Britishournalofphthalmology, 1991,75, 13-17

Cotton-wool spots and retinal light sensitivity indiabetic retinopathy

Toke Bek, Henrik Lund-Andersen

AbstractIn 14 eyes of 14 patients with diabetic retino-pathy the light sensitivity of retinal cotton-wool spots was studied by computerisedperimetry, and the visual field data wereaccurately correlated with the correspondingmorphology as seen on fundus photographsand fluorescein angiograms. In 12 of the eyesthe examinations were repeated within oneyear in order to follow changes in retinal lightsensitivity during the evolution of the lesions.Retinal cotton-wool spots were in all eyesassociated with localised non-arcuate scoto-mata in the visual field. In four eyes the cotton-wool spots disappeared within three months ofthe first examination, and in two of these casesthe corresponding scotomata disappearedtogether with the morphological lesions. Ineight eyes the cotton-wool spots (and thecorresponding scotomata) had not resolvedone year after the first examination. The meanblood pressure showed no significant dif-ference between the patients in whom thelesions resolved within three months and thepatients in whom the lesions persisted longer.

The retinal cotton-wool spot is a frequent findingin a variety of diseases which involve the ocularfundus.1 In diabetic retinopathy the lesion maybe among the initial signs of the disease, andwhen the lesions are numerous they may indicate

rapidly progressing retinopathy.2 Although it isknown that the cotton-wool spot can be causedby focal retinal ischaemia, no single explanationhas been given which consistently accounts forthe aetiology of the lesion in all cases.3The retinal cotton-wool spot has been mainly

investigated by photographic and histologicaltechniques which demonstrate the morpho-logical aspects of the lesion. The inclusion oftechniques for the assessment of neurosensoryfunction can be expected to supplement ourunderstanding of its pathophysiology. In a priorstudy the visual field of six diabetic patients withretinal cotton-wool spots was examined by amanual perimetric technique,4 but the exactcorrelation between visual field data and thecorresponding fundus morphology was notaccounted for, and the visual field findings werenot systematically followed during the evolutionof the lesions.

In the present study the light sensitivity ofretinal areas with cotton-wool spotswas examinedby computerised perimetry, and by a newlydeveloped optical technique the visual field datawere accurately correlated with the corres-ponding fundus morphology as seen on fundusphotographs and fluorescein angiograms. Theexaminations were repeated within one year inorder to follow changes in retinal light sensitivityduring the evolution of the lesions.

Materials and methods

Figure IA A left eyefundus photograph ofa patient with diabetic retinopathy dominated bycotton-wool spots. The perimetric stimulus pattern extendedfrom degree co-ordinates (x, y) =(-9, -10) to (1, -2), and the visitalfield data have been superimposed on to the correspondingfundus morphology. Two areas with low decibel values are seen to correlate with retinal cotton-wool spots (arrows). The low decibel values are predominantly located on the peripheral aspectofthe lesions.

SUBJECTSFourteen eyes of 14 patients with insulin depen-dent diabetes mellitus in which retinal cotton-wool spots had been detected by funduscopicexamination were subjected to computerisedperimetry, and the visual field data were

accurately correlated with the correspondingmorphology as seen on fundus photographs andfluorescein angiograms. The patients underwentroutine ophthalmic examinations, includingvisual acuity, slit-lamp examination, tonometry,ophthalmoscopy, fundus photography, andfluorescein angiography. Their informed consentwas obtained. The blood pressure was measuredat the initial examination or was obtained frommedical records within two months of the initialexamination. The ametropia of the eyes rangedbetween -2-0 D and +1-25 D, and the mostsevere astigmatism was 1-5 DC. Visual acuitywas 6/9 in one patient and 6/6 or better in all theother patients.Except for funduscopic signs of retinopathy

the other part of the ophthalmological examina-tion was normal in all the patients included. In 12eyes the examinations were repeated within threemonths of the first examination and, in cases

Department ofOphthalmology,University ofCopenhagen, GentofteHospital, 2900 Hellerup,DenmarkT BekH Lund-AndersenCorrespondence to:Toke Bek, MD.Accepted for publication30 July 1990

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Figure IB Afundus photograph ofthe same eye three months later. The cotton-wool spotswhich were studied by perimetry have now resolved, but an area with low decibel values persistswhere one ofthe cotton-wool spots was located (arrow). Another cotton-wool spot has nowappeared below the examined area.

where the cotton-wool spots persisted, again oneyear after the initial examination.

