Contrast Sensitivity Loss Is Coupled With Capillary Dropout in Patients With Diabetes

Transcription

1 Contrast Senstvty Loss Is Coupled Wth Capllary Dropout n Patents Wth Dabetes Olver Arend* Andreas Remky* Davd Evans~\ Renhard Stber* and Alon Harrs"\X Purpose To assess the relatonshp of foveal mcrocrculaton to contrast senstvty functon n early dabetes melltus Methods Twenty patents wth dabetes wth vsual acuty of 2/25 or better wthout clncally sgnfcant macular edema were evaluated Measurements of contrast senstvty at four spatal frequences (3 6 2 and 8 cycles/degree [c/deg]) macular capllary blood velocty (CBV) capllary densty (PIA: perfoveal ntercapllary area) foveal avascular zone (FAZ) and mcroaneurysm count were performed Contrast senstvty data collected from agematched normal subjects and prevously publshed normal angographc data were used for comparson wth our cohort wth dabetes Results The CBV was sgnfcantly reduced (P < ) and PIA and FAZ were sgnfcantly enlarged (P < ) when compared wth healthy subjects Contrast senstvty was sgnfcantly lower n the group wth dabetes at 6 (P= ) and 2 (P 2) c/deg as compared wth healthy control values FAZ and PIA correlated sgnfcantly (FAZ; r = 6 P = 5; PIA; r = 54 P = 2) wth contrast senstvty at 2 c/deg Conclusons The alteratons of the perfoveal network are related to selectve dsturbances of central vsual functon as measured by contrast senstvty In patents wth dabetes measurement of contrast senstvty may provde a clncal adjunct n further dentfyng early schemc dabetc maculopathy Invest Ophthalmol Vs Sc 997;38:89824 A o understand defne and treat schemc dabetc maculopathy further clncal tools have to be developed for early dentfcaton of progressve schemc damage For example treatment of macular edema wth focal photocoagulaton s less effectve f the procedure s performed after macular capllary nonperfuson occurs Although fluorescen angography s effectve for detecton and quantfcaton of early macular capllary changes these changes are not reflected n vsual acuty loss untl the dsease s well progressed 2 3 Data show that patents wth dabetes wth normal vsual acuty (2/25 or better) exhbt abnormally enlarged foveal avascular zone (FAZ) compared wth healthy subjects 4 A vsual functon measurement From the * Department of Ophthalmology Medcal School of the Techncal Unversty of Aachen Aachen Germany and the Departments of\ Ophthalmology and % Physology Indana Unversty School of Medcne Indanapols Indana Supported by the Deutsche Forschungsgemenschaft Re 5225/ &2 and supported n part by Natonal Insttutes of Health grant EY8 and by Research to Prevent Blndness Submtted for publcaton December 2 996; revsed March 3 997; accepted March Propretary nterest category: N (OA AR AH); IC (DE) Reprnt requests: Olver Arend Department of Ophthalmology Medcal School of the Techncal Unversty of Aachen Pauwelsstrasse 3 Aachen 5257 Germany that reflected early changes n retnal crculaton would potentally be useful for quantfyng dsease progresson Contrast senstvty has been wdely studed n dabetc eye dsease and the dssocaton of vsual acuty and contrast senstvty n patents wth dabetes wth normal vsual acuty s well establshed 5 6 A recent report noted that patents wth dabetes wth normal vsual acuty but depressed contrast senstvty exhbted an acute recovery of contrast senstvty to normal levels whle breathng pure oxygen suggestng an assocaton between contrast senstvty and retnal tssue schema 7 The purpose of ths study was to determne n patents wth dabetes wth normal vsual acuty and wthout clncally sgnfcant macular edema the assocaton f any between retnal mcrocrculaton and contrast senstvty MATERIALS AND METHODS Scannng laser vdeo fluorescen angograms (SLO Rodenstock Insttute Ottobrunn Germany) com Investgatve Ophthalmology & Vsual Scence August 997 Vol 38 No 9 Copyrght Assocaton for Research n Vson and Ophthalmology 89 Downloaded From: on 2/24/28

