Eye (2007) 21, 633-638
`© 2007 Nature Publishing Group All rights reserved 0950-222X/07 $30.00
`www. nature com/eye
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`How red is a white
`eye? Clinical grading
`of normal
`conjunctival
`hyperaemia
`
`Abstract
`
`Purpose To quantify the level of normal
`bulbar conjunctival hyperaemia using the
`Cornea and Contact Lens Research Unit
`
`(CCLRU) grading scale, and to investigate
`inter-observer agreement.
`Methods Bulbar conjunctival hyperaemia
`was assessed by two trained observers, using
`the CCLRU grading scale (zero to four units)
`interpolated into 0.1 increments, on the right
`eye of 121 healthy, non-contact lens-wearing
`subjects (male =—58, female = 63, median
`age = 28 years, range 16-77). The eye was
`observed using a slit-lamp bio-microscope
`(x10 magnification) under diffuse, white
`illumination. The subject’s position of gaze
`was directed to allow grading of four
`quadrants: superior, nasal, inferior, and
`temporal conjunctiva. Bulbar redness was
`defined as the average of those four grades of
`conjunctival hyperaemia. A further twenty
`subjects were recruited to assess inter-
`observer agreement (male =—8, female = 12,
`median age = 23 years}.
`Results The average bulbar redness was
`1.93 (+0.32 SD) units. The nasal (2.3+0.4)
`and temporal (2.1+0.4) quadrants were
`significantly redder than the superior
`(1.6+0.4) and inferior (1.7+ 0.4) quadrants
`(P< 0.0001). Males had redder eyes than
`females by 0.2 units. Inter-observer 95%
`limits of agreement for bulbar redness was
`0.38 units.
`
`Conclusions The average bulbar redness of
`1.9 units was higher than expected, reflecting
`the design of the grading scale. A bulbar
`redness of greater than 2.6 units may be
`considered abnormal, and a change in
`bulbar redness of >0.4 units may be
`significant.
`Eye (2007) 21, 633-638. doi:10.1038/sj.eye.6702295,;
`published online 3 March 2006
`
`PJ Murphy', JSC Lau', MML Sim' and RL Woods?
`
`Keywords: clinical grading; bulbar redness;
`conjunctival hyperaemia
`
`Introduction
`
`Conjunctival hyperaemia is caused by
`vasodilation of the conjunctival blood vessels
`against the white background of the sclera. The
`vasodilation produces the red appearance of the
`white of the eye, and so the condition is
`sometimes referred to as ‘red eye’, whereas an
`apparently healthy eye with no vasodilation is
`referred to as a ‘white eye’ (Figure 1).
`Increased conjunctival hyperaemia is a
`clinical sign for a wide range of ocular disease,
`inflammation, and irritation. Among the many
`conditions it has been recorded with are
`
`meibomian gland dysfunction and marginal
`blepharitis,’ conjunctivitis?“ contact lens
`wear,” cosmetics,” hypertension, diabetes,*
`acute angle-closure glaucoma, autoimmune
`disease, chemical injury,”° episcleritis,
`uveitis,’sickle cell disease,” and
`pharmaceutical drug use.’*
`Clinical grading scales that allow the
`assessinent of severity have been developed for
`many ocular conditions, including the anterior
`chamberangle,"* iris neovascularisation,’*
`retinal nerve fibre layer atrophy,”* focal
`narrowing ofretinal arterioles in glaucoma,”
`diabetic retinopathy," hypertensive
`arteriosclerosis,’’ tarsal abnormalities,*" and
`lens opacities.*! Similar scales have been
`developed to grade conjunctival hyperaemia.
`These bulbar redness scales have utilised verbal
`
`22-36
`
`descriptions, photographs, or paintings that
`illustrate an increasing level of conjunctival
`hyperaemia, and they have been particularly
`used in clinical studies of contact lens wear and
`dry eye???" The grading scale is typically
`divided into four or five grades. However, the
`
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`"Cardiff University, School of
`Optometry and Vision
`Sciences, Cardiff, UK
`
`*Schepens Eye Research
`Institute, Harvard Medical
`School, Boston, MA, USA
`
`
`
`Correspondence:
`PJ Murphy,
`School of Optometry and
`Vision Sciences,
`Cardiff University,
`King Edward VIl Avenue,
`Cardiff CF10 3NB, UK
`Tel: +44 2920 874703;
`Fax: + 44 2920 874859.
