Functional loss in age-related Bruch's membrane...

Investigative Ophthalmology & Visual Science, Vol. 33, No. 2, February 1992Copyright © Association for Research in Vision and Ophthalmology

Functional Loss in Age-Related Bruch's MembraneChange With Choroidal Perfusion Defect

J. C. Chen, F. W. Firzke, D. Pauleikhoff, and A. C. Bird

During a prospective study of age-related macular degeneration, evidence of diffuse Bruch's membranedisease was sought using fluorescein angiographic evidence of a prolonged choroidal filling phase.Dark-adapted static perimetry was done on eight eyes with this angiographic sign and on six eyes with asimilar number of drusen but no manifest choroidal perfusion abnormality. Scotopic threshold wasmeasured using the Humphrey automated perimeter and fine matrix mapping. In eyes without delayedchoroidal perfusion, no discrete areas of increased threshold were found compared with the backgroundsensitivity. By contrast, in seven of the eight eyes with fluorescein angiographic evidence of prolongedchoroidal filling, discrete areas of scotopic threshold elevation (up to 3.4 log units) were recorded; thesecorresponded closely to regions of choroidal perfusion abnormality. It was postulated that diffusedeposits of abnormal material might account for both the perfusion abnormality and functional loss byacting as a diffusion barrier between the choriocapillaris and the retinal pigment epithelium. InvestOphthalmol Vis Sci 33:334-340,1992

There is a well-recognized association between..̂ ose lesions causing visual loss in age-related macu-lar disease, namely subretinal neovascularization andpigment epithelial detachments, and accumulation ofdebris in Bruch's membrane.1"9 This debris collectseither as discrete or diffuse deposits.5"9 Drusen are con-sidered to be the clinical correlate of the discrete de-posits; there is evidence that their form correlates bothwith the type of lesion likely to occur and with themagnitude of risk of visual loss.10"13 However,currently, no clinical signs are recognized suggestingthe presence of the diffuse (linear) deposits. There-fore, the influence of such debris on disease cannot bestudied clinically.

By analogy with Sorsby's fundus dystrophy,14-15 achoroidal perfusion abnormality, as shown by fluores-cein angiography, may indicate diffuse Bruch's mem-brane disease in the aging eye.16 By contrast with thenormal rapid filling of the choroid, in these eyes ma-jor choroidal blood vessels are seen before the chorio-capillaris is filled, and the dye appears initially in theinner choroid as small points of fluorescence which

From the Department of Clinical Ophthalmology, Institute ofOphthalmology, London, England.

Supported in part by the Wellcome Trust and by Medical Re-search Council (United Kingdom) grant G8709312 N. JCC is therecipient of a fellowship from the McLaughlin Foundation, Can-ada. DP is the recipient of a fellowship from the Deutsche Fors-chungsgemeinschaft and Wacker Foundation.

Submitted for publication: November 21,1989; accepted August22, 1991.

Reprint requests: A. C. Bird, Professorial Unit, Moorfields EyeHospital, City Road, London, England EC IV 2PD.

gradually enlarge and coalesce over several frames ofthe angiogram.14'16 Continuous fluorescence, indistin-guishable from the surrounding normal fundus, is notapparent until the venous phase of retinal circulation.Its appearance is similar to that seen in experimentalocular hypertension17 and in choroidal ischemia inhumans.18"20 A causal relationship between this angio-graphic sign and the presence of diffuse Bruch's mem-brane deposits has been postulated.1416

During a prospective study of age-related maculardisease, we documented angiographic evidence ofprolonged choroidal filling.16 To establish the poten-tial significance of this clinical sign, visual sensitivitywas measured in eight eyes with this angiographic find-ing and in six eyes with a similar number of drusenbut normal choroidal filling.

Patients and Methods

The patients were derived from the first 100 casesenrolled in a prospective study on age-related maculardegeneration. Of these, 26 had evidence of a delayedand prolonged choroidal filling phase by fluoresceinangiography.16 Eight eyes of eight patients with thisangiographic sign and six eyes of six patients with nochoroidal perfusion abnormality were studied. Alleyes had a visual acuity of 6/12 (20/40) or better anddrusen visible in the posterior ocular fundus. The ap-pearance of the ocular fundus, visual acuity range,and age range were similar in the two groups. Themean visual acuity in the abnormal choroidal perfu-sion group was 6/8 (range, 6/5-6/12); in the normalchoroidal perfusion group, it was 6/7 (range, 6/5-

