British Journal of Ophthalmology, 1981, 65, 307-311

Reversal of diabetic retinopathy by continuoussubcutaneous insulin infusion: a case reportM. C. WHITE,' EVA M. KOHNER,1 J. C. PICKUP,2 AND HARRY KEEN,2From the 'Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, and the2Unit ofHuman Metabolism, Guy's Hospital Medical School, London

SUMMARY We report the case history of a 20-year-old diabetic girl with long-standing poorlycontrolled disease who presented with severe retinopathic features and who was treated withcontinuous subcutaneous insulin infusion (CSII). When first seen she had macular oedema and avisual acuity of 6/18 in her only eye, together with multiple blot haemorrhages and intraretinalmicrovascular abnormalities. Marked reversal of the retinal lesions occurred within 65 days ofinitiating CSII and after only 36 days of constant normoglycaemia. Subsequent good blood glucosecontrol on conventional subcutaneous insulin injections has been achieved, and the retinopathyremains quiescent with a visual acuity of 6/5. We suggest that CSII may be a potentially usefulmethod of arresting and reversing early diabetic retinopathy.

Many factors, genetic and environmental, influencethe appearance and severity of diabetic retinopathy,but evidence from animal studies strongly suggeststhat poor diabetic control is important in itsinitiation and evolution.' In the human diabetic thedifficulty of achieving a prolonged near-normalmetabolic state with conventional methods of insulinadministration has made the role of 'control' inretinopathy difficult to evaluate. The introduction ofthe new technique of continuous subcutaneousinsulin infusion (CSII) with a portable variable-ratebattery-operated syringe pump2 has provided themeans of observing the effects of dramaticallyimproved control on diabetic retinopathy. CSII notonly maintains near-normoglycaemia in fully ambu-lant patients for several months34 but also returnsthe circadian profiles of some major intermediatemetabolites towards the nondiabetic state.5 6We therefore submitted a diabetic girl with severe

retinopathy, previously poorly controlled on conven-tional insulin injections, to a trial of CSII in the hopethat a period of prolonged metabolic near-normalisa-tion might retard the progression of her retinopathy.

Case report

The patient was a 20-year-old girl with insulin-dependent diabetes for 15 years who had a single

Correspondence to Dr E. M. Kohner, Department ofMedicine, Royal Postgraduate Medical School, HammersmithHospital, London W12 OHS.

morning injection of protamine zinc insulin (PZI)26 units and soluble insulin (SI) 32 units. She neverperformed home urine tests and only rarely hadplasma glucose concentrations estimated. At the ageof 7 years an accident blinded her right eye. Visionin her left eye had been previously good but haddeteriorated in the months before admission.Retinopathy was noted in this her only functionaleye, and she was referred for urgent management.7When first examined she had a visual acuity of

6/18. Fundal abnormalities included multiple micro-aneurysms, large blot haemorrhages, and venousdilatation (Fig. la). Fluorescein angiography8showed extensive microvascular changes, capillarydilatation, small areas of capillary nonperfusion, andon late pictures extensive leakage (Figs. lb-d).

She was admitted to a metabolic ward for initialassessment and stabilisation. On the first day plasmaglucose was measured (glucose oxidase method)2-hourly for 24 hours on the conventional insulinregimens, and subsequently when she was stabilisedon CSII (Table 1).

Highly purified porcine insulin (Actrapid, NovoIndustries) was continuously infused through a finenylon cannula (Portex Ltd, Hythe, Kent). Its distalend was implanted under the skin of the anteriorabdominal wall, and the other end connected to aportable battery-driven syringe pump (Mill Hillinfuser, Model 1001A, Muirhead Ltd, Beckenham,Kent) which had been adapted to deliver the insulinsolution at two rates (50p.1 and 400 ,ld/hour). Thehigh rate was activated by the patient 30 minutes

307

on Septem

ber 13, 2020 by guest. Protected by copyright.

http://bjo.bmj.com

/B

r J Ophthalm

ol: first published as 10.1136/bjo.65.5.307 on 1 May 1981. D

ownloaded from

M. C. White, Eva M. Kohner, J. C. Pickup, and Harry Keen

lb

Ic ldFig. I (a) Fundus photograph of left macula showing multiple blot haemorrhages, microaneurysms, and generalisedvenous dilatation. (b) Fluorescein angiogram in capiliary phase illustrates generalised capillary dilatation and areas ofnonperfusion (arrowed). (c) Macular detail ofFig. 1 (b) showing more clearly areas of dilatation, capillary nonperfusion,and microaneurysms. (d) Fluorescein angiogram in the late venous phase illustrating extensive capillary leakage.

before main meals and automatically returned to thebasal rate after 17 minutes. The pump was worn ona belt round the waist.The patient was taught to estimate capillary

blood glucose concentrations using glucose oxidasestrips (Dextrostix, Ames and Miles), and did so atleast 4 times a day while in hospital and at home.She also replaced and refilled her syringe daily withinsulin (diluted as instructed with 0154 mmol/1

saline). After initial stabilisation on CSII in hospitalthe infusion was continued at home under very closeand regular hospital supervision. Altogether she wasmaintained on CSII for 65 days, which was con-tinuous except for 3 days when the cannula becameaccidentally dislodged from its subcutaneous site.Subsequently she has been controlled on a twice-daily regimen of Actrapid and Semitard (NovoIndustries).

