can retinopathy be prevented?

Indian J Pediatr (Suppl) 1989; 56 : S',~-':;10'7

Can Retinopathy Be Prevented ?

Weber B, Hbvener G,* Burger W, Hsrtmann R, and Enders I

Kinderklinik, Universit~tsklinikum Rudolf Virchow, Standort Charlottenburg, Kaisenn Augus te Victoria h.~us, Freie Universit~t, Berlin, *Augenklinik, Universit~tsklinikum Stegli~, Fro:,::

Universit~t Berlin

Clinical retinopathy eventually develops in the majority of insulin depe~dent diabetics during several decades of metab-~lic abnormality. Early structural lesions short of clinical significance rP~y 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 wessure.

As long as the metabolic disease cannot be prevented altogether, any endeavor to prevent retinopathy has to attempt the normalization of metabolic abnormalities and blood pressur& Up to date, however, at best some medium term "near" -normalization of glycemia in a very cooperative elite of patients can be achieved, despite improvement of technical fa- cilities for insulin substitution, like multiplc-in- jention regimens and continuous insulin infu- don. Only some auto-regulatory blood glucose- monitored insulin infusion- device seems to promi.~ better long-term glycemic regulation and hence effective prevention of secondary complications. Overt hypertension in diabetics should be treated as in non-diabetic patients. As yet, however, no clear-cut philosophy exists for gradually rising blood pressure values as long as they remain within the normal range. Presumable, antihypertensive treatment should be started at this point already.

Secondary prevention of severe proliferative

Reprint requ~ts : Dr. Mcd. Bruno Weber, ifinderldinik der Freicn Univcrsit~it, l.Jniversi~tsklinikum Rudolf Virchow, Standort Cl~rlottenburg, Kai~rin Auguste Victoria ltaus, l'teubnerwcg 6, D-1000 Berlin 19 (West)/Germany.

retinopathy and vision loss can often be pro- vided by photo-coagulation of severe pre-proliferative and early proliferative changes.

Clinical symptoms of neurovascular complications in insulin-dependent diabetics (IDDM) usually do not occur before one or (more frequently) two decades of metabolic abnormality have passed. Sophisticated non..invasive ~nd little invasive diagnostic techniques, however, permit the detecnon of structural and func- ti~mal abnormalities related to mit~oangi,:i.,:~thy and ncuropathy long before. ]'hczefotc, ~:con- dary changes of IDDM can be detectecl :tlso in children and adolescents. 2"~,~~

"ihe particular and t:asy accessibility of the retina via the light path .greatly favors the de- tectability of early structural retinal !,'~;;~?.:,:: t~c fore any im/;amnent of global functmn, i e , f vision, occurs. Avascular areas and talC'tom),-,. rysms may be found, if only looked for by ap- propriate means, alter few years of diabetes. Their clinical significance is doa~trul. Ncvet- theless these cvcntuaily rever~ble mc~pient changes seem to mark the dynamic process of retinopathy which grad,ally develops into a clinically, significant retinal :.iisease The so- called background retinopathy with a growing number ol c:,i;,~aty infarclions indicated by

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S100 THE INDIAN JOURNAL OF PEDIATRIGS Vol. 56, No. 1

avascular areas, microaneurysms, intraretinai hemorrhages and extravasations of plasmatic constituents, intraretinal microvascular abnormalities (IRMA) and venous dilatations usually needs more time to develop, hence rarely occurs before puberty and before i0 years of diabetes duration. Frequently, only few of these potential abnormalities, which mark the early phase of background retinopathy, namely microaneurysms and avascular zones around the

macula, may be observed in young IDDM patients during their second decade of life. Very rarely, more advanced stages of retinopathy, i.e. late background retinopathy and vision-threatening pre-proliferative and proliferative retinal lesions, are encountered during childhood and adolescence.

Prevalence of retinopathy, as detected in this ag~ group by opthalmoscopy and fluorescein angiography, is shown in Table 1. No infor-

TABLI/1 Prevalence of Retinopathy Detected by Ophthalmoscopy (0) and Fluorescein Angiography (FA) in

Young IDDM Subjects

Author, year Duration Prevalence (%) Duration Author, year IDDM (yrs) O FA IDDM (Yrs)

Hardin, 1956 10-29 (16") 51 White, 1956 10--15 19

16-20 59 Larsson, 1960 15-33 (21") 82 Knowi~, 1971 11-41 (18") 64

13

18

14

Francois, 1979 10-15 14 16-20 38

Lestradet, 1981 0-26 43

13 6

11

13 Palmberg, 1981 6-9 32

10-16 62 Jackson, 1982 0-20 11

7

16 Sterky, 1986 10 .30

20 81

22

52 < 5 to > 10 Barta, Brooser, 1971-1978

34 < 5 to > 10 Dorchy, Toussaint, 1974-1979

75 < 5 to > 10 Malone, 1977

17 7 Frost-Larsen, 1981 21 < 5 to > 10 Hoffmann, 1980 18 < 5 to > 10 Frank, 1980-1982 31 < 5 to > 10 H6vener, 1981 41 < 5 to > 10