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No. 2 VISUAL LOSS AND AGE-RELATED MACULAR DISEASE / Chen er ol 335

Table 1. Patient data and summary of results of finematrix mapping

Patient

123456789

1011121314

Sex

MMFMMMFFFFFFFF

Age(years)

7255606061785858586172547267

Visualacuity

6/96/96/96/126/96/66/66/56/66/96/66/66/96/5

Backgroundthreshold

PCFP* (log)

+ 0.4+ 0.5+ 0.9+ 0.1+ 0.5+ 1.5+ 0.5+ 0.8

0.40.60.40.80.80.9

Discreteelevation

(log)

3.41.82.52.52.52.9—2.0——————

• PCFP = prolonged chorodial filling phase.

6/9). In the abnormal choroidal perfusion group, themean patient age was 63 yr (range, 55-78 yr); in thenormal choroidal perfusion group, it was 64 yr (range,54-72 yr; Table 1). There was no evidence of detach-ment of the retinal pigment epithelium, serous retinaldetachment, or subretinal neovascularization in anyeye. The study was supervised by the Hospital Ethicalcommittee, and signed informed consent was ob-tained from each patient before entering the study.

Each patient was dark adapted for 45 min beforescotopic static perimetry was done. Pupil dilatation of6-7 mm was achieved by instilling one drop each ofphenylephrine 10% and cyclopentolate 1%.

The scotopic threshold of the posterior central 30°was measured at 6° intervals using a modified central30-2 program of the Humphrey automated perimeter(Allergan Humphrey, San Leandro, CA).21 With thebackground illumination turned off, the size V stimu-

lus was presented after passing it through theHumphrey blue filter (OCLI [Edinburgh, UK]dichroic long wavelength cutoff filter, 50% transmit-tance at 506 nm) mounted on a separate filter wheelwith a 1.2 log unit neutral-density filter. An infraredsource illuminated the bowl and an infrared CCDcamera (Philips, Eivhoven, Holland) was used tomonitor eye movements.

A more detailed study of scotopic retinal functionwas done using fine matrix mapping.22-23 This tech-nique employs a television screen to present flashes ofblue stimuli under scotopic conditions. The size of thestimulus, distance between subjacent stimuli, and sizeof the field tested are controlled by entering the de-sired parameters into the computer. A red light-emit-ting diode attached to the television screen for fixa-tion can be moved, depending on the retinal area ofinterest. For our purposes, retinal sensitivity wastested at 100 positions on a 10 X 10 square matrixover a 20° X 20° test field, and stimuli were presentedat 2° intervals with each stimulus subtending 10 minof arc. Subsequent processing of the data produced athree-dimensional representation of rod thresholds:the higher the elevation from baseline, the greater theloss of function compared with established normalvalues. The sensitivities were compared with themean scotopic threshold of normal volunteers aged30-42 yr.

To compare the sensitivity losses with the areas ofdelayed choroidal perfusion seen on the angiogram, aphotographic print of the fluorescein angiogram wasdigitized at 256 X 256 X 8 bit resolution using a pho-ton CCD camera (EEV, Chelmsford, UK), a HawkV10 frame grabber board (Wild Vision, UK), and anArchimedes 440 RISC computer with ARM 3 proces-sor (Acorn, Cambridge, UK). The area where the mea-surements of scotopic function were made was super-

Fig. 1. Fine matrix perimetryin a patient with drusen but nor-mal choroidal filling showing abackground threshold elevationof 1.0 log units (10 dB), but nomajor discrete threshold eleva-tion. The small elevation of 0.2log units (2 dB) close to fixation isoften seen in normal individuals,and is thought to be due to lutealpigment and the reduced numberof rod photoreceptors at the fo-vea.


I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I < I I I I I I

i i i i i i i i i i i i ' i i i i

i—| i i i i i i i i i | i | i i—i i I ' I ' I ' I ' I i I i I i I ii i i i i i i i ii i [ i i i I i .1 .i ,1—i

i i i i i i i [—i—[—i i—i—i—i I-1—I—l—|—l—I—I—| I I I—I—I

Fig. 2. Montage of two-dimen-sional plots of sensitivity profiles re-corded by fine matrix mapping.(A-H) are derived from patients1-8, respectively, with a prolongedchoroidal filling phase, and (I-N)from patients 9-14 with normal fill-ing (Table 1). Contour steps: 0.1 logunit.



imposed on a corresponding 10 X 10 matrix grid onthe fluorescein angiogram image where this fell in thecircular aperture outline of the photograph. Eachsquare of this matrix consisted of 17 X 17 pixels onthe fluorescein angiogram image. The mean of 289pixels was taken and used for comparison with thesensitivity measurements from the correspondingsquare of the fine matrix grid.