PHOTOGRAPHYPhotography was performed with a Canon CF-60Z fundus camera employing Ektachrome 64(EPR 135-36) film for fundus photography, andIlford HP-5 black-and-white film for fluoresceinangiography. 5 ml 10% fluorescein sodium was

injected into an antecubital vein for fluoresceinangiography. Angiograms were taken of thecentral fundus in fast sequence during the fillingphase ofthe vessels, and at regular intervals until15 min after injection. Prior to photographycycloplegia and mydriasis were induced withmetaoxedrine 10% and tropicamide 1%eyedrops.S -- . r t \ i d

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Figure IC Afluorescein angiogram ofthe same eye obtained on the same day as Fig IB, andvisualfield data have been superimposed. The retinal areas corresponding to the persistingscotoma shows some pathology, mainly asfocal leakage offluorescein.

PERIMETRYPerimetry was carried out with a HumphreyField Analyzer (HFA). Full-threshold examina-tions were performed in stimulus patterns with adensity of 10 employing Goldmann stimulus sizeI. These were the best parameters available onthe HFA for the detection of small scotomata.5Since the minimum density of customised stimu-lus patterns on the HFA is 2°, four intersectingpatterns with a displacement of 10 in the verticaland the horizontal plane were subsequentlytested, and finally merged. The stimulus patternswere placed in areas of the visual field thatapproximately corresponded to the retinal areaswhere morphological lesions had been observedby prior funduscopic examination.

Threshold values that deviated more than 5 dBfrom the expected value calculated on the basis ofanswers from adjoining points were retested(standard procedure on the HFA). The blindspot was delimited with Goldmann stimulus sizeII with a single intensity of 10 dB in two specialpoint patterns located in the area of the blindspot, one (pattern A) extending from degree co-ordinates (x,y)=(11,-7) to (19,3) and one(pattern B) from degree co-ordinates (x,y)=(12,-8) to (18,2). By merging these two patternsa spatial resolution of 1.40 could be obtained inthis area. All patients could see the perimeterscreen sharply during perimetry without theaddition of a corrective lens. Fixation was con-tinuously checked on the fixation monitorsupplied on the HFA, which displays the eye ona video screen during perimetry. Fixation wasstable during all test sessions in all the patientsincluded.

SUPERIMPOSITION TECHNIQUEThe superimposition of visual field data on tofundus pictures was carried out according to atechnique previously described.6 This techniqueis applicable to a fundus photograph (subtendingapproximately 600 with the camera employedhere) with the foveal region in the centre andwith the accuracy of the overlay or visual fielddata on to the corresponding fundus photographmore than 10. Briefly, with knowledge of theoptical imaging in the fundus camera, the visualfield printout is reduced to match the size of thecorresponding fundus photograph. The visualfield is inverted about a horizontal axis, and theoverlay is subsequently done on the basis of twopoints of reference. One of them, the fixationpoint in the visual field, is laid over the foveola onthe fundus picture, and the other, the blind spotin the visual field, is laid over the optic nervehead on the fundus picture.

ResultsIn Figs 1 to 3 representative examples of visualfield data correlated with corresponding fundusmorphology are shown. The numbers indicatethreshold decibel values obtained with Goldmannstimulus size I, and each number has beensuperimposed on to the corresponding fundusmorphology. In points where the threshold hasbeen tested twice, the average of the two decibelvalues has been employed. The fixation point is

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Cotton-wool spots and retinal light sensitivity in diabetic retinopathy

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Figure 2A A righteyefundussphotograph ofa patient withnsulindependent diabmellitus. The only sign ofretinopathy is a cotton-wool spot located above the optic nThe perimetricstimulus pattern extendedfrom degree co-ordinates (x, y)=(6, -16) tThe visualfield data have been supeimposed on to the correspondingfundus morphlow decibel values (a relative scotona)have been supeamposed on to the cotton-woe

indicated with a cross. In the screenemployed to delimit the blind spot opeindicate seen points, whereas closegindicate points not seen.