2 82 Investgatve Ophthalmology & Vsual Scence August 997 Vol 38 No 9 TABLE l Clncal and Demographc Data for the Patents Wth Dabetes Melltus Number (male/female) Age (years) Systolc blood pressure (mm Hg) Dastolc blood pressure (mm Hg) Hb Ale (%) Duraton of dabetes (years) Values are mean ± SD Study Group 2 (4/6) 42 ± 2 33 ± 2 8 ± 8 76 ± 5 3 ± 9 bned wth an mage analyss system (IBAS Kontron Munch Germany) 8 allow the evaluaton of mean capllary blood velocty (CBV) the perfoveal ntercapllary area (PIA) the foveal avascular zone (FAZ) 4 and mcroaneurysm counts The CBV was measured by observng the transt of hypofluorescent fronts through the perfoveal vasculature (rouleaux formatons of red blood cells) 9 PIA provdes an estmate of capllary densty n the network around the FAZ (5 ) The perfoveal ntercapllary areas were marked by nteractvely drawng around the surroundng capllares wth the cursor n the dgtal mage The area descrbed by the cursor was calculated wth the pcture analyzng system One hundred randomly selected areas surrounded by capllares were marked n the 5 area of nterest and the mean area was calculated from these measurements for each patent Coeffcents of varaton calculated among the subjects characterze the homogenety of CBV (cv[cbv]) and PIA (cv[piaj) presented n ths study In addton to these parameters the number of mcroaneurysms was counted Ths approach has shown a good correlaton wth stage of retnopathy In modfcaton of exstng methods a crcle was centered over the FAZ Ths area of nterest was chosen because of the possblty that the number of mcroaneurysms mght reflect the severty of dabetc maculopathy In a standardzed fashon only hyperfluorescent dots wth a dameter of 2 //m or greater were consdered as beng mcroaneurysm formatons All angogram analyses were performed n a masked fashon wthout pror knowledge of vsual acuty or contrast senstvty results Patents Prospectvely 2 patents wth dabetes melltus and vsual acuty of 2/25 or better were recruted for ths study The clncal and demographc data of the patent group wth dabetes are presented n Table Informed consent was obtaned from each subject ncludng detaled explanatons of all procedures before partcpaton n ths study The study protocol was approved by the human study nsttutonal board of the techncal unversty of Aachen and followed the tenets of the Declaraton of Helsnk Slt lamp examnaton of the anteror segment was normal n all subjects The fundus photographs of all patents wth dabetes were classfed as havng no clncally sgnfcant macular edema accordng to Early Treatment Dabetc Retnopathy Study Group (ETDRS) gudelnes In all patents no cystod edema whch s easly detectable by scannng laser angograms 2 was present and revew of the latephase angograms revealed no presence of vascular leakage Retnopathy level was estmated by means of fundus photography accordng to ETDRS crtera 3 The patent group conssted of 6 patents (3%) havng no retnopathy (level ) 8 patents (4%) wth mcroaneurysm formaton only (level 2) 4 patents wth mld retnopathy (level 35) one wth severe nonprolferatve (level 53) and another wth prolferatve (level 6) dabetc retnopathy Reference values for comparson of the angographc measures were taken from prevous studes 4 and derved from healthy subjects of smlar age (47 ± years) An age and sexmatched group of 2 healthy control subjects (age 47 ± years) wth no evdence or hstory of any ocular or systemc dsease was examned to compare the results of contrast senstvty Best corrected vsual acuty was determned by an ophthalmologst usng objectve refractometry (Rodenstock Germany) the lghtng condtons and standardzed charts as descrbed by DIN followed by a complete ophthalmologc examnaton Best corrected contrast senstvty