Clinical Practice
JOHN E. SUTPHIN, MD, SECTION EDITOR
The Association Between Symptoms of
Discomfort and Signs in Dry Eye
MICHAEL E. JOHNSON, PHD, FCOPTOM
ABSTRACT There is an intuitive causal link between the
signs of dry eye observed by clinicians and the severity of
symptoms experienced by patients. However, this expectation
is challenged by asymptomatic patients with obvious tear
film anomalies and extensive ocular surface compromise and,
conversely, by patients with intolerable symptoms of dryness
in whom only minimal disease can be observed. Knowledge
of how symptoms reflect the state of disease would enable
clinicians to better understand and manage patients with
apparently idiosyncratic disease presentations. This paper
reviews the literature and describes the difficulties of inves-
tigating the correspondence between symptoms and signs in
dry eye. The measurement of and analytical methods used to
compare these two clinical areas are discussed. Theoretical
aspects of the relationship between symptoms and signs are
also covered. Typically, a positive relationship exists between
the severity of symptoms and objective tests in dry eye, but,
on balance, data suggest that the association between symp-
toms and the majority of these tests is not strong; thus, the
power of predictive inference of one from knowledge of the
other is low. Firm conclusions cannot be made on the nature
of the relationship at this time because of limitations in our
ability to measure either individually.
KEY WORDS dry eye, Ocular Comfort Index, ocular sur-
face, Ocular Surface Disease Index, patient questionnaire,
signs, symptoms, tear film
Accepted for publication July 2009.
From the Department of Ophthalmology, Bristol University, Bristol, UK.
Dr. Johnson was a paid consultant to Pfizer in connection with the develop-
ment of this manuscript. Dr. Johnson developed the Ocular Comfort Index
(OCI) that is referred to in the article.
Single-copy reprint requests to Dr. Michael E. Johnson (address below).
Corresponding author: Dr. Michael E. Johnson, Senior Optometrist,
Department of Optometry, Bristol Eye Hospital, Lower Maudlin Street,
Bristol BS1 2LX, United Kingdom. Tel: +44 117 923 0060. E-mail: John-
sonMyoptometrist@gmail.com.
©2009 Ethis Communications, Inc. The Ocular Surface ISSN:
1542-0124. Johnson ME. The association between symptoms of
discomfort and signs in dry eye. 2009;7(4):199-211.
THE OCULAR SURFACE / OCTOBER 2009, VOL. 7, NO. 4 / www.theocularsurface.com
I. DRY EYE SYMPTOMS
A. Nature of Symptoms
he symptoms of dry eye include ocular surface
T
discomfort, light sensitivity, and variable blurred
vision.1-5 Some individuals with dry eye complain
of red eyes as a cosmetic disfigurement, and, thus, redness
can also be considered a symptom.6 This paper focuses
exclusively on ocular surface discomfort, which is herein
understood to encompass dryness, irritation, grittiness,
scratchiness, sandiness, foreign body sensations, soreness,
pain, stinging, burning, itch, and ocular fatigue/tiredness.
The Ocular Comfort Index (OCI) and the ocular symptoms
domain of the Ocular Surface Disease Index (OSDI) consist
of questions about some of these symptoms, and it has been
established that these questionnaires are unidimensional
(measure only one thing),7,8 which suggests that the large
number of symptoms describing ocular surface discomfort
reflects individual and regional differences in word choice,
rather than different qualities. This is not inconsistent with
the possibility that some symptom questions are more likely
to elicit lower scores than others, eg, pain versus tiredness.8
The cornea is densely innervated, and its sensory
nerves have a steep stress-response curve.9 This is usually
advantageous by creating consciousness of threats to ocular
integrity, but a negative consequence is that even minor tear
anomalies and subsequent disturbance to the ocular surface
can lead to disproportionately severe levels of discomfort.
It is the view of the author that in dry eye, pain outlives
its usefulness as a warning system and instead becomes
chronic and debilitating.
B. Basis of Ocular Discomfort
The origin of ocular discomfort in dry eye is not truly
known, and it is likely that several mechanisms are responsi-
ble.10 Innervation of the cornea is almost exclusively by sen-
sory nociceptors, which by definition are activated only by
noxious or near-noxious stimulation above a threshold.11,12
Some of these nociceptors respond only to mechanical
stimulation, whereas others are also able to sense changes
in the chemical environment and temperature. 13,14
A moderate increase in the osmolarity of tears has been
reported in dry eye,15,16 which typically increases during
199
 ASSOCIATION OF SYMPTOMS AND SIGNS IN DRY EYE / Johnson
OUTLINE
I. Dry eye symptoms
A. Types of symptoms
B. Basis of ocular discomfort
II. Measurement of symptoms in dry eye
A. Test strategies
B. Direct questioning
III. Measurement of signs in dry eye
IV. Association between symptoms and signs in dry eye
A. Group comparisons
B. Correlation analyses
V. Theoretical considerations
A. Artificial test environment
B. Nonlinear sensory response to stress
C. Altered sensory responsiveness with time
D. Duration of disease
E. Masquerading disease and comorbidity