Results

Using the modified Humphrey automated static pe-rimeter, a discrete area of scotopic threshold elevationof more than 1.0 log unit (10 dB) above normal wasdetected in six of eight eyes with a prolonged choroi-dal filling phase but in none of 6 eyes with drusenalone. These areas of abnormal threshold elevation in(1) eyes with choroidal filling abnormality and (2) sus-picious areas of threshold elevation less than 1.0 logunit in other eyes then were selected for fine matrixperimetry testing.

On fine matrix mapping, eyes with normal choroi-dal filling had a mean scotopic threshold above nor-mal of 0.7 log units (7 dB; range, 0.4-1.2 log units or4-12 dB). Beyond 5° from fixation, no discrete areaof increased threshold above background levels wasfound (Table 1, Fig. 1)

Eyes with choroidal perfusion abnormality showeda mean background threshold above normal of 1.0 logunit (10 dB, Table 1). In addition, seven of these eighteyes also had discrete areas of scotopic threshold ele-vation above normal of 1.8 (18 dB) to more than 3.4log units (34 dB, Fig. 2). The area of depressed sensitiv-ity corresponded with the area of slow choroidal fill-ing, and there was a quantitative correlation betweenthe intensity of fluorescence during transit and thresh-old (Figs. 3, 4). One eye with minimal drusen and theangiographic sign of poor choroidal perfusion did nothave an area of discrete threshold elevation.

Discussion

Although the number of patients involved in thisstudy was small, our results strongly suggest that eyeswith the angiographic sign of slow choroidal fillinghave a higher threshold than eyes with normal choroi-dal filling. Furthermore, areas of angiographic abnor-mality corresponded well with areas of discrete thresh-old elevation. Departure from perfect registry wouldbe expected, given the imprecise quantitative natureof photographic recording of fluorescence. These find-ings support the proposal that this angiographic signhas significance in age-related macular disease.

Dark-adapted threshold elevation in the maculararea in eyes with age-related macular disease has beendocumented by others.2425 However, no correlation

Fig. 3. Patient 1 had a disciform lesion in the right eye with avisual acuity of counting fingers at 2 feet. With the left eye thepatient experienced symptoms of easy fatigability on prolongedreading or TV watching but a visual acuity of 6/9. Few drusen wereseen by ophthalmoscopy. Fluorescein angiography shows signs ofdelayed choroidal filling (A), and an area of threshold elevation ofgreater than 3.4 log units (34 dB) is demonstrated near the fovea byfine matrix perimetry surface plot (B). The threshold plot has beenrotated so that it corresponds with the fundus, and lines "A" and"B" on the fundus photography correspond with those on thresholdplot.

between the sensitivity and the number of drusen wasfound, and the threshold elevation over areas withand without drusen was similar. On the basis of thesefindings, it was concluded that more diffuse pigmentepithelial or retinal dysfunction must be present otherthan that caused by drusen.

No established pathogenetic concepts are readilyavailable to explain either the changes in choroidalfluorescence or the functional loss. Diminution of the


338 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1992 Vol. 33

l1.0 2.0 3*0 4*0 3.0 6*0 1.0 8.0 9.0 10.0

Grayscale - • - Sensitivity

3 4 5 6 7 B 9

Retinal Location10

Greyscale —©— Sensitivity

2 3 4 5 6 7 8

Retinal Location10

Fig. 4. Patient 3 had delayed choroidal filling on fluorescein angiogram (A), and static perimetry demonstrated discrete threshold elevationof up to 1.8 log units (18 dB) (B). The threshold plot has been rotated so that it corresponds with the fundus photograph. The area of discretethreshold elevation as shown on a contour plot (C) corresponds closely to the area of choroidal perfusion abnormality (D). There is topographiccorrelation between the intensity of fluorescence and the thresholds (E, F). The two horizontal cuts illustrated correspond to lines 2 and 4 onthe fine matrix plots in (C) and (D).

choroidal capillary bed with age has been shown bystructural studies, but the absence of change in thearteries make it unlikely that it is caused by arterial

obstruction or systemic hypertension.26"28 It is doubt-ful that capillary changes result from physical displace-ment by the debris because the same angiographic phe-



nomenon occurs in Sorsby's fundus dystrophy14 inwhich the deposits are internal to the inner collage-nous layer of Bruch's membrane.15 Furthermore, ob-servations on acute and chronic choroidal ischemiamake it unlikely that there would be significant reti-nal dysfunction as a consequence of the observed per-fusion abnormality.1929-30