In all 14 eyes examined the retinal cotspots were associated with localised scothe visual field which appeared notwithin the area ofthe visual field tested.these cases the non-functioning reticorresponding to the scotoma extendecthe peripheral aspect of the morphologi4(see Fig 1), a finding which could not be eas a result of inaccuracies of the superintechnique.Twelve eyes were re-examined. In I

the lesion had disappeared within thre(

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Figure 2B A fundus photograph ofthe same eye three months later. Visualfield dat that time are superimposed. The cotton-wool spot has now entirely disappeared, 6scotoma is detected in the vtsualfield.

of the initial examination. In two of these casesthe scotoma and some angiographical pathology

- }_ corresponding to the now resolved cotton-woolspot persisted (Fig 1). In the other two cases thescotoma had disappeared together with thefunduscopic lesion, and no angiographic traces

) of the lesion persisted (Fig 2). In eight eyes thecotton-wool spots, though changed in appear-ance, were still present together with the corres-ponding visual field scotomata one year from theinitial examination (Fig 3).There was no significant difference between

the mean blood pressure of the patients in whomcotton-wool spots resolved within three months- systolic mean, 155 (range 140-170) mmHg,

j diastolic mean, 88 (range 75-95) mmHg - andS the blood pressure of the patients in whom thefl lesions persisted longer - systolic mean, 148

(range 120-175) mmHg, diastolic mean, 90(range 70-100) mmHg.

ieteserve head.o(18, -9). Discussionology, and The findings of the present study considerably1 spot. extend the findings4 from a quantitative peri-

metric technique and an accurate technique forsuperimposing visual field data on to the corres-

Ling tests ponding fundus morphology. Retinal cotton-mn circles wool spots were consistently associated withd circles localised non-arcuate scotomata in the visual

field. Of 12 eyes which were re-examined thetton-wool cotton-wool spots had disappeared within a fewtomata in months in four, and in two of these the corres-n-arcuate ponding scotoma disappeared together with theIn five of morphological lesion. In the other eight eyesinal area the cotton-wool spots (and the correspondingd beyond scotomata) persisted for more than one year.cal lesion Retinal cotton-wool spots are defined on the~xplained basis of their funduscopic appearance; typicallynposition they are white fluffy areas of retinal opacity with

feathery margins. This appearance is assumed tofour eyes reflect focal swelling of the nerve fibres, which ise months due to intracellular fluid and organelles accumu-

lated secondary to interrupted axoplasmic flow.7The aetiology of axonal disturbance at the site ofthe lesion is controversial, and no single explana-tion consistently explains the available data.3 It isgenerally believed, however, that focal retinalischaemia is often a factor in its pathogenesis.The natural history of the cotton-wool spots

followed in the present study showed twodifferent patterns. In one group of patients thelesions resolved within three months ofthe initialexamination, whereas in another group thelesions persisted for more than one year. Sincethe age of the cotton-wool spots at the time of theinitial examination is unknown, it is uncertainwhether the lifetime of the lesions actuallydiffered. If it did, however, the observeddifference in natural history of the lesions might

\ perhaps reflect differences in their pathophysio-logical basis. This view is supported by studies

j which have shown the lifetime of cotton-woolspots to vary considerably in different retinaldiseases, such as for example hypertensive anddiabetic retinopathy.89 The fact that no differ-ence was found between the mean blood pressure

btained in the two groups of patients, however, arguesand no against raised blood pressure as a cause of the

lesions in one of these groups. This view finds

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Figure 2C A fluorescein angiogram ofthe same eye obtained on the same day as Fig 3B,visualfield data have been superimposed. No angiographic traces ofthefunduscopicallyresolved cotton-wool spot can be seen.

Figure 3A A right eyefundus photograph ofa diabetic patient with background retinopaofheterogeneous morphology. The perimetric stimulus pattern extendedfrom degree co-ordi?(x, y)=(-20, 8) to -8, 16). The visualfield data have been superimposed on to thecorrespondingfundus morphology, and a scotoma in the visualfield is seen to correspond toretinal cotton-wool spot at the lower temporal branch.

Figure 3B A fundus photograph ofthe same eye 12 months later. The retinal cotton-wool(though changed in appearance) is seen to persist together with a scotoma in the visualfield (decibel values). Other cotton-wool spots along the upper temporal arch and nasal to the opt,nerve head (compare with Fig 3A) have now disappeared.

further support in a prior study that showed nocorrelation between blood pressure and retinalcotton-wool spots in diabetic retinopathy. "I

The scotomata found in association withcotton-wool spots did not extend in an arcuate

