Long-term glycemic control has a nonlinear association to the frequency of background retinopathy in adolescents with diabetes. Follow-up of the Berlin Retinopathy Study.

OBJECTIVE: To assess the influence of long-term glycemic control on the development of background retinopathy in adolescents followed longitudinally from the onset of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: Repeated retinal fluorescein angiographies, in intervals of 1-2 years, were evaluated prospectively in 346 patients (190 males, 156 females; 19.8 [8.8-35.4] years of age; diabetes duration of 10.4 [1.1-27.4] years at their latest eye examination, median [range]). The influences of long-term HbA1c (mean of 18 [1-95] determinations per person) and microalbuminuria (> or = 2 of > or = 3 measurements > or = 15 micrograms/min x 1.73 m2) were studied by multiple linear regression, life-table analysis, and trend analyses. RESULTS: The rate of background retinopathy per 100 patient-years increased with poorer glycemic control from 0.7 (long-term HbA1c < 7% to 7.3 (HbA1c > 11%) following an exponential function. Life-table analysis after subdivision in HbA1c quartiles of equal sizes (HbA1c < 8, 8-9, 9-10, and > 10%) revealed an individual median expectation of background retinopathy after more than 25, 16.2, 12.7, or 12.0 years of diabetes, respectively. However, significant differences were found only between 8-9% and 9-10%, calculated either as prevalence, life-table analysis, or relative incidence, thus suggesting that a threshold model may also fit the data. After 12 years of diabetes, < 25% of those patients exhibiting microalbuminuria (n = 18) were expected to be free from retinopathy compared with 81% of those with normoalbuminuria (n = 86). CONCLUSIONS: Two statistical models are appropriate to explain the relationship between glycemic control and risk for background retinopathy: 1) a continuous exponential relationship as described by the DCCT or 2) the presence of a threshold HbA1c level at 9%. Thus, diabetes treatment in children should aim at long-term HbA1c levels < 9.0%, but every progress closer to normal may further reduce the risk.

A randomised prospective study on treatment of central retinal vein occlusion by isovolaemic haemodilution and photocoagulation.

Thirty eight patients with ischaemic and non-ischaemic central retinal vein occlusion were evaluated for the effect of isovolaemic haemodilution. They were allocated at random to a haemodilution group (19 patients, panretinal photocoagulation and isovolaemic haemodilution) and a control group (19 patients, panretinal photocoagulation). Haematocrit was lowered in steps to 30 to 35% in the haemodilution group by repeated exchanges of whole blood for plasma and dextran (MW 40 000) and kept at this level for a period of six weeks. The haemodilution did not lead to serious complications. Three months after starting the treatment eight of 19 patients with haemodilution showed a better visual acuity, whereas only one of 19 control patients had improved. Seven of 17 patients with haemodilution, but only one of 17 control patients, retained a better visual acuity after one year. In the haemodilution group there were fewer patients with macular fibrosis and more with only minor foveal changes. The haemodilution seems to be more effective in patients with ischaemic than with non-ischaemic central retinal vein occlusion. It is concluded that isovolaemic haemodilution improves the visual outcome of patients with central retinal vein occlusion, probably mediated by enhanced retinal blood flow.

Monitoring for retinopathy in children and adolescents with type 1 diabetes.

In children with an average diabetes onset at 11 y of age, the first retinal changes can be expected after a median diabetes duration of 9 y, while the median time until clinically relevant background retinopathy is 14 y. Periodic examinations of the retinal status become necessary with the onset of puberty or after 5 y of diabetes duration. Only sensitive methods should be used for retinopathy screening; the minimum recommended standard is a stereoscopic slit-lamp biomicroscopic examination in mydriasis. The degree of glycaemic control, both before and after puberty, appears to be of outstanding importance for the development of retinopathy, but the contribution of other factors (arterial blood pressure, lipid abnormalities, sex steroids, smoking and genetic factors) may be of varying relevance in the individual patient. Thus, to improve the long-term prognosis for children with diabetes appropriate screening for retinopathy and associated risk factors is mandatory.

Can retinopathy be prevented?

Clinical retinopathy eventually develops in the majority of insulin dependent diabetics during several decades of metabolic abnormality. Early structural lesions short of clinical significance may occasionally be detected in children much more frequently, however, after puberty. Major factors modulating the development of retinopathy are duration of diabetes, glycemic control and blood pressure.

[Photocoagulation in proliferating diabetic retinitis (author's transl)]. / Photokoagulation bei Retinopathia diabetica proliferans.

Results obtained in 64 patients with proliferating diabetic retinitis (PDR) are reported and discussed; photocoagulation was performed between 1970 and 1977, and regular check-ups were carried out for more than six months. Twenty-five patients were treated unilaterally and 39 bilaterally. Of the various photocoagulation techniques peripheral ablation with the xenon coagulator, in some cases in combination with the argon laser, has proven to be the most successful form of therapy at present. In 70% of the eyes the condition was alleviated or arrested. The number of patients blinded in both eyes was minimized at 12.5% for the total collective and 14.3% for patients observed for more than five years. The indications, limitations and side effects of photocoagulation are discussed, and the prognosis for PDR is presented as a function of the degree of severity of the retinitis and the occurrence of vitreous hemorrhages.

