vit c dan e tx uveitis anterior

8/2/2019 Vit C Dan E TX Uveitis Anterior

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Oral vitamins C and E as additional treatment inpatients with acute anterior uveitis: a randomiseddouble masked study in 145 patients

Jeroen van Rooij, Sicco G W S thoe Schwartzenberg, Paul G H Mulder, Seerp G Baarsma

Abstract

AimTo investigate the eVect of addi-

tional oral vitamins C and E on acuteanterior uveitis.

MethodsA placebo controlled double

masked study on the eVect of vitamin C500 mg in combination with vitamin E 100mg twice daily in 145 patients with acute

anterior uveitis. As a primary end pointvariable, laser cell/flare measurementswere performed. Best corrected and

stenopeic visual acuity (VA) testing andclinical variable scores were measured.

ResultsLaser flare measurements (ph/s)before treatment were 207.1 (SD 258) inthe vitamin group and 143.6 (156) in theplacebo group. After 3 days corresponding

values were 80.2 (129) and 54.7 (82), after 7days 89.2 (187) (12.5) and 85.8 (208), after14 days 47.1 (109.5) and 40.5 (116) after 28days 23.1 (53.6) and 23.1 (48), and after 56days 15.6 (26) and 15.3 (17). There was nosignificant diVerence in time trend be-tween the two treatment g roups(RMANOVA; p = 0.53). Baseline VA (log-MAR) was 0.106 (0.241) in the vitamingroup and 0.128 (0.456) in the placebogroup. VA after 3 days was 0.236 (0.293)and 0.344 ( 0.489), after 7 days 0.204 (0.292)

and 0.292 (0.479), after 14 days 0.162(0.274) and 0.193 (0.454), after 28 days0.096 (0.232) and 0.158 (0.436), and 0.026(0.213) and 0.106 (0.437) after 56 days.Although no significant diVerence in timetrend was detected, evaluation of the VAdata of the last time point (56 days) bymeans of the MannWhitney test showed asignificantly better VA in the vitamingroup (p = 0.01).ConclusionsThere was no significanteVect of vitamins C and E on laser flaremeasurements. The significant eVect ofthe oral vitamins on visual acuity at 8weeks after start of the oral vitamins C

and E may indicate a protective eVect inpatients with acute anterior uveitis.(Br J Ophthalmol 1999;83:12771282)

Free oxygen radicals have an important role inthe initiation and perpetuation of inflamma-tion associated with experimental uveitis.16

These radicals are generated locally by poly-morphonuclear leucocytes as well as by retinalcells.7 8 Morphological and biochemical inves-tigations indicated that free radicals are gener-ated on sites of uveoretinitis3 4 7 9 and that reti-nal damage associated with experimental

uveitis is initiated by oxygen radicals causingperoxidation of retinal cell membrane lipids.3 10

In the anterior segment of eyes with experi-mental uveitis free radical tissue damage couldbe detected.11

In experimental uveitis, several antioxidantsand scavengers of free radicals were shown toact as anti-inflammatory agents and to protectthe eye from inflammation mediated tissuedamage.1 2 1216 For instance, vitamin E (-tocopherol) diminished inflammation and tis-sue damage associated with both lens andS-antigen induced uveitis in rats.17 18 Vitamin C

(ascorbic acid) has radical scavenging, as wellas antioxidant, properties.19 One function ofthe normally existing high concentration ofascorbic acid in the aqueous humour is inhibi-tion of the activity of polymorphonuclearleucocytes.20 During experimental uveitis andalkali burns, vitamin C concentration in theaqueous diminishes significantly.21 22

The antioxidant and radical scavengingproperties of vitamin E (-tocopherol) are wellestablished, although the limited mobility of-tocopherol in membranes may interfere within vivo activity.23 Vitamin E inhibits both cyclo-oxygenase and lipo-oxygenase activity andconsequently prostaglandin synthesis.18 In ex-

perimental uveitis, high concentrations ofprostaglandin and inhibition of the activeaccumulation of prostaglandins by the anterioruvea were associated with disease activity.21