VI. Summary and conclusions
the day,17-19 as do symptoms.3,20 It has been reasoned that
the osmolarity of the thin tear film overlying the cornea is
raised further than indicated by published data, which has
been based on sampling tears from the inferior meniscus,
because evaporation removes a greater percentage of wa-
ter when the ratio of surface area to volume is high.21,22 A
time-linked association, dose-response effect, and biological
plausibility suggest that hyperosmotic stress leads to corneal
nerve stimulation. However, a causative relationship has
not yet been confirmed experimentally. A hyperosmolar
tear film can generate symptoms by several mechanisms,
including the direct stimulation of polymodal nerves, or,
indirectly, through mechanical stress from tissue deforma-
tion or through activating signaling pathways in epithelial
cells.13,23,24 Alternatively, dry eye symptoms can be gener-
ated by mechanically sensitive nerves that are stimulated
by increased shear-stress between the eyelids and globe in
response to reduced tear volume,25 or tractional forces gen-
erated by mucus filaments anchored to surface epithelium.26
Inflammation of the ocular surface occurs in dry eye to
variable degrees.27,28 Mechanisms include desiccating envi-
ronmental stress, chronic hyperosmolarity of the tear film,
microtrauma from poorly lubricated movements of the eye-
lids, and alterations in the composition of tears secondary
to lacrimal gland inflammation.23-25,29-32 In nonocular sites,
inflammation causes epithelial cells to release inflammatory
mediators that directly activate polymodal nociceptors and
lower their response threshold.13,14,33
II. MEASUREMENT OF SYMPTOMS IN DRY EYE
A. Test Strategies
It is difficult to evaluate symptoms or signs accurately
in dry eye, and this presents a significant limitation to
quantifying their relationship. This difficulty is self-evi-
dent for symptoms, which are a subjective quality. Patient
200 THE OCULAR SURFACE / OCTOBER 2009, VOL. 7, NO. 4 / www.theocularsurface.com
symptoms are usually assessed indirectly by questioning,
either through interviews or questionnaires. Alternatively,
physiological responses, such as blink frequency, or the pa-
tients’ actions, eg, how often they instill ocular lubricants,34
can be monitored, but the legitimacy of these surrogate
methods is uncertain, because they do not directly assess
the subject of interest.
B. Questionnaires
The severity of symptoms can be assigned a grade based
on judges’ opinion of interview answers or through math-
ematical operations to questionnaire responses. Interviews
with open questions are useful when descriptive informa-
tion is desired, or when there is little prior knowledge
of the nature of the response. However, self-completed
questionnaires with closed questions are preferable when a
single outcome variable is required, as these questionnaires
provide standardization and relative ease of codification.
Answers to questions reflect both the level of discomfort
experienced and behavioral responses. The former is influ-
enced by the physical nature of stimuli, the ability of the
peripheral nervous system to code and transmit to the brain,
and subsequent modifications by central processes involv-
ing the thalamus and cerebral cortex.35 It is likely that an-
swers to questions are scaled relative to past experiences.36
Other possible influences include age, gender, culture, the
perceived likelihood of eventual relief and control over the
situation, and presence of other stimuli competing for at-
tention.37-43 As will be discussed, the challenging situation
is compounded by the use of questionnaires that are not
optimal at scaling symptom severity, for reasons that include
asking too few questions, multi-dimensional scales, and
potentially inappropriate assumptions in scoring methods.
Classic measurement theory holds that increasing the
number of questions leads to a reduction in bias from mis-
interpretation and random measurement error, and thus fa-
cilitates more stable estimates with improved reliability.44-48
This is analogous to the concept of signal-to-noise in signal-
response theory, which asserts that the ratio of information
to noise increases as a function of the square-root of the
number of questions asked.46 Short questionnaires have
the advantage of quicker completion, and, thus, there is a
trade-off between convenience and precision.49,50 Decisions
about instrument length should consider the variability of
responses and the intended use of the questionnaire. Fewer
questions are appropriate in clinical practice and epidemio-
logical studies when rapid completion is important, and
some questionnaires have been developed with this as a
design feature.51,52 However, more questions are desirable
in clinical trials, where the overriding concern is precision,
and, thus, the ability to detect change.
It is common for dry eye questionnaires to gather data
on domains other than ocular surface discomfort. Domains
explored include demographic and medical risk factors
for dry eye; the presence, type, frequency and intensity of
symptoms; and the functional consequences and impact of
dry eye on quality of life. Collecting diverse types of data
 ASSOCIATION OF SYMPTOMS AND SIGNS IN DRY EYE / Johnson

