British Journal of Ophthalmology, 1979, 63, 489-497

Excessive permeability in diabetic maculopathyMARGARET KEARNS, A. M. HAMILTON, AND EVA M. KOHNERFrom the Hammersmith Hospital, Royal Postgraduate Medical School, and Moorfields Eye Hospital,London

SUMMARY Four cases of diabetic maculopathy with excessive permeability are described. Fluores-cence angiography is distinctive, showing profuse early leakage from the entire capillary bed of theposterior pole. Careful studies have failed to reveal any cause for this excessive permeability responseat the macula or any constantly associated medical abnormality. The prognosis for visual acuityis poor, and photocoagulation has only rarely been successful in maintaining or improving visionin these patients.

Diabetic maculopathy continues to be a majorproblem in diabetic patients of all ages. Visualacuity is often severely affected, and treatment byphotocoagulation has not had the same highlyfavourable results as in the treatment of proliferativeretinopathy with disc new vessels (DRS, 1976;British Multicentre Group, 1977). The naturalhistory of diabetic maculopathy has never beenclearly elucidated, probably because it embracesseveral subgroups which behave differently. In thiscommunication we describe one particular raresubgroup. This unusual form of maculopathy ischaracterised by excessive permeability of allcapillaries of the posterior pole. On examination,little or no abnormalities are seen apart from theoedema. On fluorescein angiogram there is earlyextensive leakage from the capillaries in the maculararea.

Case reports

CASE 1A 29-year-old nursing sister was referred to theHammersmith Hospital in 1974 because of diabeticretinopathy. In the past she had episodes of iritisin both eyes (1970-72). She had noticed gradualdeterioration in vision in her left eye in 1972 andmore sudden, severe loss of vision especially in theright eye in 1973. She had been diabetic since theage of 13. Her treatment was a single daily dose oflente insulin, initially 100 units, reduced to 44 unitsin recent years, and she always had heavy glycosuria.Over the 6 months before coming to the Hammer-

Correspondence to Dr Eva M. Kohner, HammersmithHospital, Du Cane Road, London W12 OHS

smith Hospital she had noticed swelling ofher ankles.it was only partially controlled by taking frusemide80 mg daily.On examination, her visual acuities (VA) were

6/18 on the right (R) and 6/24 on the left (L).She had no rubeosis, her intraocular pressure wasnormal, as were her anterior chambers. She hadearly cortical cataracts. The vitreous was normal;in particular no cells were seen. Fundus examinationshowed cystic macular oedema and early disc newvessels in both eyes (Fig. la). General examinationshowed that she was of ideal body weight; herblood pressure (BP) was 140/80 mmHg lying andstanding. She had foot and ankle oedema, absentankle reflexes, and reduced vibration sense.

Investigations showed normal blood urea, creati-nine, cholesterol, triglycerides, haemoglobin (Hb),and white cell count (WBC). Serum proteins werenormal, but albumin was at the lower limit ofnormal. Her blood sugar control was poor, andmost blood sugars were over 15 mmol/l whatevertime of day they were taken.

Florescein angiograms showed good initialcapillary perfusion, with early profuse leakage fromall the capillaries in the macular region, and discleakage (Fig. lb and c).

Medical course. General diabetic control wasimproved by changing her insulin dosage to solubleand isophane (NPH) 8 units each twice daily. Overthe last 4 years her urine has been mostly free ofsugar and blood sugar levels were mostly less than9 mmol/l. Her ankle oedema persists but isimproved on frusemide 120 mg/day and spirono-lactone 50 mg 3 times daily. In 1978 further bloodtests investigating capillary endothelial damage bymeasuring factor VIII levels, platelet aggregation,

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serum fibrinogen, and fibrin degradation productswere normal. Blood urea, serum electrolytes,creatinine, and proteins remained normal, and nospecific cause for the excessive capillary leakage wasthus found.

Ocular course. In 1974, because of the severeretinopathy, she entered the paired eye photocoagu-lation study (British Multicentre Group, 1977).The right eye was drawn for treatment with thexenon arc (448 bums given as a pattern bombing).The left eye was untreated as a control. Over the 4years' follow-up the vision in the right eye hasremained static. Vision in the left eye has deteriorated

Fig. 1 (a) From a colour photograph ofR macularregion from Case 1 when patient first seen. The perifovealarea looks featureless and there are only a few hardexudates and haemorrhages peripherally. (b) Fluoresceinangiogram in capillary phase from Case I when first seen.Diffuse leakage. (c) Same as Fig. lb but in late phaseshowing extensive leakage throughout posterior pole

to 6/60 (partly owing to increase in lens opacities).The macular oedema persisted, and fluoresceinangiograms of the right eye remained the same(Fig. 2a-c). New vessels in both eyes have improved.