From the above it follows that additionaltreatment with vitamins E and C may have aneVect on the duration and intensity of uveitisand that the deleterious eVects of radicals onretinal cells may be diminished. There are sev-eral reasons to administer both compoundssimultaneously. Vitamin E is a lipophilic com-pound and is mainly active in structures with ahigh lipid content such as cell membranes orserum lipids. Vitamin C is hydrophilic andtherefore is mainly active in compartments like

blood serum, intracellular and extracellularcompartments. By using a combination of thetwo compounds, both the lipophilic andhydrophilic compartments are reached. Addi-tionally, vitamin C plays a role in regenerationof oxidised vitamin E.24 Toxic reactions to vita-min C and to moderate doses of vitamin E arevery rare.2527

In this study, the potential additional eVectof oral vitamins C and E on inflammation andvisual acuity changes associated with acuteanterior uveitis treated with local steroids and amydriatic were investigated.

Br J Ophthalmol 1999;83:12771282 1277

Eye HospitalRotterdam,Rotterdam,Netherlands

J van RooijS G W S t

SchwartzenbergS G Baarsma

Department ofEpidemiology andBiostatistics, Erasmus

University, Rotterdam,NetherlandsP G H Mulder

Correspondence to:S G Baarsma, Eye HospitalRotterdam, PO Box 70030,3000 LM, Rotterdam,Netherlands

Accepted for publication29 June 1999

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Subjects and methodsAll patients presenting with a first or recurrentepisode of anterior uveitis between May 1994and April 1996 at the first aid department of

the Eye Hospital Rotterdam were asked to par-ticipate. Exclusion criteria were signs of poste-rior uveitis, Fuchss iridocyclitis, retinitis pig-mentosa (as prescription of vitamin E mightbe deleterious to patients with retinitispigmentosa28), severe cataract, corneal graft,stromal opacities, or corneal oedema in the eyeunder study, and patients who already were oncorticoid treatment or any other treatment foruveitis. To prevent adverse eVects of thevitamins administered, patients were not al-lowed to enter the study if they had a history ofa coagulation disorder or regular treatmentwith anticoagulants, severe hypertension (di-astolic pressure > 95 mg Hg despite therapy), ahistory of breast cancer, a history of renalimpairment or kidney stones, haemochromato-sis, polycythaemia, leukaemia, current use ofillegal drugs or excessive alcohol consumption,pregnancy, lactation or inadequate use of con-traception during the trial, or who took anykind of vitamin preparation.

Patient characteristics are presented inTable 1.

The study was submitted to the ethics com-mittee of the Eye Hospital Rotterdam and allsubjects gave written acknowledgment ofinformed consent to participate before thestart of the study.

Immediately after inclusion, all patients weretreated with one drop of prednisolone acetate

1% six times daily in the aVected eye, one dropof scopolamine 0.25% three times daily, and 1cm of prednisolone 0.5% ointment beforesleeping. All local treatment was taperedaccording to clinical resolution.

All patients were randomised to treatmentfor 30 days with either two capsules daily eachof which contained 500 mg of ascorbic acidand100 IUof-tocopherol (vitamin E) or withtwo matching placebo capsules. The vitamin

capsules were manufactured at and distributedby the hospital pharmacy. A randomisationtable prepared by the statistician was sentdirectly to the pharmacy; only the treatmentnumber was visible during the follow up visits.Treatment allocations were kept doublemasked until the last patient completed thestudy.