can be helpful in deriving

an index to identify indi- Table 1. Correlation data from studies comparing three clinical tests commonly used in
viduals at risk of having dry eye examinations.
the condition in screening Study Sample, n Test Correlation P-value
ρ
situations, or in gathering Afonso et al 63 N & DE, 80 F/S—Schirmer –0.39 P < 0.01‡
information in a structured F/S—Schirmer –0.20 ρ –
format during a dry eye Begley et al 67 N & DE, 122 F/S—TBUT –0.44 ρ –
examination. However, to Schirmer—TBUT 0.26 ρ –
grade the severity of ocular Cedarstaff & Tomlinson 57 N & DE, 10 Schirmer—TBUT –0.10 * r P > 0.05
discomfort, the data on this ρ
N, 51 Schirmer—TBUT 0.34 –
domain must be collated Kallarackal et al66
DE, 62 Schirmer—TBUT 0.02 ρ –
separately to avoid ambigu-
ρ
ity in the derived index. F/S—Schirmer –0.13 P < 0.01‡
N & DE, ρ
Most questionnaires Lin et al 69 F/S—TBUT –0.07 P < 0.05‡
1361 ρ
Schirmer—TBUT 0.25 P < 0.01‡
that assess the level of ocu-
ρ
lar discomfort in dry eye use Macri & Pflugfelder64 N & DE, 99 F/S—Schirmer –0.41 P < 0.01‡
ρ
a scoring method that sums F/ST —Schirmer –0.32 P < 0.01‡
ρ
or averages the numerical Nichols et al 68 DE, 75 F/ST —TBUT –0.20 P = 0.08
response to each question, Schirmer—TBUT 0.40 ρ P < 0.01‡
although a recently devel- Pflugfelder et al62 N & DE, 50 F/ST —Schirmer –0.51τ P < 0.01‡
oped instrument uses a There is typically a concurrent worsening of both tests in a pairing, either positive or negative correlation
maximum likelihood scor- coefficient depending on the tests.
ing algorithm based on a * = exception to this general trend.
variant of item-response N = Non-dry eye subjects; DE = Dry eye subjects.
theory. 8 Implicit in the F/S = Fluorescein staining (cornea); F/ST = Total fluorescein staining (cornea and conjunctiva);
traditional approach is the TBUT = Tear breakup time.
assumption that sequential Correlation coefficient abbreviations: r = Pearson; ρ = Spearman; τ = Kendal;
steps between categories ‡ = Statistically significant result, with Type 1 error set at 5%.
represent a constant incre-
ment in severity and that all questions are equally likely to that different objective tests are intended to assess distinct
elicit the same numerical response. Scales scored in this properties of the tears or the ocular surface; however, a
manner are ordinal rankings, rather than more informative poor relationship is common even between tests intended
interval scales.53,54 Also, if questions are not equally likely to assess similar qualities. Examples can be found in the
to register the same numerical response, then the average literature for pairs of tests that assess aqueous sufficiency,
score will be influenced by what questions are omitted in namely, the Schirmer test, phenol red thread, tear meniscus
incomplete questionnaires, and, thus, these scoring systems height, and fluorophotometry55,56,59,65,71; tear stability with
do not satisfactorily account for missing data. invasive and noninvasive breakup time58,61 and breakup
time with tear evaporation57; and ocular surface integrity
III. MEASUREMENT OF SIGNS IN DRY EYE with staining methods and impression cytology.70 As an
The assessment of physical signs in dry eye also has its exception, a good correlation has been reported between
difficulties. Objective tests for dry eye can be categorized as fluorescein and rose bengal staining.62 Higher correlation
those that examine tears or those that examine the integrity coefficients have generally been reported between question-
of the ocular surface. The former can be further subdivided naires designed to grade the severity of ocular discomfort,
into tests that investigate the quantity, composition, or func- but, to the author’s knowledge, only three peer-reviewed
tional properties of tears. Most of the tests used to assess studies and an abstract have examined such associations
tears or the ocular surface do not correlate well.55-71 In this (Table 2).8,73-75 Furthermore, many objective tests do not
regard, some studies have found a statistically significant agree well with themselves when repeated on different
association, but the strength of this relationship is generally occasions.76-79 This presents a major problem in attempt-
weak to moderate (Table 1). It should be noted that some of ing to assess the relationship between objective tests, or
the authors of these studies have claimed that statistically sig- between symptoms and signs, because it is impossible for
nificant relationships in their data show strong correlations, two tests to agree strongly with each other if either agrees
but this is based on an incorrect interpretation of low P-val- poorly with itself.80
ues that only provide evidence on the likelihood of some The relatively poor repeatability of dry eye objective
relationship being present.72 Indeed, the highest correlation tests reflects measurement error and, probably of at least
coefficient of 0.51 in Table 1 denotes that only 26% of the equal importance, the innate temporal variability of tear
variation of one test is predictable by knowledge of the other. parameters.17-19,78,81-85 It is to be expected that objective tests
Some of this lack of correlation is explained by the fact will be more repeatable as dry eye severity increases, particu-

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 ASSOCIATION OF SYMPTOMS AND SIGNS IN DRY EYE / Johnson