8 0-32 Levin, 1982 49 0 - 1 3 Salardi,1983 64 8-17 Doff, 1984 23 Lcvy-Marchal, 1984

47 5-15 Burger, 1986

"Mean

WEBER ET AL : RETINOPATHY S101

mation is available concerning the comparabil- ity of these data with regard to the respective degrees of retinal abnormalities and the levels of glycemic control. However, two consistent messages can be gathered from this table, i.e. that the prevalence of retinal microangiopathy increases with diabetes duration and that fluorescein angiography is superior to fundoscopy in detecting early retinal lesions. This is the rea- son why this method has widely and successfully been applied as a research tool also in children and adolescents.

The longitudinal Berlin Retinopathy Study, which included a non-selected population of IDDM subjects old enough to coopcratc during fluorescein angiographic retinal examinations

(i.e. older than 7-8 years of age) and represent- ing about 70% of all I D D M children above 8 years of age in Berlin (West), has now collected information on theret inal states of 323 subjects aged 18.2 _ 4.1 (X _+ s, 8-35) and diabetic for 8.9 -,- 5.1 (0-27) years 4,s0. After preliminary results had revealed only incipient cha=nges (ser below) in 4 out of 117 children younger than 15 and diabetic for less than 5 years, all subjects meeting these criteria were exempted from further studies until at least one of the two criteria was met. The a, ngiograhic findings were classi- fied according to a modif icat ion 19 of MALONE's classification m as subclinical incipient retinopathy (sub-divided into two stages: < 5 microaneurysms (MA) in a 30 ~

N = ~ 2 3

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Fig. I. Devclopmcnt of rctinopathy in children and adolescents with tTpr ] diabetes Statistical analysis : Life-tables. Thc 'survwat'" curves indicate the development of (from left to right) - incipicnl retinopathy diagnosed by fluorcscein angiographv (FA) (I) - incipient rctinopathy dctccted by ophthahnosCnl,y (thick line) ( l i ) - early background retinopathy detected byfluorescein angwgraphy (111) The vertical lines indicate the median risk of every patient at the onset of diabetes to develop the..se respective degrees of rctinopathy.

S102 THE INDIAN JOURNAL OF PEDIATRICS Vol. 56, No. I

photographic field of the posterior pole and 6- 10 MA)), early (11-50 M_A, <25 leakages of the f i u o ~ dye) and late (> 50 MA, >25 leakages) background retinopathy with growing clinical significance, and finally intra-, epi- and pre-retinal vision-threatening proliferative retinopathy. The results were analysed by life- table analysis permitting the use of all data available-even after patients drop out of the study-for the calculation of individual risks at the onset of the metabolic disorder. (in years of diabetes duration) to develop any of the above defined stages.of retinopathy. This is shown in Fig. 1 for incipient and early background retinopathy detected by fluorescein angiography and ophthalmoscopy. The Figure demon- strates fluorescein angiography to be superior in detecting earlier changes, in as much as it ad- Vances the detection limit of ophthalmo~opy by around 3 years 4~. Furthermore, the detection of subclinical earliest structural lesions and the emergence of clinically relevant early b~k- ground retinopathy seem to be closely related, suggesting a causal relationship.

Major factors influencing or modulating development and progression of rctinopathy seem to be the duration of the metabolic disorder 4. 9, t3. t4. ~. m 30, 33, ~ age at onset 4 puberty4, i.t, ,~, 3~

st and sex hormones sz, blood pressure "~, z,. so) and glycemic control (e.g. *, is, 2s, ~, 27, 40, 50)

partly explaining the great variation of incidence and severity of retinopatby. Only the proliferative type of retinopathy seems to be influenced by smoking ~'4a. On the other hand, great differences in the susceptibility for microvascular and neural diabetogenic changes remain unexplained, ranging e.g. from vision- tI',r~terdng proliferative to only subclinical cha~gcs after qmilar duration of diabetes and comparable Iongterm control (see also S- Sh:~,.~:d curves in Fig. I. Up to date, suspected co, s,,:o,t~onal and genetic influences upon the pa:h,,ge:'.,es~s and/or the progression of these c,~::~ge :,'''~' are hard to prove and may or may no' b~ re',a~ed to, t~e major histocomp.qtibilily Ic~: ~':." o~ly factors to be influenced by treat- n<'.~. "2;~gb agpe:;r to be bl,,od pressure,

glycemic control and smoking. In children and adolescents with diabetes,

significantly increased blood pressure is only rarely encountered, at any rate far less frequently than retinopathy is. The influence of glycemic control, however, is demonstrated in Fig.2. showing significant differences for the periods of time needed to develop incipient and early background retinopathy following long- term better or worse control. Furthermore, age at onset during childhood significantly influences the median duration of diabetes before the development of detectable structural lesions, which leads to the manifestation of retinopathy around puberty in all,hence pro- voking a more rapid progression in the older as compared to those younger at onset 4.25.