After inclusion, patients were scheduled tovisit one of the investigators at 3, 7, 14, 28, and56 days after initiation of therapy. On eachvisit, cells and flare were quantified with the aidof a laser cell flare meter (Kowa FC1000). Aslaser flare measurements are an objective,reproducible, and quantitative variable of ante-

rior segment inflammation,

2936

these were con-sidered as the primary end point. Clinical vari-ables such as best corrected visual acuity (VA)and semiquantitative scores according to theHogan-Kimura scale for uveitis37 (that is, pain,photophobia, hyperaemia, keratic precipitates,fibrin, synechiae, cells, flare, and ocular pres-sure) were assessed, as well as the number ofprednisolone and mydriatic drops taken by thepatient.2936

A venous serum sample was taken from eachpatient 12 weeks after start of the therapy. Inthis serum sample the vitamin E concentrationand HLA-B27 status were determined.

From all patients dietary intakes of vitaminC and E were assessed by means of an

extensive interview performed by the hospitaldietician.

STATISTICAL ANALYSIS

Flare and cell measurements were analysedafter log transformation and visual acuity (VA)measurements were transformed to logMARequivalents. A repeated measures analysis ofvariance (RMANOVA) was used to estimate alinear time trend of these variables and to testwhether this time trend diVered between thetwo treatment groups (vitamins and placebo).For flare data, additional analyses were per-formed with vitamin E serum concentrationsas a covariate, and with exclusion of subjects

receiving parabulbar steroid injection(s). Theclinical variables were analysed (also after logtransformation) using a linear random coeY-cients model with time. A RMANOVA wasused to estimate an average time trend acrossall patients and to test whether this time trenddiVered between the two treatment groups.

As the diVerence in VA at the end of thestudy was considered of clinical importanceand a time trend was observed in theRMANOVA, an additional analysis was per-formed. VA data of the separate measuringtime points were compared using the MannWhitney test. Logistic regression analysis was

Table 1 Patient characteristics

Vitamin C/E Placebo

Average age (min, max) 43.7 (18, 75) 44.7 (21, 70)Sex (M/F) 35/33 36/31Concomitant diseases

none 55 51articular 10 13autoimmune* 2 2other 1 1

Race: white/other 57/11 57/10HLA positive 37 45

Bilateral uveitis 5 0Former uveitis episodes:0 26 251 11 122 or more 30 30

Contralateral recurrences0 38 441 7 82 or more 22 15

*In case of autoimmune articular diseases, this was included asarticular disease.Number of recurrences in the treated eye before the episode ofuveitis under study.

Table 2 Average laser cell and flare measurements (SD) for the placebo and vitamintreated groups

Time (days)

Flare (ph/s) (SD) Cells (no/0.075 mm3) (SD)

Vitamin C/E Placebo Vitamin C/E Placebo

0* 207.1 (258) 143.6 (156) 16.2 (18) 15.9 (19)3 80.2 (129) 54.7 (82) 5.7 (8) 9.0 (35)7 89.2 (187) 85.8 (208) 6.0 (10) 5.9 (10)14 47.1 (109.5) 40.5 (116) 2.7 (6) 2.2 (5)28 23.1 (53.6) 23.1 (48) 2.2 (5) 1.8 (4)56 15.6 (26) 15.3 (17) 2.1 (5) 1.9 (5)p value 0.53 0.74

*Time 0 days is the measurement before treatment (baseline value).Repeated measures analysis of variance.

1278 van Rooij, Schwartzenberg, Mulder, et al

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used to test the eVect of the two treatments onVA data; this was followed by the same analysisof the VA data stratified by HLAB27 status.

Statistical analysis was performed with theaid of SPSS PC+ version 5 and module 5V ofBMDP (BMDP Statistical Software Inc, LosAngeles) statistical software.