larly in absolute terms. This

is because the lacrimal se- Table 2. Correlation data of questionnaires designed to assess the severity of ocular
cretory system in severe dry discomfort.
eye has a reduced capacity Study Sample, n Test Correlation P-value
to generate reflex tears,86,87 Johnson &
which are a large source of N & DE, 337 OCI vs OSDI 0.73 ρ P < 0.01‡
Murphy8
variability. It is also possible
Simpson et al74 N & DE, 97 DEQ (abridged) vs OSDI 0.76 ρ P < 0.05‡
that the error of a test may ρ
vary as a percentage of the Solomon et al 75 N & DE, 86 OSDI vs SPEED 0.54 P < 0.01‡
measure, rather than being Vitale et al73 N & DE, 42 NEI-VFQ (ocular pain) vs OSDI 0.62 ρ P < 0.01‡
a fixed amount for all mea- All correlations indicate a concurrent worsening of symptoms with both questionnaires in a pairing.
surement values, and so the N = Non-dry eye subjects; DE = Dry eye subjects.
absolute error of a test is DEQ (abridged) = Dry Eye Questionnaire (symptom questions 4 to 12);
lower for low test measures. NEI-VFQ (ocular pain) = National Eye Institute Visual Function Questionnaire (ocular pain subscale);
Data supporting this asser- OCI = Ocular Comfort Index; OSDI = Ocular Surface Disease Index;
SPEED = Standard Patient Evaluation of Eye Dryness.
tion have been reported for
ρ = Spearman correlation coefficient; ‡ = Statistically significant result, with Type 1 error set at 5%.
the Schirmer test and tear
meniscus height, where the
difference between two replicate measures increased with vided, the worst symptoms were invariably experienced by
their mean,77,78 and similarly for tear breakup time, where those classified as having more severe disease, or those with
the standard deviation of three replicates increased with a diagnosis of Sjogren syndrome, in whom severe disease is
their mean.79 Because of the dynamic nature of tears and expected.7,20,62,67,90,92,94,95 Similarly, the severity of symptoms
apparent diurnal variation in parameters, 17-19,81-85 it seems has typically been reported to be worse in individuals who
reasonable to anticipate that tests that examine the ocular have registered an abnormal result with objective tests of
surface should have an improved reproducibility compared the tear film or ocular surface (Table 4).4,69,90,96-98 Most of
to tests that directly assess tears. these latter studies have not, however, been able to reject the
null hypothesis of no difference, at least not for all objective
IV. ASSOCIATION BETWEEN SYMPTOMS AND tests when several have been investigated.
SIGNS IN DRY EYE
A. Group Comparisons B. Correlation Analyses
The association between ocular discomfort and observ- Correlation analyses indicate the direction and strength
able signs in dry eye is most simply assessed by grouping of association, and are, thus, more informative than group
subjects according to diagnosis or to a predetermined cut-off analyses that are only able to identify differences (Table
value in an objective test, and comparing symptoms across 5).4,63,64,73,93,95,96,99-104 Null-hypothesis tests are possible
groups. Indeed, diagnosis is often based on a sequence of with these correlation methods, but must be interpreted
objective tests, so the two methods of grouping can be al- with care, because weak associations can attain statistical