Prevention of retinopatby, therefore, would only be possible, if either clinical diabetes with permanent metabolic abnormality could be prevented altogether or if metabolic abnormality could ideally be controlled by treatment. Blood pressure would have to be kept permanently within normal ranges. Smoking should be dis- couraged. Secondary prevention, i.e. prevention of progression to vascular proliferation and vis- ual impairment, could be achieved if an effective treatment of late background and pre-proliferative lesions influencing the pathophysiol- ogy of the proliferative process were available.

At present, effective and safe prevention of the metabolic disorder is still hypothetical, based on the assumption that diabetes is due to a rather slow autoimntune destruction of the B- cell organ, which might be interrupted before leading to clinically detectable metabolic abnormalities. So far, however, this pre-diabetic state cannot be diagnosed by sufficiently reli- able methods. Only after its clinical onset experimental immune-suppressive intervention (e.g. with cyclosporin A ) has achieved a pro- longation of the partial remission phase with no exogenous insulin requirement in more than half of the patients treated t'47.After cessation of immunosuppression diabetes relapses.

Normalisation of metabolic abnormalities by treatment of overt type 1 diabetes has been an

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Fig. 2. Development of retmopathy in childrcn and adolesccms wilh type 1 dmbctes Influence of long-term glycemic control (including all values measured) on the development of - incipient retinopathy detecled by t-A (upper panel) - early background retinopathy detected hy FA (lower panel} The separati~,n at 11bA I < 10 or > 10% is arbitrary but compares cohorts of similar sizes.

Non-diabetic controls : 5.9 "- 0.9% (~ • 1 ~).

$104 THE INDIAN JOURNAL OF PEDIATRICS Vol. 56, No. 1

almost unattainable goal, as long as whatever external regulation of interventions is required. Even continuous insulin substitution via the subcutaneous, intravenous or intrapcritoncal route, adapted to individual basal and meal-related requirements, at best achieves some "near-normoglycemia" over longer periods of time. A potentially effective autoregulation of exogenous insulin administration (implanted pump, blood glucose-monitored by implanted or changeable glucose sensors) or a r-e-institu- tion of some auto-regulatory endogenous insulin secretion (transplants of islets, islet cells, etc.) are being examined only in experimental protocols. Thus, at present, the best objective to be achieved may be a metabolic compensa- tion which retards progression but none which prevents the development of retinopathy. Retrospective and prospective studies attempt- ing to improve long-term control have clearly demonstrated this 6'8'9,11,12'13.16"22"23.25'32.'t~176

Epidemiological studies in different cohorts of insulin-dependent patients, demonstrating clear-cut effects of permanent proteinuria and hypertension on retinopathy z~2~2~ suggest that blood pressure also should permanently be kept within the normal range. But little is known about the effect of slowly increasing, still "nor- mar ' blood pressure on both renal and retinal functions. Is it necessary, for instance, to start antihypertensive treatment at this stage already? To date, we are short of sufficient information answering this question, but preliminary investigations examining such a possibility are in progress.

Another aspect worth to be discussed in this context is the secondary prevention of severe vision-threatening retinal vascular proliferation. Since 19593s photo-coagulation of a substantial part of the retina by xenon light and argon laser has clearly improved the prognosis of vision in a great number of subjects, preserving retinal perfusion, in particular around the macula, at the expense of the periphery:The incidence of vision loss can be reduced to'one half within 5 years after photo-coagulation ~s. During recent years, early performed photo-coagttlation,e.g, in

cases of pre-proliferative background retinopathy, has proved to be effective in preventing proliferation and further deterioration of vision.4Z -u

CONCLUSION

At present the development of retinopathy during long-term IDDM can be retarded but not totally prevented in subjects genetically or individually susceptible to its development. Long-term good metabolic control with mean blood glucose levels as close to the normal range as achievable and narrow limits of glycemic excursions during the day presumably are the most important preventive measures influencing both the dynamics and the severity of diabetogenic retinopathy. In addition, blood pressure has to be kept within the normal range. After manifestation of clinical retinopathy early photo-coagulation of the retina during the pre and early proliferative phases of the disorder may still be effective in preventing or at least retarding severe vascular proliferations and vision loss. This however, requires detection of clinical retinopathy at an early stage of development, hence periodic retinal examinations starting e.g after around 5 years of diabetes, which should be repeated every 2 years before the onset of puberty, and annually thereaf- ter. Since therapeutic intervention has to be considered only at a rather late stage of retinopathy, which is usually detectable by an expert ophthalmologist via the dilated pupil, this method seems to be adequate for long-term periodic supervision of the patient's clinical retinal status. The more sophisticated methods of retinal examination like fundus-photography and fluorescein angiography, on the other hand, seem tobe well suited to advance the detection of subclinical early structural changes, hence hopefully increasing the time range for any attempt to improve glycemic control as a preventive measure.

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W E B E R E T A L : R E T I N O P A T H Y $105

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can retinopathy be prevented?

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