ResultsA total of 145 patients were included in thestudy. Five patients were excluded because aposterior or granulomatous uveitis developedafter randomisation. Five patients were lost tofollow up; four did not adhere to the study pro-tocol and in one patient cataract flare measure-

ments were not possible.The average daily dietary intake of vitamin Ewas 14.4 (8.6) mg for the vitamin group and12.2 (6.2) mg for the placebo group. For vita-min C dietary intake this was 120.6 (76.6) mgand 124.2 (63.6) mg respectively. Average vita-min E serum concentrations were 36.8 (13.3)mol/l for the vitamin group and 24.0 (13.3)mol/l for the placebo group. In seven patientsof the group treated with vitamin capsules theserum vitamin E concentration was below 23mol/l; in these patients compliance wasdoubted or absorption was not adequate. Asserum vitamin E concentration was used as a

covariate in statistical analysis, these subjectswere not excluded.

No statistically significant diVerences be-tween the two treatment groups were found forany of the semiquantitative clinical variables,nor for the daily number of prednisolone dropstaken (p>0.1 for all time points; 2 test).

Laser flare measurements before treatmentwere 207.1 (258) photons per second (ph/s) inthe vitamin group and 143.6 (156) ph/s in the

placebo group (Fig 1, Table 2). After 3 dayscorresponding values were 80.2 (129) ph/s and54.7 (82) ph/s, after 7 days 89.2 (187) ph/s and85.8 (208) ph/s, after 14 days 47.1 (109.5) ph/sand 40.5 (116) ph/s, after 28 days 23.1 (53.6)ph/s and 23.1 (48) ph/s, and after 56 days 15.6(26) ph/s and 15.3 (17) ph/s. Concerning thelaser flare data, repeated measures analysis ofvariance did not reveal a significant diVerencein time trend between the two treatmentgroups (p = 0.53). No significant diVerenceswere detected in the additional analyses withvitamin E serum concentrations as a covariate(p=0.19), or with exclusion of subjects receiv-ing parabulbar steroid injection (p=0.63).

Comparison of the flare data of the last meas-uring point (56 days) by means of theMannWhitney test did not reveal a significantdiVerence (p = 0.9).

The average number of cells/0.075 mm3 asmeasured by the laser cell flare meter beforetreatment was 16.2 (18) in the vitamin groupand 15.9 (19) in the placebo group (Table 2).After 3 days corresponding values were 5.7 (8)and 9.0 (35), after 7 days 6.0 (10) and 5.9(10), after 14 days 2.7 (6) and 2.2 (5) after 28days 2.2 (5) and 1.8 (4), after 56 days 2.1 (5)ph/s and 1.9 (5). There was no significant dif-ference in time trend between the two treat-ment groups for the laser cell data (p = 0.74);

the same was the case when the data of the lastmeasuring point were compared (p = 0.41).

Baseline visual acuity was 0.106 (0.241) log-MAR in the vitamin group and 0.128 (0.456)logMAR in the placebo group (Fig 2; Table 3)Corresponding Snellen visual acuity data arevisualised in Figure 3. LogMAR visual acuityvalues were 0.236 (0.293) logMAR and 0.344(0.489) logMAR after 3 days, 0.204 (0.292)logMAR and 0.292 (0.479) logMAR after 7days, 0.162 (0.274) logMAR and 0.193(0.454) logMAR after 14 days, 0.096 (0.232)logMAR and 0.158 (0.436) logMAR after 28days, and 0.026 (0.213) logMAR and 0.106(0.437) logMAR after 56 days. No significantdiVerence between the two treatments wasdetected with RMANOVA; however, evalua-tion of the VA data of the last time point (56days) by means of the MannWhitney testshowed a significantly better VA in the vitamingroup (p = 0.013; Table 3). Logistic regressionanalysis on the influence of the type oftreatment (vitamins or placebo) on VA dataalso revealed a significant eVect for the lasttime point (p = 0.021 for 56 days). Thevitamin treatment eVect on VA data was notaltered significantly by HLA-B27 status (pvalue for the eVect of HLA status on VA data:0.67 for 28 days and 0.22 for 56 days).

Figure 1 Average laser flare measu rements for the vitamin (tr iangle; n = 68) and pl acebo(circle; n = 67) treated patients.