most equivalent. Such studies have differed in the facet of significance if there are many pairs of data, and, conversely,
symptom experiences that they have appraised. These facets false-negatives can occur. The latter is more likely when
include the number of symptoms present, the frequency or correlation is attenuated by measurement error and vari-
intensity of symptoms, and the severity of symptoms (con- ance restriction (eg, artificial truncation by examining only
sidered by the author to be the combination of frequency subjects with or without dry eye). Also, specifically for the
and intensity). It has previously been reported that subjects Pearson product-moment correlation test, which indicates
tend not to differentiate between frequency and intensity,3,8 how tightly pairs of data cluster about a straight line, corre-
so it appears that these components of symptom severity lation is attenuated by nonlinearity and a nonconstant error
can be interpreted as equivalent. The same may not be true variance.105 Moreover, unpredictable effects on correlation
when the number or type of symptoms are chosen from a coefficients may occur in the presence of outliers, observa-
finite list that asks about more than one domain of symptom tions numerically distinct from the majority of the data, and
experiences. Statistical tests impose a dichotomous interpre- when using the Pearson test on ordinal data, information
tation; thus, analyses based on such tests may overlook true based on metrics where the meaning of intervals may differ
relationships when statistical power is low. The risk of false- at different locations on the scale (eg, most questionnaires
negative results is relatively high, because statistical power or categorical scoring of clinical tests), rather than interval
is reduced when information is discarded in the process of data, which shows both the order of magnitude and degree
categorization,88 and test reproducibility is poor. of magnitude, as the test assumes. In contradistinction to
When assessed across groups, individuals with dry eye the Pearson test, the alternative Spearman rank correlation
have universally been reported to have worse symptoms test does not make any assumption about the particular
as compared to those without dry eye (Table 3).2,7,20,67,89-93 nature of the relationship between variables, can be used
Furthermore, in studies where the dry eye group was subdi- on ordinal data, and is less sensitive to bias due to outliers

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 ASSOCIATION OF SYMPTOMS AND SIGNS IN DRY EYE / Johnson

effects. It follows that the Spearman test is generally prefer-
able in symptom and sign correlation analyses because it is
less prone to give misleading results.
Almost all studies that have examined the correlation
between the severity of symptoms and signs in dry eye have
found an association in the expected direction. This associa-
tion has not always attained statistical significance, but it
is noteworthy that the studies reporting negative statistical
significance have invariably been designed or analyzed in
a manner that increased the likelihood of false-negative
reporting of statistical outcomes. For example, with one ex-
ception,96 all studies that the author is aware of which report

Table 3. Comparison of symptoms in groups with and without dry eye.