[Photocoagulation for central vein occlusion (author's transl)]. / Lichtkoagulation bei Zentralvenenverschluss.

27 patients with fully developed central vein occlusion were treated by means of photocoagulation. In all cases, a relatively quick regression of retinal hemorrhage and retinal edema occurred, as well as an extensive nomalisation of the caliber of the veins. In over 1/3 of cases, improvement of visual acuity could be achieved; acuity decreased in 1/3 of cases because of macula alterations (fibrosis, cystic edema, pigmentary dystrophy). The results, however, showed a general improvement as compared to disease courses left untreated. None of the patients developed secondary glaucoma during case control which can be assessed as the most significant result of photocoagulation.

[The influence of refraction on diabetic retinopathy (author's transl)]. / Der Einfluss der Refraktion auf die Retinopathia diabetica

Two groups of patients with diabetic retinopathy were tested by refraction. Patients with advanced retinopathy and those with early diabetic retinopathy had about the same propor-tion of refractive errors as the normal population. The only important difference was seen in middle- and high myopic eyes, which occurred less frequently when diabetic retinopathy was present. Illustrated from 4 cases of high myopia the inhibitory influence of diabetic retinopathy on the formation of shortsightedness is shown. Possible causes for this are discussed.

Annual progression of retinopathy in conventionally treated children and adolescents with type I diabetes mellitus.

In a cohort of 268 type I diabetic patients, aged 19.6 +/- 4.1 years (Mean +/- 1 SD), with a diabetes duration of 10.4 +/- 4.9 years, treated by the same team, using the same conventional treatment regime during the total observation period, the progression rate of early retinopathy within the first two decades of diabetes was deduced from observed transitions of the retinal status from one stage of retinopathy (as defined by fluorescein angiography) to a higher one (Malone et al., 1977) within one year. A total number of 83 such events were evaluated. After a gradual development of earliest changes within the fifth year of diabetes, the median annual rate of progression was found to be 12-13%, independent of the previous duration of diabetes and the actual retinal state.

Diabetic angiopathy in children.

Among the secondary complications of diabetes, early stages of retinopathy and nephropathy are of foremost importance in paediatrics. Regular examinations of retinal status and of urinary albumin excretion therefore become necessary with the onset of puberty or after 5 years of diabetes duration. With fluorescein angiography, the first retinal changes can be expected after a median diabetes duration of 9 years, while the median time to clinically relevant background retinopathy is 14 years. This diagnosis is delayed by 4 and 6 years, respectively, if retinopathy is staged exclusively by ophthalmoscopy. Approximately 10 to 20% of children may develop microalbuminuria, starting in early puberty. Several risk factors for the development of diabetic angiopathy have been identified. The degree of glycaemic control, both before and after puberty, appears to be of outstanding importance, but the contribution of other factors may be of varying relevance in the individual patient. These include arterial blood pressure, lipid abnormalities, sex steroids, smoking and genetic factors. Apart from the best possible metabolic regulation, early treatment with antihypertensive drugs has been shown to be beneficial in hypertensive adolescents but may also be renoprotective in normotensive adolescents with permanent microalbuminuria. However, the relatively high prevalence of intermittent and transient microalbuminuria in paediatric patients (2 and 3% respectively), with unknown prognostic relevance, complicate the decision to start such treatment for a lifetime. Nevertheless, the early detection of risk factors and the implementation of appropriate intervention strategies are necessary to improve the long-term prognosis for children with diabetes.

Factors modifying the effect of hyperglycemia on the development of retinopathy in adolescents with diabetes. Results of the Berlin Retinopathy Study.

The Berlin Retinopathy Study follows children from the onset of diabetes with serial retinal examinations by fluorescein angiography. It confirmed that long-term poor glycemic control, both before and after puberty, is the major risk factor for the development of retinal changes. The relationship between long-term HbAlc and background retinopathy follows an exponential, non-linear function. Apart from glycemia, several other factors (age at onset, puberty, lipids, blood pressure, genetic factors, smoking) may be of varying relevance in the individual patient. Nevertheless, best glycemic control from the onset of diabetes appears to be of outstanding importance as the HbAlc levels already during the first year of diabetes are related to the later development of background retinopathy.

Lipid profiles and blood pressure: are they risk factors for the development of early background retinopathy and incipient nephropathy in children with insulin-dependent diabetes mellitus?