300

250

150

200

100

50

056494228 35

Time (days)

Flare(ph/s)

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Figure 2 Average visual acuity in logMAR for the vitamin (tr iangle; n = 68) andplacebo (circle; n = 67) treated patients. *p Value for Mann-Whitne y tes t on delta VA(relative to day 0).

1.00

0.75

0.25

0.50

0.0056494228 35

Time (days)

p < 0.01*

LogMAR

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Vitamins C and E in anterior uveitis 1279

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DiscussionIn this study no significant diVerence betweenoral vitamins C and E and placebo could bedetected regarding the eVect on laser flare andcell measurements. In spite of higher initialflare values in the vitamin treatment group and

faster decline during treatment, the compari-son of the course of flare measurements of thetwo treatment groups over time by means ofRMANOVA did not indicate statistical signifi-cance. The reason for this may be either thatfree radical scavengers do not influence theblood-aqueous barrier in acute anterior uveitisin humans, or that treating all patients withpotent local steroids possibly prevented thedetection of an eVect of the vitamins on vascu-lar leakage. In studies using experimental uvei-tis models, free radical scavengers were dem-onstrated to have an eVect on uveal and retinalinflammation.12 13 17 18 In the only animal studywith assessment of eVects on the anterior

chamber reaction,

16

in contrast with posteriorsegment reactions no eVect on cells or on flarecould be detected.

Although the possibility that a higher vita-min E dosage exerts more eVect cannot beexcluded, it is improbable that the vitamindosages used in this study were insuYcient.The daily dosage of 200 mg of vitamin E asused in this study was demonstrated to beeVective in reducing oxidised serum lowdensity lipoprotein (LDL) cholesterol.38 Afteroral administration to rats, a clear relationexists between dose and total ocular vitamin Econcentrations.17 18 The fact that in several

studies a preventive eVect of vitamin E onretinopathy of prematurity could be detected39

indicates that the bioavailability of this vitaminin the human eye is also proportional (it shouldbe remembered that high vitamin E dosages innewborns can be hazardous). In this study theserum vitamin E concentration was deter-mined in each patient in order to be able toadjust for therapy compliance. The averageplasma vitamin E concentration in the subjects

treated with vitamins (36.8 (13.3) mol/l) iscomparable with plasma concentrations foundin subjects taking 4401320 mg of vitamin E. 40

Concerning vitamin C, in guinea pigs concen-trations of ascorbate in aqueous humour andvitreous were proportional to oral doses41 42

with a plateau being reached at higher doses.42

This, in combination with the probability thatmost of a daily dosage above 200 mg of vitaminC will be excreted by the kidneys,24 suggeststhat a dosage of vitamin C higher than used inthis study will have no additional eVect.

Although baseline visual acuity in bothtreatment groups was similar (Figs 2 and 3),the curve of the vitamin treated patients

consistently describes a better average visualacuity on all time points. For the last measure-ment performed at 2 months after the start ofthe treatments, the diVerence in visual acuitycompared with baseline values was statisticallysignificant (p=0.01). The diVerence betweenthe average end point VA values expressed inSnellen equivalents was 0.16; 0.94 for the vita-min group and 0.78 for the placebo group.RMANOVA analysis did not show a significanttime-treatment interaction; however, a timetrend was detected, which can also be readfrom the curve of the VA data (Figs 2 and 3).For this reason and the clinical significance ofthe diVerence in VA, additional analyses bymeans of MannWhitney tests were performed

at the separate time points, revealing asignificant diVerence at 2 months after start ofthe treatments. This result was confirmed bythe logistic regression analysis of the visualacuity data. At the last measuring point (56days), treatments (including mydriatics anddrops containing preservatives possibly aVect-ing the corneal epithelium) were stopped invirtually all patients, omitting eVects of theseon visual acuity. Additionally, in virtually allpatients disease activity can be expected tohave subsided 2 months after the start of thetreatments, permitting correct comparisons ofVA data at this time point. As the averagecourse of HLAB27 positive anterior uveitis