`E-mail: MurphyR@
`cfac.uk
`
`Received: 5 July 2005
`Accepted in revised form:
`15 January 2006
`Published online: 3 March
`2006
`
`This work was presented at
`fhe Association for Research
`in Vision and
`
`Ophthalmology Annual
`Meeting, Fort Lauderdale,
`Florida, 25th-29th April
`2004
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`634
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`How red is a white eye?
`PJ Murphy ef af
`
`
`
`Figure 1 Typical ‘normal’ white eye (courtesy of Dr Trefford L
`Simpson, Centre for Contact Lens Research, School of Optome-
`try, University of Waterloo, Canada).
`
`scales can be interpolated into decimal intervals to
`increase their sensitivity.”Papas“ showed that by
`decimalising the Cornea and Contact Lens Research Unit
`(CCLRU) grading scale for bulbar redness, the grading
`approximates an interval scale. The problem of an
`ordinal grading scale, producing unequal grading
`divisions, has also been considered by using digitised
`morphing of the grading scales, or by removing the
`subjective input of the observer through image analysis
`of the image.*”
`Although conjunctival hyperaemia is accepted as an
`important clinical sign of ocular disease or inflammation,
`and grading scales are frequently used to assess the
`severity or degree of change in bulbar redness, no
`previous studies have been presented that consider the
`normal, unstimulated level of conjunctival hyperaemia.
`An understanding of what can be considered normalis
`crucial when assessing any presenting conjunctival
`hyperaemia. In this paper, we report the prevalence of
`conjunctival hyperaemia in healthy, non-contact lens
`wearing eyes, in a cross-sectional study and inter-
`observer agreement of the CCLRU bulbar redness scale.
`
`Materials and methods
`
`Prevalence study
`
`A total of 121 healthy subjects (male = 58, female = 63,
`median age = 28 years, range = 16-77) participated. All
`subjects had no current or previous ocular disease or
`systemic disease, medication, or allergy knownto affect
`bulbar redness. Subjects with subclinical minor ocular
`conditions, such as marginal blepharitis, may have been
`included. As such, our sample represents a typical
`population that may be present in a clinic. Contact lens
`wearers were included, if the contact lenses had not been
`
`worn during the previous 2 weeks. A duration of 2 weeks
`has been considered as sufficient time for any contact
`lens-related conjunctival hyperaemia to have resolved.**
`Conjunctival hyperaemia was assessed by twotrained
`observers (JL, MS) using the CCLRU grading scale,
`interpolated to 0.1 unit increments. This photographic
`scale was developed by the CCLRUat the University of
`New South Wales, Australia and comprised four images
`that increase in severity of the condition, and are labelled
`as follows: 1, very slight; 2, slight; 3, moderate; 4, severe.
`Only the right eye of each subject was examined using a
`slit-lamp bio-microscope (x 10 magnification) under
`diffuse, white illumination. The subject’s position of gaze
`was directed to allow grading of four quadrants:
`superior, nasal, inferior, and temporal. The bulbar
`redness score was defined as the average of the scores of
`the four quadrants.
`
`Inter-observer study
`
`A further 20 subjects (male =8, female = 12, median
`age = 21 years, range = 19-28) were recruited to assess
`the inter-observer agreement between the two observers,
`at the completion of the prevalence study. The study
`procedure was repeated using the same selection criteria
`and grading procedures. The four quadrants of the right
`eye of each subject were independently graded by the
`two observers (JIL, MS) (ie masked from each other's
`observations), and the order of subject assessment by
`observer was randomised.