The objective of this study is to examine the influence of lipid profiles and blood pressure on the development of microvascular complications in adolescents with insulin-dependent diabetes mellitus (IDDM) in a matched pairs study. Patients with early background retinopathy (n = 21) or microalbuminuria (n = 15) and their respective statistical twins participated in the study. Serum total cholesterol, high-density lipoprotein (HDL) cholesterol, fasting triglycerides, glycosylated haemoglobin A1c (HbA1c), and systolic and diastolic blood pressure during 3 years prior to the development of early background retinopathy or incipient nephropathy were examined. The multivariate discriminant analysis demonstrated glycaemic control and HDL cholesterol to be the most important variables related to the development of retinal lesions (84% correctness), and diastolic blood pressure to be associated with microalbuminuria (57% correctness). In addition to poor glycaemic control, different factors seem to be important for the early retinal or renal lesions of juvenile IDDM.

Absence of muscle capillary basement membrane thickening and retinopathy in patients with myocardial infarction and impaired i.v. glucose tolerance.

We have investigated the possible contribution of an early capillaropathy to the increased incidence of myocardial infarction (MI) in patients who had impaired glucose tolerance (IGT) during an i.v. glucose tolerance test (IVGTT). In lieu of the myocardium, biopsies from the quadriceps femoris muscle were studied for muscle capillary basement membrane (MCBM) thickening. Fluorescence angiography was performed to detect capillary retinopathy. Plasma growth hormone (GH) concentrations were determined during IGT. Data were obtained from 14 male patients with MI and IGT on IVGTT. Nine healthy subjects served as controls. MCBM thickness was similar in patients and controls (1,107 +/- 55 vs 1,067 +/- 88 A). None of the patients had signs of capillary retinopathy, and plasma GH concentrations were not higher in the patients as compared to control subjects. It is concluded that, in patients with IGT on IVGTT, MCBM thickening is probably not a factor for the development of MI.

Prevalence and development of retinopathy in children and adolescents with type 1 (insulin-dependent) diabetes mellitus. A longitudinal study.

In 231 subjects with Type 1 diabetes mellitus aged 17.6 +/- 4.0 years, with a diabetes duration of 8.5 +/- 4.9 years at the end of the study, the prevalence and the development of retinopathy during a period of 5 years were studied. All patients were examined between one and six times both by ophthalmoscopy and fluorescein angiography. A total of 626 fluorescein angiographies were evaluated. By the end of the study, 109 out of 231 patients (47%) had developed retinal changes, half of which were classified as minimal (less than 5 microaneurysms). Thirty-eight patients (35% of those affected) had background (n = 28) or proliferative (n = 10) retinopathy. In subjects less than 15 years of age and diabetic for less than 5 years, retinal lesions were rare. With increasing age and duration of diabetes, both the prevalence and severity of retinal changes increased markedly. Life-table analysis was used to calculate the median individual risk for the development of early retinal changes, which was 9.1 years of diabetes duration. This risk differed in sub-groups with different ages at onset of diabetes, i.e. 12.1, 8.9 and 6.6 years (p less than 0.0001), with diabetes starting below 4, between 5 and 9, and after 10 years of age respectively. After 18 years of diabetes, every patient demonstrated at least incipient structural changes. Fluorescein angiography allowed the detection of retinopathy, on average, four years earlier than with ophthalmoscopy. The median interval between the 'onset' of retinopathy, as indicated by a few microaneurysms, and background retinopathy was 5 years.

Risk factors for the development of retinopathy in children and adolescents with type 1 (insulin-dependent) diabetes mellitus.

In our preceding paper, the prevalence and development of retinopathy in 231 Type 1 diabetic children and adolescents were reported to be associated with the duration of diabetes and its age at onset. This paper analyses the relationships between the development of retinopathy and the following factors: age, sex, puberty, blood pressure, insulin dosage, HLA antigens, long-term glycaemic control, and serum cholesterol and triglycerides. All these variables were longitudinally evaluated in a cohort of 322 insulin-dependent patients aged 16.2 +/- 4.9 years with diabetes for 7.4 +/- 5.2 years, including those 231 subjects whose eyes were examined once or repeatedly by ophthalmoscopy and fluorescein angiography. Long-term glycaemic control from the onset of diabetes to the retinal examination was assessed by both an arbitrary score comprising different parameters and by mean values of glycosylated haemoglobin, and was categorised as good, fair, and poor. With life-table analysis, the overall median individual risk for developing early retinal changes (9.1 years) was found to be significantly influenced by glycaemic control. Minimal lesions developed earlier (8.0 years) with poor control, but later with fair (10.5 years) and good glycaemic control (12.5 years) (p less than 0.01). Mean HbA1 values below 10% delayed the onset of both incipient (10.8 years) and background retinopathy (16.6 years), while values above 10% advanced it (8.0 and 11.8 years respectively) (p less than 0.05 and less than 0.008). By multivariate regression and stepwise discrimination analyses, only 4 out of 14 variables were found to exert significant independent influences on the development of retinopathy: diabetes duration, long-term glycaemic control, serum triglycerides and age.(ABSTRACT TRUNCATED AT 250 WORDS)