It has been suggested that a continuous layer of de-bris in Bruch's membrane may act as a barrier to meta-bolic exchange between the retinal pigment epithe-lium and the choroidal capillaries.1416 If this is true, itmight explain both the angiographic and psychophy-sical findings observed in this and other studies. Thereis circumstantial evidence that the behavior charac-teristics of the choriocapillaris are determined by theretinal pigment epithelium,3132 and it has been pro-posed that diffusible agents from the pigment epithe-lium modulate the choroidal vasculature.33 Based onthese hypotheses, it was proposed that a barrier todiffusion at the level of Bruch's membrane would re-sult in changes in the choroidal capillaries.1416

Normal photoreceptor function depends on thefree diffusion through Bruch's membrane of large-molecule complexes as they pass from the chorioca-pillaris to the pigment epithelium.34 Predictably, suchmolecules would not pass freely through a continuouslayer of debris. This has been suggested as a mecha-nism for the changes in proteoglycans in the interfibermatrix of Bruch's membrane.35 However, the debrisdeposited into Bruch's membrane by the retinal pig-ment epithelium is likely to be a more important de-terminant of conductivity. The magnitude of changewould depend on the thickness and chemical compo-sition of Bruch's membrane, and the disturbancewould be particularly marked in the presence of alarge quantity of lipids.36

Visual acuity and fundus appearance were identicalin patients with and without abnormal choroidal per-fusion; neither clinical attribute segregated these twopopulations. Although there are no simple clinicalclues to identify those patients with loss of scotopicsensitivity, functional correlates were evident to thepatients. They reported the need for increased lightintensity for reading, fading vision after a few minutesin bright light, slow recovery of vision after exposureto bright light, and easy fatiguability when doing closework.

To determine the significance of these findings tothe long-term outcome of age-related macular dis-ease, a number of patients would have to be reviewedlongitudinally. By stratifying patients according tocharacteristics of their drusen and fluorescein angio-graphic evidence of prolonged choroidal filling phase,a better index of Bruch's membrane disease might be

obtained, and better predictor of visual function andprognosis might be achieved.

Key words: age-related macular degeneration, scotopic reti-nal sensitivity, choroidal perfusion, Bruch's membrane,drusen

References1. Gass JDM: Pathogenesis of disciform detachment of the neuro-

epithelium: 3. Senile disciform macular degeneration. Am JOphthalmol 63:617, 1967.

2. Hogan MJ and Alvarado J: Studies on the human macula: IV.Aging changes in Bruch's membrane. Arch Ophthalmol77:410, 1967.

3. Hogan MJ: Role of the pigment epithelium in macular disease.Trans Am Acad Ophthalmol Otolaryngol 7:4, 1972.

4. Gass JDM: Drusen and disciform macular detachment anddegeneration. Arch Ophthalmol 90:206, 1973.

5. Sarks SH: Ageing and degeneration in the macular region: Aclinico-pathological study. Br J Ophthalmol 60:324, 1976.

6. Green WR and Key SN: Senile macular degeneration: A histo-pathological study. Trans Am Ophthalmol Soc 75:180, 1977.

7. Grindle CMJ and Marshall J: Ageing changes in Bruch's mem-brane and their functional implications. Trans OphthalmolSoc UK 98:172, 1978.

8. Burns RP and Feeney-Burns L: Clinico-morphological correla-tions of drusen and Bruch's membrane. Trans Am OphthalmolSoc 78:206, 1980.

9. Feeney-Burns L and Ellersieck M: Age related changes in theultrastructure of Bruch's membrane. Am J Ophthalmol100:686, 1985.

10. Bressler NM, Bressler SB, Jacobson L, Gragoudas ES, and Sed-don JM: Clinical characteristics of drusen in patients with exu-dative versus non-exudative age-related macular lesions. Ret-ina 8:109, 1988.

11. Chuang EL and Bird AC: The pathogenesis of retinal pigmentepithelial tears. Am J Ophthalmol 105:285, 1988.

12. Pauleikhoff D, Barondes MJ, Minassian D, Chisholm IH, andBird AC: Drusen as risk factors in age related macular disease.Am J Ophthalmol 109:38, 1990.