`
`Data analysis
`
`As the prevalence (Figure 2a—e) and the inter-observer
`difference (Figure 4) data were approximately normally
`distributed, and this grading scale approximates an
`interval scale,“ and Barbeito and Simpson” have argued
`that parametrical statistical tests can be applied to such
`data, we used parametric statistical tests. Inter-observer
`agreement was determined as the 95% limits of
`agreement,” which is 1.96 times the standard deviation
`of the inter-observer difference scores (ie grade from
`observer 1 minus grade from observer 2).
`
`Results
`
`Prevalence study
`
`As shownin Figure 2, a significant difference in redness
`was found between quadrants (repeated measures
`ANOVA,F360 = 281, P-<0.0001). Post hoc paired t-tests
`found significant differences in redness betweenall
`quadrants (f29>4.3, P<0.0001), with the nasal (2.3+0.4)
`(mean units+S5D) and temporal (2.1+0.4) quadrants
`
`
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`PJ Murphy et af
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`Superior
`
`b Inferior
`
`Temporal
`
`d Nasal
`
`a
`
`on
`
`0.56
`
`1.0
`
`1.6
`
`2.0
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`2.5
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`3.0
`
`0.5
`
`1.0
`
`1.6
`
`2.0
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`25
`
`3.0
`
`numberofeyes a
`Bulbar redness 0.5
`
`grade (units
`
`f
`
`Temporal
`
`1.0
`
`15
`
`2.0
`
`2.5
`
`3.0
`
`
`
`
`Superior
`
`Inferior
`
`2.3+0.4 Nasal
`
`redness grade (units)
`
`Figure 2. Distribution of (a-d) the redness scores for each quadrant, (e) bulbar redness scores, and (f) the quadrant mean redness
`scores.
`
`redder than the superior (1.6+0.4) and inferior (1.7 +0.4)
`quadrants.
`The average bulbar redness was 1.93 (40.32) units
`(Figure 2e). Figure 3 showsthat bulbar redness appeared
`to increase slightly with age by about 0.05 units per
`decade (ry145 = 0.23, P=0.01); however, a multiple
`regression analysis (F113 =9.4, P =0.0002) found that
`most of the apparent effect of age was explained by
`males having redder eyes than females by 0.22 units (age:
`ts = 1.48, P=0.14; gender: fy, = 3.43, P = 0.0008), there
`being more older subjects who were male and more
`younger subjects who were female. One observer had a
`slight tendency to record higher redness scores, which
`wasnot accounted for by differences in subject ages or
`genders (difference in average bulbar redness 0.22 units,
`Fi 13 =4-1, P=0.045).
`
`3.0
`
`25
`
`2
`52.0,
`®
`8
`o
`
`1.5 4
`
`Bulbar redness
`
`°
`
`
`
`?
`
`25
`a
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`20
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`30
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`50
`40
`age (years)
`
`&
`
`+
`60
`
`Female
`© Male
`+
`70
`
`80
`
`redness appeared to increase with age
`Figure 3 Bulbar
`(n=121), but the effect was explained by the greater bulbar
`redness of males.
`
`Inter-observer study
`
`Nosignificant difference was found between the grading
`of the two observers, overall or for each quadrant
`
`(ti9<1.54, P>0.14), except for the temporal quadrant
`(ty = 2.54, P = 0.02). Figure 4 showsthe inter-observer
`comparison of redness scores for the average bulbar
`redness, and the tendency for one observerto give higher
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`How red is a white eye?
`
`PJ Murphy et af
`636
`
`Bulbar redness
`
`(units)
`difference
`
`Inter-observer agreement in bulbar redness (1 = 20)
`Figure 4
`was good, with a coefficient of agreementof 0.4 units.
`
`microscope at x 10 magnification. Conjunctival
`hyperaemia is often observed unaided at a distance of
`about 1 m (eg facing a patient across a desk). Even at our
`low slit-lamp magnification, smaller blood vessels
`become evident and may influence the observer’s
`perception of the clinical grade. However, the CCLRU
`grading scale was designed with the expectation that the
`observer would useaslit lamp. Efron”® reported a similar
`0.5
`4
`1.5
`2
`2.5
`3
`higher than expected hyperaemia grading, indicating
`grade by observer 1 (units)
`that a grade of more than 2 (with the Efron Grading
`Scale) is abnormal. The Efron scale offers a similar
`grading range to the CCLRUscale, but is pictorial. It
`seemslikely, then, that the normal ‘white’ eye is redder in
`appearance than commonly determined through casual
`observation.