treated in a similar way as in this study does notextend beyond 1014 days for most patients, 34

results of a longer follow up are not expected tobe very diVerent. We examined the eVect ofHLAB27 (+ or ) status on the vitamin treat-ment eVects exerted on visual acuity data.Logistic regression resulted in a p value of0.22, indicating that there was no eVect ofHLAB27 status on VA data. This means that inour patients HLAB27(+) or HLAB27()status did not aVect the protective eVect of freeradical scavengers on photoreceptors.

The better preservation of visual acuity inthe patients treated with vitamins is possibly

Figure 3 Average visual acuity in Snellen equivalents for the vitamin (triangle; n = 68)and placebo (circle; n = 67) treated patients.

1.50

1.25

1.00

0.75

0.25

0.50

0.0056494228 35

Time (days)

VA(Snellen)

21140 7

Table 3 Average visual acuity (logMAR (SD)) for theplacebo and vitamin treated g roups

Time (days)

Visual acuity in logMAR* (SD)

p ValueVitamin C/E Placebo

0 0.106 (0.241) 0.128 (0.456)3 0.236 (0.293) 0.344 (0.489) 0.137 0.204 (0.292) 0.292 (0.479) 0.1014 0.162 (0.274) 0.193 (0.454) 0.6628 0.096 (0.232) 0.158 (0.436) 0.0956 0.026 (0.213) 0.106 (0.437) 0.013

*logMAR is the negative 10th power logarithm of Snellen visualacuity. p Values for delta VA (relative to day 0) in logMAR;MannWhitney test. Time 0 days is the measurement beforetreatment (baseline value).


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achieved by the free radical and antioxidantproperties of one or both of the vitamins used.The existence of free radicals in the posteriorsegment of animals with experimental uveitiswas studied with the aid of histochemicalmethods4 7 and chemiluminescence9 and freeradical tissue damage could be detected in theanterior segment of eyes with experimentaluveitis.11 In experimental uveoretinitis lipids ofthe membranes of retinal cells are oxidised by

the free radicals.5 43 The membranes of the rodouter segments are particularly vulnerable toperoxidation as in this segment more than 65%of the membrane fatty acids arepolyunsaturated.39 Peroxidation of cell mem-brane lipids can lead to necrosis of photorecep-tors and other retinal cells.3 9 Several antioxi-dants and scavengers of free radicals, includingvitamin E, were shown to protect the eye frominflammation mediated tissue damage.1 2 1218

The data of the aforementioned experimentalstudies may indicate that, in the patients in thisstudy who were treated with vitamins C and E,the photoreceptors were protected from freeradical damage leading to a better preservation

of VA. The fact that in experimental uveitisvitamin C concentration in the aqueous dimin-ishes significantly21 22 suggests that oxygenradicals are indeed scavenged during uveitisand that there may be an insuYcient buVer ofvitamin C during moderate to severe uveitis.Apart from the possible protective eVect of thevitamins on photoreceptors, other mechanismsmay explain the diVerence in VA. Cystoidmacular oedema (CMO) is a well recognisedmechanism of transient or definite loss of VA inuveitis patients, and this may not be detectedon indirect funduscopy (as was performed oneach follow up occasion). Although the patho-physiology of CMO is not well understood,prostaglandins may have a role, and vitamin E

was reported to influence prostaglandinmetabolism.18 As free oxygen radicals aregenerated early in the inflammatory cascade, aprotective eVect on CMO of free radicalscavengers cannot be excluded. There was nosignificant eVect of HLAB27 status on endpoint visual acuity, suggesting that a possibleprotective eVect of free radical scavengersapplies to both HLAB27 positive and negativepatients.