2 fashion within the area of the visual field tested,which would be expected if the nerve fibrestraversing the lesions were injured. It thus seemsthat these fibres are still viable despite probablyextensive structural changes at the site of thelesion. Other studies support the idea that nervefibre function is rather resistant to the damagecaused by cotton-wool spots. In one study meta-bolic enzyme activity was found to be preservedin nerve fibres adjacent to cotton-wool spots,"and the results of another study strongly suggestthat the formation of the lesion itself requiresthat the axoplasmic flow of the nerve fibres is

and preserved.7 The fact that the non-functioningretinal areas corresponding to the cotton-woolspots in some cases extended beyond theperipheral aspects of the lesion remains to beexplained. The finding, however, could perhapsbe a parallel to evidence from experimentallyproduced cotton-wool spots showing that axonsmay penetrate some way into the lesion beforeswelling is seen histologically.7The fact that some scotomata persisted after

resolution of the cotton-wool spots probablyindicates that the recorded visual loss is notalways entirely due to opacity of the lesionblocking the perimetric stimulus light fromreaching the retinal photoreceptors, but probablyis also due to structural injury to some part of theretina. This injury is probably reflected in thepersisting angiographic pathology at the site ofthe resolved cotton-wool spot in these cases. Insome studies it has been reported that scotomatasometimes occur in the visual field of diabeticpatients without any lesion in the fundus.'2'3These scotomata have been interpreted as anindication that neurosensory cell damage occurs

rthy before the development of morphological lesionsnates in this disease. This interpretation, however,

may easily be wrong if the scotomata representla the remaining signs of a resolved cotton-wool

spot.In conclusion, the findings of the present

study show that cotton-wool spots of diabeticretinopathy cause localised non-arcuate scoto-mata in the visual field which may persist whenthe funduscopic lesions resolve. They indicatethat the function of nerve fibres traversing the

X.~ lesions is probably preserved and that smallscotomata in the visual field of diabetic patientsmay represent the remaining signs of a resolvedcotton-wool spot.

The skilful assistance of photographer Hans Henrik Petersen isgratefully acknowledged.The present study was supported by the Mimi and Victor

Larsens Foundation, the Carl Larsens Foundation, and the Johnand Birthe Meyer Foundation.

1 Brown GC, Brown MM, Hiller T, Fischer D, Benson E,Magargal LE. Cotton-wool spots. Retina 1985; 5: 206-14.

2 Roy M, Rick ME, Higgins KE, McCulloch JC. Retinal cotton-spot wool spots: an early finding in diabetic retinopathy? Br J(low Ophthalmol 1986; 70: 772-8.

3 Ashton N. Pathophysiology of retinal cotton-wool spots.Br Med Bull 1970; 26: 143-50.

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Cotton-wool spots and retinal light sensitivity in diabetic retinopathy

4 Williams DK, Drance S, Harris GS, Fairclough M. Diabeticcotton wool spots: an evaluation using perimetric andangiographic techniques. CanJI Ophthalmol 1970; 5: 68-77.

5 Bek T, Lund-Andersen H. The influence of stimulus size onperimetric detection of small scotomata. Graefes Arch ClinExp Ophthalmol 1989; 227: 531-4.

6 Bek T, Lund-Andersen H. Accurate superimposition of visualfield data onto fundus pictures. Acta Ophthalmol (Kbh) 1990;69:11-8.

7 McLeod D, Marshall J, Kohner EM, Bird A. The role ofaxoplasmic transport in the pathogenesis of retinal cotton-wool spots. BrJ Ophthalmol 1977; 61: 177-91.

8 Hodge JV, Dollery CT. Retinal soft exudates. A clinical studyby colour and fluorescence photography. QJ7Med 1964; 129(N Ser 33): 117-31.

9 Kohner EM, Dollery CT, Bulpitt CJ. Cotton-wool spots indiabetic retinopathy. Diabetes 1969; 18: 691-704.

10 Esmann V, Lundbaek K, Madsen PH. Types of exudatesin diabetic retinopathy. Acta Med Scand 1963; 174: 375-84.

11 Diezel PB, Willert HG. Morphologie und Histochemie derHarten und weichen Exsudate der Retina bei Diabetesmellitus und essentieller Hypertonie. Klin Monatsbl Augen-heilkd 1961; 139:475-91.

12 Bloom A, Heath JH, Kelsey PR, Hunter PR, Bridgden WD.The use of the Roth-Keeler central field scotometer in thestudy of diabetic retinopathy. Ophthalmic Res 1972; 3: 166-73.

13 Roth JA. Central visual field in diabetes. Br Ophthalmol1969; 53; 16-25.

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