308

on Septem

ber 13, 2020 by guest. Protected by copyright.

http://bjo.bmj.com

/B

r J Ophthalm

ol: first published as 10.1136/bjo.65.5.307 on 1 May 1981. D

ownloaded from

Reversal of diabetic retinopathy by continuous-Awktyeous insulin infiusion: a case report

2a

Fig. 2 (a) Fundus photograph of left macula 65 days after starting CSII. Improvement in haemorrhages and lessvenous dilatation; but cotton-wool spot has developed (arrowed). (b) Fluorescein angiogram in same phase as Fig.1 (b). Note reduction in capillary dilatation. Revascularisation ofsome areas ofprevious nonperfusion is now present(arrowed). (c) Enlarged detail of macular area shown in 2 (b). Marked reduction in capillary dilatation andimprovement in areas of capillary nonperfusion. (d) Fluorescein angiogram in same phase as Fig. I (d). Markedreduction in capillary leakage present.

Continuous physiological levels of blood glucose(<97 mmol/1) were not obtained on CSII for 28days because of a technical problem with the pump,but thereafter were almost always normal. Therewas a highly significant reduction in plasma glucoselevels (p <001) after stabilisation on CSII from thelevels on conventional therapy (Table 1). Mainten-

ance of blood glucose concentrations within thephysiological range has been achieved for most ofthe time while on the current regimen of twice-dailysubcutaneous injections, though the results are notas good as on CSII alone (Table 1).Repeat fundoscopic examinations 65 days after

the initiation of CSII and only 36 days after con-

309

on Septem

ber 13, 2020 by guest. Protected by copyright.

http://bjo.bmj.com

/B

r J Ophthalm

ol: first published as 10.1136/bjo.65.5.307 on 1 May 1981. D

ownloaded from

M. C. White, Eva M. Kohner, J. C. Pickup, and Harry Keen

3a 3b

Fig. 3 (a) Fundus photograph of left macula 18 monthsafter initiation ofgood diabetic control. Markedreduction in number ofmicroaneurysms and haemorrhages.No cotton-wool spots present. (b) Fluorescein angiogramin capillary phase shows further improvement ofcapillary bed. (c) Fluorescein angiogram in the latevenous phase showing continued improvement in leakage.

tinuous normoglycaemia had been establishedshowed absorption of some of the haemorrhages anda reduction in the microaneurysms previouslydemonstrable, but a few cotton-wool spots haddeveloped (Fig. 2a). Fluorescein angiographyrevealed a marked reversal of microvascular lesionsand leakage (Figs 2b, c). There was normal revas-cularisation in some areas of previous nonperfusionand a reduction in capillary dilatation (Fig. 2d).Visual acuity had improved from 6/18 to 6/6 by theend of the period of CSII. Following the infusion theretinopathy showed signs of continued improvement

18 monthscontrolledinjections.

later (Figs. 3a-c) with the patient wellon twice daily subcutaneous insulin

Discussion

This case shows that some of the retinal micro-vascular complications of diabetes can be rapidlyreversed when continuous near-normoglycaemia isachieved with CSII, and the improvements maycontinue when good diabetic control is establishedon a conventional subcutaneous insulin regimen.

310

on Septem

ber 13, 2020 by guest. Protected by copyright.

http://bjo.bmj.com

/B

r J Ophthalm

ol: first published as 10.1136/bjo.65.5.307 on 1 May 1981. D

ownloaded from

Reversal of diabetic retinopathy by contfinuoussubcitaneous-iWui?P.infusion: a case report

Table 1 Blood glucose levels before, during, and afterCSII

Mean blood glucosemmol/l (± SD)

Once daily insulin prior to CSII 11 1±3 6(2-hourly levels over 24 hours)

After initial stabilisation on CSHI 4-9±2-4(2-hourly levels over 24 hours)

Over 65 days on CSII 6-1±2-1(4 estimations/day)*

Over 18 months on twice-daily insulinafter CSII (4 estimations/day)t 7-6±2-3

*Estimated by Dextrostix. tEstimated by Dextrostix and home bloodglucose monitor.