CASE 2A 50-year-old parole officer was referred to theHammersmith Hospital in February 1974 becauseof blurred vision. The ocular symptoms had beenpresent since he began treatment for his diabetes 2years previously. His vision had previously beenexcellent. At the age of 48 years he had presented tohis local doctor with blurred vision, impotence for

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Fig. 2 (a) Same as Fig. Ja, but 4 years later.Photocoagulation scar seen lateral to macula. Noteapparent normality of macular area. (b) Fluoresceinangiogram of right macula of Case 1, 4 years afterphotocagulation. Extensive leakage in capillary phasestill present. (c) Extensive leakage from all capillaries inlate phase offluorescein angiogram

2 years, and increasing thirst, polyuria, and weightloss. The diagnosis of diabetes was made, andtreatment with a 120-g carbohydrate diet, glibencla-mide 12-5 mg, and long-acting phenformin 50 mgdaily started. From that time blood sugars takenat the clinic were all well under 10 mmol/l.On examination his visual acuities were R 6/6

and L 6/9. He had no rubeosis, normal intraocularpressures, and normal anterior chambers. Fundusexamination showed bilateral cystic macular oedema(Fig. 3a). His BP was raised at 180/115 mmHg, andhe had reduced vibration sense. Otherwise medicalexamination was normal, and in particular he hadno ankle oedema, no signs of peripheral neuro-

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pathy, and was only 5% above ideal body weight.Investigations showed normal blood urea, pro-

teins, triglycerides, cholesterol, Hb, and WBC. Bloodsugars were under 10 mmol/l. He had no proteinuria.

Fluorescein angiography showed symmetricalmaculopathy with early good perifoveal perfusion,and early profuse leakage from all the capillariesat the posterior pole (Fig. 3b-c). There was alsosome peripheral capillary non-perfusion.

Medical course. Blood pressure was controlledwith clonidine and beta blockers, but diabeticmanagement has been maintained unchanged. Hehas kept in good health and maintained good controlof his BP and diabetes. In 1978 further blood tests

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searching for evidence of generalised capillaryendothelial damage showed factor VIII levels,platelet studies, fibrinogen, and fibrin degradationproducts to be in the normal range.

Ocular course. In 1974 he was entered in thepaired eye photocoagulation trial (British Multi-centre Group, 1975), and the left eye was drawnfor xenon arc photocoagulation (335 burns as apattern bombing). The right eye was untreated as acontrol. Over the 4 years' follow-up vision hasdecreased gradually to 6/60 in both eyes by 1978.Visual loss has been due to persistent gross leakageat the maculae leading to cystic macular oedemaand finally bilateral macular holes (Fig. 4a-c).

Fig. 3 (a) Case 2 from colour photograph of left maculkrarea showing haemorrhages and exudates in the macularregion. (b) Fluorescein angiogram in capillary phaseshows good perfusion and early leakage. (c) Fluoresceinangiogram in late phase shows diffuse leakage throughloutthe macular area

CASE 3A 42-year-old builder presented to Moorfields EyeHospital in 1977 complaining of decreasing visionin both eyes. Diabetes had been diagnosed at 32years of age when he presented to his local doctorwith weight loss and polyuria. He was treated with44 units lente insulin as a single daily dose. Hiscontrol had always been poor, showing 2% glyco-suria most of the time. Control was made difficultby his high daily alcohol intake (approximately 16pints of beer and 3 double whiskies). On examinationhis visual acuity was 6/9 in both eyes. He had norubeosis, normal intraocular pressures, and normalanterior chambers. Fundus examination showed

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Fig. 4 (a) Case 2, 4 years after photocoagulation.Scars lateral to macula, cystic oedema, and macularhole. (b) Fluorescein angiogram in capillary phase showsthat all remaining capillaries leak fluorescein. Notemacular hole. (c) Fluorescein angiogram in late phaseshows extensive leakage; unchangedfrom pretreatmentangiogram

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cystic macular oedema. General examination re-vealed a fit-looking man of ideal body weight,without diabetic complications apart from reducedvibration sense and absent ankle reflexes.

Investigations showed normal blood urea, tri-glycerides, cholesterol, Hb, and WBC. Factor VIIIlevel, fibrinogen, fibrin degradation products, andplatelet function tests were normal. His blood sugarlevels were always above normal.

Fluorescein angiography showed good initialcapillary perfusion and profuse early leakage fromall the capillaries in the macular region.

