T I E N T S W I T H AND W I T H O U T R E T I N O P A T H Y *
Therapy Group (No.)
No Retinopathy, ng/ml (mean ± SEM)
Background Retinopathy, ng/ml (mean ± SEM)
P Value
Insulin (52) Oral hypoglycemics (31) Total (83)
14.20 ± 0.82 (28) 14.55 ± 1.24 (24) 14.35 ± 0.69 (52)
14.77 ± 0.85 (24) 16.10 ± 2.29 ( 7) 15.07 ± 0.81 (31)
NS NS NS
*Numbers in parentheses indicate number of patients; NS, not significant.
344
AMERICAN JOURNAL OF OPHTHALMOLOGY
SEPTEMBER, 1979
TABLE 3 VITREOUS FLUORESCEIN CONCENTRATIONS IN DIABETES MELLITUS PATIENTS W I T H AND W I T H O U T H Y P E R T E N S I O N *
Therapy Group
Normotensive, ng/ml (mean ± SEM)
Hypertensive, ng/ml (mean ± SEM)
P Value
Insulin Oral hypoglycemics Combined
14.68 ± 0.68 (41) 13.18 ± 0.98 (15) 14.27 ± 0.56 (56)
13.66 ± 1.03 (11) 16.46 ± 1.74 (16) 15.32 ± 1.13 (27)
NS NS NS
*Numbers in parentheses indicate number of patients; NS, not significant.
is no correlation between the disease du ration and increasing vitreous fluorescein accumulation. This may be partly be cause of the difficulty in ascertaining the exact duration of diabetes in adult-onset patients compared to juvenile-onset pa tients. As in the juvenile-onset group, there is no difference between those pa tients with and without early background retinopathy as detected by fluorescein angiography. Patients with more florid, ad vanced background retinopathy or proliferative disease have an increased accu mulation of fluorescein in the vitreous compared to those with minimal or no background retinopathy. 2 Vitreous fluorophotometry measure ments are similar in those adult diabetics who required insulin and those main tained with oral hypoglycemic agents. Significantly more patients taking insulin had detectable background retinopathy, however, when compared to those receiv ing oral agents, despite a similar duration of diabetes for both groups. Because the presence of early background diabetic retinopathy does not influence the vitre ous fluorophotometry measurements in either group, this suggests that our meth ods for detecting morphologic changes are not sufficiently sensitive or that differ ent elements are involved in the physio logic breakdown of the barrier and the morphologic changes of microaneurysms. Physiologic breakdown of the
blood-retinal barrier occurs much earli er than presently detectable anatomic changes and does not appear to be influ enced by the addition of early morpho logic changes. Systemic hypertension may contribute to the increased vitreous fluorescein val ues in the group maintained with oral agents. This is worthy of further study, because severe hypertension can cause significant retinal vascular abnormali ties with exudation and breakdown of the permeability barrier of the retinal blood vessels. More patients taking oral hypo glycemic agents require the use of sys temic antihypertensive medicine than the adult diabetic patients maintained with insulin or than normal subjects. Patients in the oral hypoglycemic group are slight ly older than those taking insulin, but the duration of diabetes is almost identical. SUMMARY
We studied the breakdown of the blood-retinal barrier in 83 patients with adult-onset diabetes mellitus, by using vitreous fluorophotometry. The patients were in good stable metabolic control and were receiving injectible insulin or oral hypoglycemic agents. Vitreous fluoro photometry readings were abnormally high but similar in both groups of pa tients, and no significant differences were found between those with and those without early background diabetic reti-
VOL. 88, NO. 3, PART I
FLUOROPHOTOMETRY IN DIABETES
nopathy. Significantly more patients tak ing oral agents were hypertensive, and significantly fewer of these patients had background retinopathy.
REFERENCES 1. Krupin, T., Waltman, S. R., Oestrich, C , Santi ago, J., Ratzan, S., Kilo, C , and Becker, B.: Vitreous
345
fluorophotometry in juvenile-onset diabetes mellitus. Arch. Ophthalmol. 96:812, 1978. 2. Cunha-Vaz, J., Abreu, J. F., Campos, A. J., and Figo, G. M.: Early breakdown of the blood-retinal barrier in diabetes. Br. J. Ophthalmol. 59:649,1975. 3. Cunha-Vaz, J. C , Fonseca, J. R., Abreu, J. F., and Ruas, M. A.: A follow-up study by vitreous fluorophotometry of early retinal involvement in diabetes. Am. J. Ophthalmol. 86:467, 1978. 4. Waltman, S. R., and Kaufman, H. E.: A new objective slit lamp fluorophotometer. Invest. Ophthalmol. 9:247, 1970.