We conclude that in this study no eVect oforal vitamins C and E on flare or cell measure-ments could be detected in patients with acuteanterior uveitis, possibly because all patientswere treated with potent local steroids.

Visual acuity at 2 months after start of thetreatment was significantly better for the pa-tients treated with vitamins C and E, althoughthis was not confirmed by RMANOVAs. Thissuggests a protective eVect of free radicalscavengers on photoreceptors in uveitis patients;possible mechanisms include prevention of pho-toreceptor damage or cystoid macular oedema.

The authors are grateful to Mr JTG Jansen, hospital pharmacistof the Eye Hospital Rotterdam, for the preparation and doublemasked distribution of the vitamins C and E capsules and MissJ van Hal, dietician of the Eye Hospital Rotterdam, for theinterviews to calculate dietary intakes of vitamins C and E.

Sponsor: the Rotterdam Association for the Blind.

1 Rao NA, Romero JL, Fernandez MA, et al. Role of freeradicals in uveitis. Surv Ophthalmol1987;32:20913.

2 Fleisher LN, Ferrell JB, Olson NC, et al. Dimethylthioureainhibits the inflammatory response to intravitreally-injected endotoxin. Exp Eye Res 1989;48:5617.

3 Rao NA. Role of oxygen free radicals in retinal damageassociated with experimental uveitis. Trans Am OphthalmolSoc 1990;88:797850.

4 Gritz DC, Montes C, Atalla LR, et al. Histochemical locali-zation of superoxide production in experimental autoim-mune uveitis. Curr Eye Res 1991;10:92731.

5 Wu GS, Sevanian A, Rao NA. Detection of retinal lipidhydroperoxides in experimental uveitis. Free Radic Biol Med1992;12:1927.

6 Marak GE, de-Kozak Y, Faure JP. Free radicals and antioxi-

dants in the pathogenesis of eye diseases. Adv Exp Med Biol1990;264:51327.

7 Wu GS, Gritz DC, Atalla LR, et al. Ultrastructural localiza-tion of hydrogen peroxide in experimental autoimmuneuveitis. Curr Eye Res 1992;11:95561.

8 Bazan NG, de-Abreu MT, Bazan HE, et al. Arachidonic acidcascade and platelet-activating factor in the network of eye.Int Ophthalmol1990;14:33544.

9 Wu GS, Goto H, Sevanian A, et al. Generation of chemilu-minescence in experimental autoimmune uveitis. Curr EyeRes 1991;10:90917.

10 Wu GS, Sevanian A, Rao NA. Detection of retinal lipidhydroperoxides in experimental uveitis. Free Radic Biol Med1992;12:1927.

11 Ishimoto S, Wu GS, Hayashi S, et al. Free radical tissuedamages in the anterior segment of the eye in experimentalautoimmune uveitis. Invest Ophthalmol Vis Sci 1996;37:6306.

12 De-Kozak Y, Nordman JP, Faure JP, et al. EVect of antioxi-dant enzymes on experimental uveitis in rats. OphthalmicRes 1989;21:2304.

13 Romero J, Marak GEJ, Rao NA.Pharmacologic modulationof acute ocular inflammation with quercetin. Ophthalmic

Res 1989;21:11217.14 Gupta LY, Marmor MF. Mannitol, dextromorphan, and

catalase minimize ischemic damage to retinal pigment epi-thelium and retina. Arch Ophthalmol1993;111:3848.

15 Marak GEJ, Sery TW, Gregerson D, et al. Pharmacologicmodulation of acute uveitis with aminonicotinamide. Oph-thalmic Res 1990;22:11116.

16 De Kozak Y, Faure JP, Thillaye B, et al. Ginko biloba extract(EGb 761) and a platelet-activating factor antagonistprotect the retina in experimental autoimmune uveitis.Ocular Immunol Inflam 1994;2:2317.

17 Pararajasegaram G, Sevanian A, Rao NA. Suppression of Santigen-induced uveitis by vitamin E supplementation.Ophthalmic Res 1991;23:1217.