Medical course. Over the 12 months to 1978 hisdiabetic control remained very poor but otherwise

he was well. Because of his poor diabetic control hewas admitted to the Hammersmith Hospital andtreated for 2 weeks with continuous subcutaneousinsulin infusion (Pickup et al., 1978). On thisregimen blood sugars were mostly below 10 mmol/lthroughout the 24 hours. He was discharged ontwice-daily soluble and isophane insulin and main-tained improved control. However, at this time onhis local doctor's advice he recommenced singledaily insulin injection, with deterioration of hisdiabetic control.

Ocular course. His visual acuity had fallen toVAR 6/36 and VAL 6/60 despite argon laser treat-ment to both posterior poles-given as a focal and

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grid pattern, 87 burns on the right and 400 burnson the left prior to admission to hospital. While oncontinuous insulin infusion his vision improved toR 6/24 and L 6/18, though the fundus appearanceand fluorescein angiogram remained the same(Fig. 5a-c). At his last visit, 2 months after dis-continuing twice daily insulin, his visual acuity haddecreased to R 6/60 and L counting fingers. Thefluorescein angiogram was unchanged.

CASE 4A 52-year-old clerical worker presented to theHammersmith Hospital in 1974 after loss of vision

Fig. 5 (a) Case 3 from a colour photograph of leftmacula after 400 argon laser burns and 2 weeks oncontinuous insulin infusion. Cystic macular oedema,haemorrhage, and laser scars visible. (b) Fluoresceinangiogram in capillary phase showing dilated leakyvessels. (c) Fluorescein angiogram in late phase showscystic macular oedema and leakage

in both eyes over the preceding 9 months. Oneyear previously she had been diagnosed diabetic,after presenting to her local doctor with symptomsof thirst, weight loss, and frequency. At that timeher vision was normal. The diabetes had beentreated with 100-g carbohydrate diet, long-actingphenformin 50 mg twice daily, and chlorpropamide500 mg daily.On examination her visual acuities were VAR and

VAL 4/60 each. She had no rubeosis, normalintraocular pressures, normal anterior chambers,and early cortical lens opacities. Fundus examinationrevealed cystic macular oedema. On general examin-

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Fig. 6 (a) Case 4. Colour photograph of right macularregion shows confluent hard exudates. There are alsomultiple haemorrhages. (b) Fluorescein angiogram incapillary phase showing marked dilatation of capillariesand leakage. (c) Extensive fluorescence ofposterior polein late phase of angiogram indicates widespreadhyperpermeability. New vessels on disc seen at edge ofpicture

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ation she was of ideal weight with very few abnormalfindings apart from slightly raised BP at 160/100, araised resting pulse of 110, and absent ankle reflexes.

Investigations showed normal blood urea, pro-teins, cholesterol, triglycerides, Hb, and WBC. Herurine was always free of sugar and protein.

Fluorescein angiography showed extensive earlyleakage from all the capillaries at the posterior polewith areas of peripheral non-perfusion.

Medical course. Her general health remained good,but her blood urea had risen to 11-4 mmol/l,while her serum creatinine remained normal. Duringthe last year her diabetic control had deteriorated

and blood sugars are now 10 to 15 mmol/l.Further investigations in 1978 for signs of generalisedcapillary damage, factor VIII, prothrombin time,fibrinogen, fibrin degradation products, and plateletstudies were all normal.

Ocular course. In 1974 she was entered in thepaired eye photocoagulation study, and the left eyewas drawn for xenon arc photocoagulation in aperipheral pattern bombing 250 burns. Both eyesdeteriorated rapidly. The right, untreated eyedeveloped disc new vessels and confluent hardexudates within 1 year (Fig. 6a-c), and thromboticglaucoma proceeded to no light perception. The

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left eye lost further vision from retinal detachmentto counting fingers at 1 metre.

Discussion

The patients presented here all had maculopathy ofof a severe nature. All the capillaries at the posteriorpole leaked fluorescein immediately the dye reachedthem.

It is not clear from our observations why thesepatients should have had such extensive leakage.There was no evidence of any inflammatory processin the eyes. Only 1 of the 4 patients (Case 1) hadmild proteinuria and severe ankle oedema, indicatinghyperpermeable capillaries in other parts of thebody. Moreover, blood tests done to identifygeneralised endothelial cell damage factor VIIIrelated antigens, fibrinogen, fibrin degradationproducts-were normal. It is known that capillariesin skeletal muscle of long-term diabetics have in-creased permeability (Trap-Jensen and Lassen, 1968),but the cause of this is not known, and it is notnecessarily associated with extensive retinal capillaryleakage leading to maculopathy in most diabetics.Schatz and Patz (1976) reported a group of diabeticswith this type of maculopathy and noted that thesepatients were all young. While 2 of our patientswere less than 45, 2 were 50 or more, indicatingthat youth is not necessarily a feature of the condi-tion. A similar type of maculopathy has beenobserved in some young, pregnant diabetics andwomen on oral contraceptive pills. In contrast tothe 4 patients reported here, in these women thecystic macular oedema has improved on treatmentwith diuretics, stopping the pill, or completing thepregnancy.