was assessed by an ophthalmologst wth the CSV (Vector Vson; Dayton OH) contrast senstvty testng nstrument For the calculatons n ths study contrast was defned by the followng: contrast = Lwmn ancenax 4 where Lumnance max s the hghest lumnance of the snusodal lumnance gradent and Lumnance mn s the lowest lumnance of the snusodal lumnance gradent 5 The CSV nstrument has recently been demonstrated to have adequate test relablty compared to treatmentrelated changes of ocular dsease 6 The nstrument provdes a retrollumnated translucent chart at a standardzed lght level of 85 cd/m 2 Four spatal frequences (3 6 2 and 8 cycles/degree [c/ deg]) were tested usng an orentatonfree twoalternatve quasforced choce procedure The patents eyes then underwent subsequent SLO fluorescen angographc studes Because the patents refractve er Downloaded From: on 2/24/28

3 Contrast Senstvty and Macular Mcrocrculaton 82 TABLE 2 Hemodynamc Values for the Healthy Reference Group 4 and the Group Wth Dabetes CBV cv(cbv) Number (mm/second) (%) Healthy subjects ± 25 2 ± 5 Group wth dabetes 2 78 ± 2 6 ± 4 P* < < * Unpared Students Mest Values are mean ± SD CBV = mean capllary velocty; cv (CBV) = mean coeffcent of varaton of capllary blood velocty rors affect the dmensons of the dynamc and morphologc measurements all data were corrected for the refractve error 7 8 Statstcal Analyss Mean value and standard devaton are gven for all samples wth normal dstrbuton (KolmogorovSmrnov test) and nonnormal dstrbuton medan and percentles (25% and 97%) The unpared Students t test was used to assess the sgnfcance of the dfferences between groups Fndngs less than 5 were consdered to be statstcally sgnfcant Pearson correlaton coeffcents were calculated to evaluate the relatonshp between the parameters P values were obtaned after performng Fshers r to z transformatons For statstcal analyss of vsual acuty the logarthmc mnmal arc of resoluton (log MAR) values were used and for contrast senstvty /contrast threshold was used RESULTS Compared to the reference normal populaton 4 the patents wth dabetes dsplayed sgnfcantly reduced CBV (P < ) (Table 2) sgnfcantly enlarged more than doubled PIA (P < ) (Table 3) and sgnfcantly enlarged FAZ (P < ) The coeffcents of varaton for CBV (cv[cbv] P = 8) and PIA (cv[pia] P < ) were also sgnfcandy greater n the populaton wth dabetes compared wth the normal reference populaton 4 ndcatng n Spatal Frequency (c/deg) Q healthy subjects & dabetc subjects FIGURE Contrast senstvty functon of the patents wth dabetes (squares) and the matched healthy control group (crcles) creased nhomogenety of perfoveal hemodynamcs and vascularty The number of mcroaneurysms ranged from to 8 n the patent group wth dabetes but ths count faled to correlate wth CBV PIA or FAZ Average statc contrast senstvty and standard devatons of patents wth dabetes (3 c/deg 64 ± 2; 6 c/deg 84 ± 4; 2 c/deg 45 ± 24; 8 c/deg 7 ± 2) and agematched healthy controls (3 c/deg 68 ± 4; 6 c/deg 96 ± 4; 2 c/ deg 67 ± 5; 8 c/deg 7 ± 5) are shown n Fgure Comparng the subjects wth dabetes wth agematched healthy controls contrast senstvty was decreased sgnfcantly at spatal frequences of 6 and 2 c/deg (6 c/deg P = ; 2 c/deg P = 2) Contrast senstvty at 2 c/deg was sgnfcantly correlated wth PIA (P = 6 r = 54) the coeffcent of varaton cv(pia) (P = 4 r = 46) and FAZ (P = 5 r = 6) ndcatng decreased contrast senstvty wth ncreased sze of PIA and FAZ and ncreased nhomogenety of PIA as expressed by cv(pia) Fgures 2 and 3 show the scatterplots wth regresson lnes of contrast senstvty at 2 c/deg wth PIA and FAZ Although abnormal CBV and mcroaneurysm count were sgnfcantly assocated wth the patents wth dabetes nether of these measures correlated sgnfcandy wth reduced contrast senstvty at any spatal frequency tested Fgures 4 and 5 show the fluorescen angograms TABLE 3 Morphologc Parameters for Group Wth Dabetes and Healthy Reference Groups Number PIA (xm 2 ) cv(pia) (%) FAZ (mm 2 ) Healthy subjects 4 Group wth dabetes p* ± ± 2375 < 34 ± 8 64 ± 23 < 25 ± ± 27 < PIA = mean of the perfoveal ntercapllary areas; cv(pia) = mean coeffcent of varaton of PIA; FAZ = foveal avascular zone * Unpared Students Rest Values are mean ± SD Downloaded From: on 2/24/28