18 Cid L, Pararajasegaram G, Sevanian A, e t a l . Anti-inflammatory eVects of vitamin E on experimentallens-induced uveitis. Int Ophthalmol 1992;16:2732.

19 Niki E. Action of ascorbic acid as a scavenger of active andstable oxygen radicals. Am J Clin Nutr 1991;54:1119S24S.

20 Williams RN, Paterson CA, Eakins KE, et al. Ascorbic acidinhibits the activity of polymorphonuclear leucocytes ininflamed ocular tissues. Exp Eye Res 1984;39:2615.

21 Bito LZ. The eVects of experimental uveitis on anterioruveal prostaglandin transport and aqueous humor compo-sition. Invest Ophthalmol Vis Sci 1974;13:95966.

22 Levinson RA, Paterson CA, Pfister RR. Ascorbic acidprevents corneal ulceration and perforation followingexperimental alkali burns. Invest Ophthalmol Vis Sci1976;15:98693.

23 Niki E. Lipid antioxidants: how they may act in biologicalsystems. Br J Cancer1987;55(suppl 8):1537.

24 Boobis AR, Burley D, Davies DM, et al. Therapeutic drugs.London: Churchill Livingstone, 1991.

25 Bendich A, Machlin LJ. Safety of oral intake of vitamin E.Am J Clin Nutr 1988;48:61219.

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27 Roberts HJ. Perspective on vitamin E as therapy. JAMA1981;246:12931.

28 Berson EL, Rosner B, Sandberg MA, et al. A randomizedtrial of vitamin A and vitamin E supplementation for retini-tis pigmentosa [see comments]. Arch Ophthalmol1993;111:76172.

29 Schalnus R, OhrloV C. Quantification of blood-aqueousbarrier function using laser flare measurement and

fluorophotometrya comparative study. Lens Eye Toxic Res1992;9:30920.30 Kuchle M, Hannappel E, Nguyen NX, et al. Correlation

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34 Guex-Crosier Y, Pittet N, Herbort CP. Evaluation of laserflare-cell photometry in the appraisal and management ofintraocular inflammation in uveitis. Ophthalmology 1994;101:72835.

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35 Ni M,Bloom JN, Lele S, et al. A laboratory evaluation of theKowa laser flare-cell meter for the study of uveitis. GraefesArch Clin Exp Ophthalmol1992;230:54751.

36 Ferguson VM, Spalton DJ. Quantification of the ocularresponse to treatment in posterior uveitis. Acta OphthalmolCopenh 1992;70:82431.

37 Hogan MJ, Kimura SJ, Thygeson P. Signs and symptoms ofuveitis. Am J Ophthalmol1959;47:15570.

38 Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin Econsumption and the risk of coronary disease in women[see comments]. N Engl J Med 1993;328:14449.

39 Muller DPR. Vitamin E therapy in retinopathy of prematu-rity. Eye 1992;6:2215.

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41 Bates C, Cowen TD. EVects of age and dietary vitamin C inthe contents of ascorbic acid and acid-soluble thiol in lensand aqueous humour of guinea-pigs. Exp Eye Res 1988;46:93745.

42 Berger J, Shephard D, Morrow F, et al. Reduced and totalascorbate in guinea pig eye tissues in response to dietaryintake. Curr Eye Res 1988;7:6816.

43 Goto H, Wu GS, Chen F, et al. Lipid peroxidation in experi-mental uveitis: sequential studies. Curr Eye Res 1992;11:48999.


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doi: 10.1136/bjo.83.11.12771999 83: 1277-1282Br J Ophthalmol

al.Jeroen van Rooij, Sicco G W S thoe Schwartzenberg, Paul G H Mulder, et

patientsrandomised double masked study in 145in patients with acute anterior uveitis: aOral vitamins C and E as additional treatment

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