Renal function was remarkably normal in ourpresent patients when they presented with visualloss. The effect of blood pressure on maculopathyhas not been clearly established, but it appears thatraised BP accelerates the progression of retinopathyin general (Harrold, 1971; Kohner, unpublishedobservation). Of the patients reported here only 1had high BP and 1 mildly raised BP. Treatment ofthe BP did not alter the course of the retinopathy,and vision continued to deteriorate rapidly, irrespec-tive of blood pressure levels. The role of diabeticcontrol has not been clearly established in thedevelopment and treatment of this condition. The 2insulin-dependent diabetics may have been favour-ably influenced by improvement of their control.The only eye which retained 6/18 vision belongs toone of the patients whose diabetes became wellcontrolled with most blood sugars under 10 mmol/l.It is tempting to implicate poor diabetic controlin the other young person as a cause of the severe

loss of vision, especially as hospitalisation with nearnormal blood sugar levels during continuous insulininfusion improved his vision significantly. However,macular oedema may be variable, particularly when,as in this case, the patient's alcohol intake is drasti-cally reduced. It remains no more than a clinicalimpression that it is worth while to optimise controlin insulin dependent (type I) diabetics.

In the type II diabetics (Cases 2 and 4) bloodsugar control was satisfactory when the severemaculopathy developed. The patient (Case 4) whopwas on maximum doses of oral hypoglycaemicagents probably should have been on insulin. Herpoor vision detered us from changing her on tothis treatment. Conclusions are difficult to make,but it is possible good control has very littlebeneficial effect on the retinopathy of type IIdiabetics. This impression is in agreement with thefindings of the study by the UGDP (1977). Further-more, it is possible that once a certain severe degreeof retinopathy is present the lesions, especially non-perfused areas, are irreversible. In this as in othermaculopathies there was a progressive occlusion ofsmall vessels in the retinal periphery. In the first 2patients it was observed at presentation. In Patient 4it occurred during the period of follow-up, and inPatient 3 after completion of the report. Capillarynon-perfusion occurs in all forms of diabeticretinopathy and is not thought to be relevant to theexcessive permeability seen in these patients.Photocoagulation is of some benefit in most formsof maculopathy (Patz et al., 1973; British Multi-centre Group, 1975). In our group it seemed to havevery little effect. This is in agreement with the findingsof Schatz and Patz (1976), whose patients withsevere macular oedema also did not respond toextensive treatment. In conclusion, in type 1 diabeticswith this rare condition good physiological diabeticcontrol should be aimed at in the first instance,photocoagulation should be tried early, but it isimportant to maintain a guarded visual prognosis.

This work was supported by a DHSS small grant and the-British Diabetic Association. The illustrations were preparedby Mr M. Beard and Mr A. Sehmi.

Haematological investigations were carried out by Mr A.McCraw and Dr P. Hilgard.

References

British Multicentre Group (1975). Photocoagulation in thetreatment of diabetic maculopathy. Lancet, 2, 110-113.

British Multicentre Group (1977). Proliferative diabeticretinopathy: treatment with xenon arc photocoagulation.Interim report of multicentre randomised controlled clinicaltrial. British Medical Journal, 1, 739-746.

Diabetic Retinopathy Study Research Group (DRS) (1976).Preliminary report on effects of photocoagulation therapy.American Journal of Ophthalmology, 81, 383-396.

Harrold, B. P. (1971). Diabetic retinopathy and hypertension

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British Journal of Ophthalmology, 55, 225-232.Patz, A., Schatz, H., Gittelsohn, A. D., and Ticho, V.

(1973). Macular oedema an overlooked complication ofdiabetic retinopathy. American Academy of Ophthalmologyand Otolaryngology, 77, 34-39.

Pickup, J. C., Keen, H., Parsons, J. A., and Alberti,K. G. M. M. (1978). Continuous subcutaneous insulininfusion: an approach to achieving normoglycaemia.British Medical Journal, 1, 204-207.

Schatz, H., and Patz, A. (1976). Cystoid maculopathy indiabetics. Archives of Ophthalmology, 94, 761-768.

Trap-Jansen, J., and Lassen, N. A. (1968). Permeability ofsmall vessels in diabetes. Scandinavian Journal of Clinicaland Laboratory Investigation, 21, 11 6-122.

University Group Diabetic Program (1977). Effects ofhypoglycaemic agents on vascular complications inpatients with adult onset diabetes. Journal of the AmericaniMedical Association, 218, 1400-1410.

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