4 Investgatve Ophthalmology & Vsual Scence August 997 Vol 38 No I I r= 46 2 u> 8 ^ gf 6 A I«I "2 2H 5 (3 I ** Perfoveal ntercapllary area ( nr) FIGURE 2 Scatterplot wth regresson lne of contrast senstvty at 2 c/deg wth the perfoveal ntercapllary area (PIA) n the patents wth dabetes Wth ncreasng sze of PIA contrast senstvty was sgnfcantly decreased {P = 6; r = 54) of two of the patents studed and ther correspondng contrast senstvty results 24 a dabetc patent P R Healthy subjects mean ±2SD f 8 n S 2H c S H DISCUSSION In ths study we evaluated patents wth dabetes wth no clncally sgnfcant macular edema Despte normal vsual acuty contrast senstvty revealed abnormaltes at spatal frequences of 6 and 2 c/deg The decrease of senstvty was related to a marked ncrease of the perfoveal ntercapllary area and sze of the foveal avascular zone The angographc measures performed n ths study have proven to be of partcular value n detectng early dabetc capllary nonperfuson even be22 JQ *" *o ox senstvt at: tc/d U) o y 2 8" ^ \ 6ODO \^ 4" O^ ^ 2" " 8 8 FIGURES Scatterplot wth regresson lne of con trast senstvty at 2 c/deg wth the foveal avascular zone (FAZ) Wth ncreasng sze of FAZ contrast senstvty was decreased sgnfcantly (P= 5; r = 6) Downloaded From: on 2/24/28 FIGURE 4 (A) Patent The fluorescen angograms of the perfoveal network (OS) of a 5yearold man wth dabetes (duraton ofdabetes year no dabetc retnopathy) wth normal vsual acuty (2/2) The pcture shows early capllary closure wth slghtly ncreased PIA (4752 fjnx*) and normal sze of the FAZ (27 mm2) (B) Contrast senstvty functon of the patent {squares) shown n A n comparson to the matched healthy control populaton (mean ± 2 standard devatons [SD]) There are no sgnfcantly dfferng results at any of the spatal frequences for the patent wth dabetes fore mcroaneurysm formaton occurs 2 The present ^^ Foveal avascular zone Spatal Frequency (c/deg) tat r= 6 B study showed that CBV PIA and FAZ as well as coeffcents of varaton of CBV and PIA were sgnfcantly affected when compared wth healthy subjects although vsual acuty remans normal In a prevous study n patents wth advanced dabetc dsease measures of capllary densty and FAZ are coupled wth decreased vsual acuty In the present study the sgnfcant correlaton of contrast senstvty wth PIA (r = 54) and FAZ (r = 6) ndcates that even n patents wth early dsease and unaffected vsual acuty alteratons n vasculature have an mpact on vsual functon Interestngly macular CBV although affected n early dsease stages2 and mcroaneurysm count had no predctve value for vsual pathway ntegrty

5 Contrast Senstvty and Macular Mcrocrculaton dabetc patent 2 Healthy subjects mean ±2SD 3 22 H < 2 f 8 L6 I" 2 8 IO B Spatal Frequency (c/deg) 8 FIGURE 5 (A) Patent 2 Fluorescen angography of the perfoveal network of a 4yearold man wth dabetes (duraton of dabetes 5 years mld nonprolferatve dabetc retnopathy) wth best corrected vsual acuty of 2/2 Moderate capllary closure around the FAZ resultng n a more than doubled sze of PIA (776 yum2) and normal FAZ sze (286 mm*) were detected (B) Contrast senstvty functon of the patent wth dabetes (squares) shown n A n comparson to the normal reference populaton (mean ± 2 SD) Decreased senstvty at 2 c/deg n the patent wth dabetes s demonstrated Frsen9 found that vsual acuty remans unaffected untl about 55% of all neuroretnal channels are affected Vsual acuty does not possess suffcent