Previous studies in man assessing the relationshipbetween diabetic control and retinopathy have beeninconclusive, largely because of the practical diffi-culties in obtaining comparable groups of diabeticswho are assigned to different levels of metaboliccontrol over adequate time periods. Neverthelessseveral authors have inferred that poor metaboliccontrol is important in the development of retino-pathy.9-11 Others, however, have argued that goodcontrol has no influence on established diabeticretinopathy12 1. In man the evidence is still anecdotal,and such a criticism could be levelled at the casehere, particularly as unexplained, apparently spon-taneous remission of retinopathy may occur.'4However, the degree and the rapidity of reversal ofretinopathic changes in our patient using CSII toinduce continuous normoglycaemia must be veryunusual.We have never observed such changes over such a

short time interval, though similar results have beendescribed in some patients 3 months after treatmentby pituitary ablation with yttrium-90.15Other methods of achieving equally good blood

glucose control may be as successful as CSII, but thelatter has the advantage of delivering insulin in amore physiological manner than conventionalmethods, and this may be of critical importance inachieving the observed effects as in this case. Onceestablished it appears that the improvement can bemaintained on a conventional insulin regimen.While conclusions cannot be drawn from a single

case, we suggest that a therapeutic trial of normalisa-

tion of blood sugar with CSII in early and prepro-liferative retinopathy may be indicated.

This work was supported by the British Diabetic Association.

References

1 Engerman R, Bloodworth JMB, Nelson S. Relationshipof microvascular disease in diabetes to metabolic control.Diabetes 1977; 26: 760-9.

2 Pickup JC, Keen H, Parsons JA, Alberti KGMM.Continuous subcutaneous insulin infusion: an approachto achieving normoglycaemia. Br Med J 1978; i: 204-7.

3 Pickup JC, Keen H, Parsons JA, Alberti KGMM.Continuous subcutaneous insulin infusion. Good bloodglucose control for up to 4 days. Diabetologia 1979; 16:385-9.

4 Pickup JC, White MC, Keen H, Kohner EM, Parsons JA,Alberti KGMM. Long term continuous subcutaneousinsulin infusion in diabetics at home. Lancet 1979;ii: 870-3.

5 Pickup JC, Keen H, Parsons JA, Alberti KGMM.Continuous subcutaneous insulin infusion: prolongationof control and correction of intermediary metabolites.Diabetologia 1978; 14: 261 (abstract).

6 Tamborlane WV, Sherwin RS, Renel M, Felig P.Restoration of normal lipids and amino acid metabolismin diabetic patients with a portable insulin infusion pump.Lancet 1979; i: 1258-62.

7 Kohner EM, Hamilton AM, Joplin GF, Fraser TR.Florid diabetic retinopathy and its response to treatmentby photocoagulation or pituitary ablation. Diabetes1976; 25: 104-10.

8 Kohner EM, Dollery CT, Paterson JW, Oakley NW.Arterial fluorescein studies in diabetic retinopathy.Diabetes 1967; 16: 1-10.

9 Kohner EM, Fraser TR, Joplin GF, Oakley NW. Theeffect of diabetic control on diabetic retinopathy. In:Goldberg MF, Fine SL, eds. The Treatment of DiabeticRetinopathy. Washington: US Public Health ServicePublication No. 1890, 1969; 119-28.

10 Miki E, Fukuda M, Kuzuya T, Kosaka K, Nakao K.Relation of the course of retinopathy to control ofdiabetes, age, and therapeutic agents in diabetic Japanesepatients. Diabetes 1969; 18: 773-80.

11 Job D, Eschwege E, Guyot-Argenton C, Aubry JP,Tchobroutsky G. Effect of multiple daily insulin injectionson the course or diabetic retinopathy. Diabetes 1976;25: 463-9.

12 Schlesinger FG, Franken S, Van Lange LTP, Schwartz F.Incidence and progression of retinal and vascular lesionsin long term diabetes. Acta Med Scand 1960; 168: 483-8.

13 Burditt AF, Caird Fl, Draper GJ. The natural history ofdiabetic retinopathy. Q J Med 1968; 37: 303-17.

14 Gerritzen FM. The course of diabetic retinopathy. Alongitudinal study. Diabetes 1973; 22: 122-8.

15 Kohner EM, Dollery CT, Fraser TR, Bulpitt CJ. Theeffect of pituitary ablation on diabetic retinopathy studiedby fluorescein angiography. Diabetes 1970; 18: 703-14.

311

on Septem

ber 13, 2020 by guest. Protected by copyright.

http://bjo.bmj.com

/B

r J Ophthalm

ol: first published as 10.1136/bjo.65.5.307 on 1 May 1981. D

ownloaded from