13. Scheoppner G, Chuang EL, and Bird AC: Retinal pigment epi-thelial tears: Risk to the second eye. Am J Ophthalmol108:683, 1989.

14. Polkinghorne PJ, Capon MR, Berninger TA, Lyness AL,Sehmi K, and Bird AC: Sorsby's fundus dystrophy: A clinicalstudy. Ophthalmology 96:1763, 1989.

15. Capon MRC, Marshall J, Kraft JI, Alexander RA, Hiscott PS,and Bird AC: Sorsby's fundus dystrophy: A light and electronmicroscopic study. Ophthalmology 96:769, 1989.

16. PauleikhoffD, Chen JC, Chisholm IH, and Bird AC: Choroidalperfusion abnormality in age related macular disease. Am JOphthalmol 109:171, 1990.

17. Dollery CT, Henkind P, Kohner EM, and Paterson JW: Effectof raised intraocular pressure on the retinal and choroidal cir-culation. Invest Ophthalmol 7:191, 1968.

18. Foulds WS, Lee WR, and Taylor WOG: Clinical and pathologi-cal aspects of choroidal ischaemia. Trans Ophthalmol Soc UK91:325, 1971.

19. Van Buskirk EM, Lessell S, and Friedman E: Pigment epithe-liopathy and erythema nodosum. Arch Ophthalmol 85:369,1971.

20. Gaudric A, Coscas G, and Bird AC: Choroidal ischemia. Am JOphthalmol 94:489, 1982.


340 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1992 Vol. 33

21. Jacobson SG, Voight WJ, Parel J-M, Apathy PP, Nghiem-PhuL, Meyers SW, and Patella VM: Automated light- and dark-adapted perimetry for evaluating retinitis pigmentosa. Ophthal-mology 93:1604, 1986.

22. Fitzke FW: Spatial properties of scotopic sensitivity. PhD the-sis, University of London, London, UK, 1985.

23. Chuang EL, Sharp DM, Fitzke FW, Kemp CM, Holden AL,and Bird AC: Retinal dysfunction in central serous retinopa-thy. Eye 1:120, 1987.

24. Sunness JS, Massof RW, Johnson MA, Finkelstein D, and FineSL: Peripheral retinal function in age-related macular degener-ation. Arch Ophthalmol 103:811, 1985.

25. Sunness JS, Johnson MA, Massof RW, and Marcus S: Retinalsensitivity over drusen and nondrusen areas: A study usingfundus perimetry. Arch Ophthalmol 106:1081, 1988.

26. Meves H: Die pathologisch-anatomischen gefassveranderun-gen des auges bie der beningen und malingen nephrosklerose.Graefes Arch Clin Exp Ophthalmol 168:287, 1948.

27. Friedman E, Smith TR, and Kuwabara T: Senile choroidalvascular patterns and drusen. Arch Ophthalmol 69:220, 1963.

28. Friedman E, Smith TR, Kuwabara T, and Beyer CK: Choroi-dal vascular patterns in hypertension. Arch Ophthalmol71:842, 1964.

29. Sarks SH: Changes in the region of the choriocapillaris in age-ing and degeneration, In XXIII International Concilium, Shi-mizu K and Oosterhuis JA, editors. Amsterdam, Exerpta Me-dica, 1979, p. 228.

30. Tso MOM and Bettman JW: Occlusion of the choriocapillarisin non-familial amyloidosis. Arch Ophthalmol 86:281, 1971.

31. Henkind P and Gartner S: The relationship between retinalpigment epithelium and the choriocapillaris. Trans Ophthal-mol Soc UK 103;444, 1983.

32. Korte GE, Repucci V, and Henkind P: RPE destruction causeschoriocapillary atrophy. Invest Ophthalmol Vis Sci 25:1135,1984.

33. Glaser BM, Campochiaro PA, Davies JL, and Sato M: Retinalpigment epithelial cells release an inhibitor of neovasculariza-tion. Arch Ophthalmol 103:1870, 1985.

34. Bok D: Retinal photoreceptor-pigment epithelium interac-tions. Invest Ophthalmol Vis Sci 26:169, 1985.

35. Hewitt TA, Nakazawa K, and Newsome DA: Analysis of newlysynthesized Bruch's membrane proteoglycans. Invest Ophthal-mol Vis Sci 30:478, 1989.

36. Pauleikhoff D, Marshall J, and Bird AC: Histochemical andmorphological correlation of aging changes in Bruch's mem-brane. Ophthalmology 97:171, 1990.


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