senstvty to provde clncal nformaton as to the mpact of altered retnal functon n early stages of dabetc eye dsease2 Others have shown that contrast senstvty and vsual acuty are dsassocated n early dsease and specfcally that contrast senstvty s sgnfcantly reduced n patents wth normal vsual acuty726 Our results showed that contrast senstvty and not vsual acuty correlates to angographc measures suggestng that contrast senstvty s a more senstve ndcator of early vsual mparment secondary to alteratons n retnal vasculature The decrease n contrast senstvty at spatal fre Downloaded From: on 2/24/28 quency of 2 c/deg related to lower capllary densty (expressed by ncreased PIA) s of partcular nterest Sokol et al6 found that the largest loss n contrast senstvty n the populaton wth dabetes tested occurred at 4 c/deg Harrs et al7 found sgnfcant dfferences n contrast senstvty at 2 and 8 c/deg between normal controls and patents wth no or early dabetc retnopathy Isocapnc hyperoxa7 mproved contrast senstvty sgnfcantly only at 2 c/deg n the patents wth dabetes suggestng that tssue hypoxa ntates both vsual and vascular dysfuncton n dabetc angopathy Whether ths result suggests a drect lnk between tssue schema and selectve contrast loss at hgh spatal frequency remans unclear Ischemc or hypoxc mechansms may have njured other spatal frequency contrast senstvty mechansms but perhaps not permanently or not to a suffcent degree such that senstvty could be mproved wth acute hyperoxc perturbaton The correlaton of capllary dropout and senstvty leads to the queston about the ste of damage Consderng the blevel capllary arrangement model2 of the retna capllares n the foveal avascular arcade are localzed as a sngle strata wthn the ganglonc layer Wth further eccentrcty capllary planes are localzed ether wthn the nerve fber layer/ganglonc layer or wthn the nner nuclear layer Usng the scannng laser technology2223 wth a confocal mode lttle depth resoluton (less than 3 //m) s possble Capllary densty measurements represent the monolayer at the edge of the FAZ and n de nerve fber and ganglonc layers Capllares of the nner nuclear layer most lkely are not reflected n ths measurement Therefore capllary densty measurement represents predomnantly the nnermost retnal capllary plexus vasculature that would have a sgnfcant nfluence on the ganglon cell (parvocellular and magnocellular) components The magnocellular and parvocellular ganglon cells are characterzed by dfferent morphology and functonalty24 Specfcally the parvocellular system shows hgher spatal resoluton and s largely responsble for chromatc processng Clncal studes have shown the exstence of early color vson defects before dabetc retnopathy occurs2526 Ths fndng n combnaton wth hgh spatal frequency loss of contrast senstvty67 ponts n the drecton of an early nvolvement of parvocellular cells or conespecfc alteratons n dabetc dsease course It s unknown what level of vascular abnormalty s requred to result n an schemc dabetc maculopathy Ths however s of partcular nterest n the decson to perform focal laser coagulaton Tcho et al have shown that patents wth macular capllary nonperfuson do not beneft from macular laser coagulaton Fluorescen angography provdes the mostsens

6 824 Investgatve Ophthalmology & Vsual Scence August 997 Vol 38 No 9 tve and objectve detecton crtera for early capllary loss However ths procedure s nvasve Contrast senstvty evaluaton may add strength to exstng clncal crtera for evaluatng dsease progresson n early dabetc schemc maculopathy Analyss of a loss at 2 c/ deg may prove to be a useful screenng crteron to select those patents who may requre further angographc study In summary the presence of perfoveal schema s related to a subtle deteroraton of vsual functon as measured by contrast senstvty In patents wthout clncally