`
`scoresto redder eyes (r* = 0.38, P = 0.004). The 95% limits
`of agreement was 0.38 units for bulbar redness, and
`varied between quadrants with a maximum of 0.85
`(inferior) and minimum of 0.50 (nasal) units. Agreement
`may have been improved by controlling gaze eccentricity,
`which may be appropriate for a research study, but is not
`practical in clinical practice.
`
`Discussion
`
`The average bulbar redness of 121 people with healthy
`(white) eyes was 1.9 units. As the upper 95% confidence
`limit was 2.6 units, a CCLRU bulbar redness grade of
`more than 2.6 may be considered abnormal. This average
`grade and upper confidence limit was higher than our a
`priori expectations. In similar studies of healthy eyes, the
`median corneal staining grade was 0.1 units and the
`upper confidence limit was 0.5 units,““ whereas the
`average upper palpebral conjunctiva grade was1.2 units
`and the upper confidence limit was 2.0 units.** Although
`the typical conjunctival staining is consistent with the
`generalised verbal grading proposed by Woods™ and
`implied by the written descriptions associated with the
`CCLRUgrading scale and other grading scales (eg Efron,
`1997), typical palpebral conjunctival grades and bulbar
`redness grades appear higher. We consider two
`alternative explanations for bulbar redness: either the
`normal ‘white eye’ appearanceis redder than previously
`assumed, or the calibration of the grading scale is wrong.
`As McMonnies and Ho* and McMonniese¢ al*®
`described how conjunctival hyperaemia can vary with
`factors such aslack of sleep, eyestrain, wind, dust, smog,
`smoke, and alcohol, we screened our subjects for these
`factors. However, 11 potential subjects who did not meet
`our selection criteria, mainly because of the use of
`medications, showed no apparent difference in bulbar
`redness compared to the 121 healthy eyes. Figure 1
`demonstrates the effect of image magnification on the
`perception of conjunctival hyperaemia. In our study, the
`eye was observed underdiffuse light, using a slit-lamp
`
`Turning to the second hypothesis,if it is assumed that
`‘normal’ should be located around the lower grades on
`the scale (eg Woods, 1989) to provide room for
`progression of the condition; then the high average
`bulbar redness and range of 1.2-2.9 units among these
`121 healthy eyes suggest that the CCLRU scale may have
`an inadequate or misplaced dynamic range. A good
`grading scale mustbe bothsensitive to the severity of the
`condition and specific in determining what is normal.
`Althoughthe average bulbar redness grade for our
`subject population was higher than weexpected, the
`wide variance of the distribution (Figure 2e) and the
`relatively small inter-observer 95% limits of agreement
`indicate that the gradeis able to distinguish between
`degrees of conjunctival hyperaemia. Figure 3 showsthat
`no eye received a bulbar redness grade of 1 unit or less.
`The photographic image used as an example for a grade
`1 (very slight) is particularly white in appearance, and
`mayillustrate unusually low conjunctival hyperaemia.
`Although this grade may not be needed for grading the
`normal appearance, it ensures that the scale provides for
`the abnormal condition of a very white eye, such as that
`produced by anaemia. It also suggests that the CCLRU
`grading scale for conjunctival hyperaemia may need to
`be extended to values greater than its current maximum
`grade of 4 units.