sgnfcant macular edema and normal vsual acuty contrast senstvty could be a clncal adjunct n further dentfyng early schemc dabetc maculopathy Key Words contrast senstvty dabetc maculopathy fluorescen angography retnal schema scannng laser ophthalmoscope References Tcho U Patz A The role of perfuson n the management of dabetc macular edema Am J Ophthalmol 973; 76: Arend O Wolf S Jung F et al Retnal mcrocrculaton n patents wth dabetes melltus: dynamc and morphologc analyss of perfoveal capllary network BrJ Ophthalmol 99; 75: Bresnck GH Condt R Syrjala S Palta M Groo A Korth K Abnormaltes of the foveal avascular zone n dabetc retnopathy Arch Ophthalmol 984; 2: Arend O Wolf S Harrs A Rem M The relatonshp of macular mcrocrculaton to vsual acuty n dabetc patents Arch Ophthalmol 995;75:664 5 Hyvarnen L Flower W Contrast senstvty n evaluaton of vsual mparment due to dabetes Ada Ophthalmol 98; 6:94 6 Sokol S Moskowtz A Skarf B Evans R Molch M Senor B Contrast senstvty n dabetcs wth and wthout background retnopathy Arch Ophthalmol 985; 3:554 7 Harrs A Arend O Dans RP Evans D Wolf S Rem M Hyperoxa mproves contrast senstvty n early dabetc retnopathy BrJ Ophthalmol 996;8: Wolf S Toonen H Arend O et al Zur Quantfzerung der retnalen Kapllardurchblutung mthlfe des ScannngLaserOpthalmoskops Bomed Tech 99; 35:334 9 Arend O Harrs A Wolf S Capllary bloodflowvelocty measurements n cystod macular edema wth the scannng laser ophthalmoscope Am J Ophthalmol 994; 7:8982 Kohner EM Sleghtholm M Does mcroaneurysm count reflect severty of early dabetc retnopady? Ophthalmology 986;93: Early Treatment Dabetc Retnopathy Study Research Group Photocoagulaton for dabetc macular edema Early treatment dabetc retnopathy study report no Arch Ophthalmol 985; 3: Arend O Remky A Esner AE Bertram B Rem M Wolf S Quantfcaton Of cystod changes n dabetc maculopathy Invest Ophthalmol Vs Sc 995; 36: Early Treatment Dabetc Retnopathy Study Research Group Fundus photographc rsk factors for progresson of dabetc retnopathy Early treatment dabetc retnopathy study report no 2 Ophthalmology Suppl 99;98: NormenausschuB Fenmechank und Optk DIN 5822 (97499) Bl 3 (974) Sehscharfenbestmmung Tel (988) Normsehzechen Tel 2 (989) AnschluB von Sehzechen Tel 3 (99) Prufung fur Gutachten Tel 4 (98) Nahvsusbestmmung Tel 5 (986) Allgemene Sehtestung Tel 6 (988) StraBenverkehrsbezogener Sehtest In: Dtsch Insttut fur Normung e V Beuth 99 5 Rassow B Zur Bestmmung der Kontrastempfndlchket Kln Mbl Augenhelk 988; 93: Pomerance G Evans D Test/retest relablty of the CSV contrast test and ts relatonshp to glaucoma therapy Invest Ophthalmol Vs Sc 994; 35: Bennett AG Rudncka AR Edgar DF Improvements on Lttmanns method of determnng the sze of retnal features by fundus photography Graefes Arch Cln Exp Ophthalmol 994; 232: Lttmann H Zur Bestmmung der wahren GroBe enes Objektes auf dem Hntergrund enes lebenden Auges Kln Mbl Augenhelk 988; 92: Frsen FM A smple relatonshp between the probablty dstrbuton of vsual acuty and the densty of retnal output channels Ada Ophthalmol 976; 54: Regan D Nema D Lowcontrast letter charts n early dabetc retnopathy ocular hypertenson glaucoma and Parknsons dsease BrJ Ophthalmol 984; 68: Sgelman J Ozancs V Retna In: Tasman W Jaeger EA eds Duanes Foundaton of Clncal Ophthalmology Phladelpha: Lppncott; 99:66 22 Plesch A Klngbel U Blle J Dgtal laser scannng fundus camera Appl Opt 987; 26: Webb RH Hughes GW Delor FC Confocal scannng laser ophthalmoscope Appl Opt 987;26: Lvngstone M Hubel D Segregaton of form color movement and depth: anatomy physology and percepton Scence 988; 24: Bresnck GH Condt R Palta M Assocaton of hue dscrmnaton loss and dabetc retnopathy Arch Ophthalmol 985; 3: Green FD Ghafour IM Allan D Barre T Me Clure E Foulds WS Color vson of dabetcs BrJ Ophthalmol 985; 69: Downloaded From: on 2/24/28