`It is interesting to note the variation in redness across
`the four conjunctival quadrants, and the age- and
`gender-related differences in average bulbar redness. The
`nasal and temporal quadrants have the highest redness
`scores, possibly reflecting their exposure to
`environmental conditions. The same variation was noted
`by McMonnies et al?* and Papaset al.*' For the purpose of
`analysis, the four quadrants were averaged to produce
`our bulbar rednessscore. As this bulbar redness includes
`
`the results of the superior and inferior quadrants,if the
`observer had chosen to grade conjunctival hyperaemia
`from the exposed conjunctiva only, then the bulbar
`redness scores would have been higher. If bulbar redness
`
`
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`had been based on the temporal and nasal quadrants
`only, the average bulbar redness would have been
`2.214036 (range 1.2-3.1) units, and the upper 95%
`confidence limit 2.92 units. When a bulbar redness score
`
`is recorded, the quadrants viewed should be recorded
`and care must be taken when comparing bulbar redness
`scores. In our study, males tended to have redder eyes
`than females by about 0.2 units, and bulbar redness
`increased by 0.05 units per decade. These findings are
`similar to McMonnies and Ho,” who observed 470 non-
`contact lens wearers (227 males and 252 females). Using
`the McMonnies scale, with its six grades and no decimal
`interpolation, they found an average difference of 0.5
`units between genders, and a grading change of 0.16
`units per decade. The gradual increase in redness with
`age may be attributable to a reduction in arteriolar wall
`muscle tone, but there is no obvious explanation for the
`difference between genders.
`A difference in bulbar redness of 0.4 units or more
`
`between observers may be considered significant,
`because such a difference would be greater than the
`inter-observer 95% limits of agreement found for our two
`observers. No significant difference was found between
`the two observers, except for the temporal quadrant.
`There was a tendency for observer 1 to give lower scores
`than observer 2 to eyes that were more red (Figure 4). In
`our study, the two observers were trainee optometrists.
`Before the study commenced, the two observers and one
`of the other authors (PJM, an experienced user ofclinical
`grading scales) discussed grading strategies and
`compared the bulbar redness grades assigned to a series
`of human subjects. No measurement of the inter-observer
`agreement was made before data collection. Trained
`observers have better inter- and intra-observer
`agreement.*”* In a similar study on clinical grading of
`the upper palpebral conjunctiva of non-contact lens
`wearers,’ the inter-observer 95% limits of agreement at
`the beginning was 0.76 units, but improved to 0.24 units
`at the end of the study. In another similar study on
`corneal staining,” the inter-observer 95% limits of
`agreement was 0.36 units, and they reported no
`differences in agreement between the start and end of the
`study. In studies on grading bulbar redness of
`photographs, Papas™ found an inter-observer 95% limits
`of agreement of 0.8 units for seven experienced
`observers, and Chonget al** found inter-observer 95%
`limits of agreements of 0.32-0.42 units for five
`experienced observers. Thus, our 0.4-unit inter-observer
`95% limits of agreement is comparable to two previous
`studies that also used real eyes,““* and similar toor
`smaller than™” studies that used photographs to assess
`inter-observer agreement.
`Intra-observer agreementis also important in the
`assessment of grading scales. Inter-observer agreement
`
`compares two (or more) independent observers, whereas
`intra-observer agreement describes the repeatability of
`an observer, the ability to give the same result at each
`time of assessment. Both can be used to interpret changes
`in grading scale scores and to determine sample sizes
`necessary for future studies. Intra-observer 95% limits of
`agreements have been reported ranging from 0.78 to 1.52
`units in studies using photographs,°47°"*! values that
`appear to be larger than comparable studies of inter-
`observer agreement. As intra-observer agreement was
`not found in our study, the significance of a change
`between observations of real eyes made by a single
`observer is not known.
`
`In conclusion, although the bulbar conjunctival
`hyperaemia of a white eye may be redder than expected,
`this probably reflects the normal physiological detail
`visible by slit-lamp microscopy and not an error in the
`design of the grading scale. Given that normal bulbar
`redness can range from 1.3 to 2.6 units, it is more
`important that the clinician make note of the baseline
`appearance, as a change in bulbar redness score of 0.4
`units or more may be significant.
`
`Acknowledgements
`
`The CCLRU grading scale is available in the UK from
`Johnson and Johnson Vision Care, or worldwide from
`the Institute for Eye Research Ltd in Australia
`{enquiry@ier.org.au) or www.ierorg.au.
`
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`SLAYBACK EXHIBIT 1026
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