Dry eye
Normal
(mild) (severe)
% above threshold or score
as indicated in method of
Study Sample, n Method of symptom assessment symptom assessment P-value
DEQ (abridged)—1 item
Frequency of dryness† 15% 57% 86%
Begley et al20 N & DE, 124 —
≥3 on ordinal 0–4 scale
DEQ (abridged)—1 item
Frequency of dryness† 0% 44% 76%
Begley et al67 N & DE, 122 —
≥3 on ordinal 0–4 scale
Bjerrum90 N & DE, 100 Presence of dryness† 5% 18% 85% —
McMonnies (abridged)—1 item
McMonnies & Ho89 N & DE, 568 19% 78% P < 0.01‡
Presence of dryness†
TERTC-DEQ—33 items
Multiple domains
Narayanan et al91 N & DE, 89 11.7 49.8 P < 0.01‡
Items have variable ordinal scales
Summed total 0–126
NEI-VFQ-25 (abridged)—2 items
Multiple domains
Nichols et al94 DE, 75 Items have ordinal 1–5 scale — 71.8% 60.8% P < 0.01‡
Percentage of max. score
n.b. o score ž m pain
McMonnies—14 items
Multiple domains
Nichols et al95 DE, 75 — 17.3 20.9 P = 0.02‡
Items have variable ordinal scales
Summed total 0–45
Severity of dryness†
Pflugfelder et al62 DE, 20 — 2.1 3.3 P ≤ 0.04‡
Ordinal 0–5 scale
IDEEL—57 items
Multiple domains
Rajagopalan et al92 N & DE, 210 9.92% 44.98% 59.25% P < 0.01‡
Items have variable ordinal scales
Percentage of max. score
OSDI—12 items
Multiple domains
Schiffman et al7 N & DE, 139 9.6% 20.8% 36.3% P ≤ 0.05‡
Items have ordinal 0–4 scale
Percentage of max. score
Average no. of symptoms present
Toda et al2 N & DE, 524 1.9 4.4 P < 0.01‡
Chosen from list of 14 symptoms
Severity of discomfort
2.5 mm 61 mm P < 0.01‡
Visual analogue scale, 0–100 mm
Tuisku et al93 N & DE, 30 OSDI—12 items
Multiple domains
5.3% 37.5% P < 0.01‡
Items have ordinal 0–4 scale
Percentage of max. score
N = Non-dry eye subjects; DE = Dry eye subjects.
DEQ = Dry Eye Questionnaire; OSDI = Ocular Surface Disease Index; TERTC-DEQ = Texas Eye Research and Technology Center Dry Eye.
† indicates that the study looked at more than one symptom, but for consistency only data on dryness is shown;
‡ indicates a statistically significant result, with Type 1 error set at 5%.

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 ASSOCIATION OF SYMPTOMS AND SIGNS IN DRY EYE / Johnson

non-statistically significant correlations between symptoms
and signs in dry eye have either used the Pearson correla-
tion, and by using this test made doubtful assumptions of
the data, or have used samples that exclusively contained
subjects with or without dry eye. However, regardless of
whether statistical significance is attained, the correlation
coefficients are generally low-to-moderate.106 Ignoring
studies at risk of attenuating correlation, namely those that
were limited to subjects with dry eye and those that used
the Pearson test on ordinal data, for common clinical tests,
the median correlation coefficient is 0.43. This indicates
that, typically, less than 20% of the variance of symptoms
is explained by signs observed with current techniques.
This means that, even when an association is present, it is
generally not possible to accurately predict the severity of
symptoms based on objective test results, or vice versa.
The study by Adatia and colleagues deserves special
attention, because it is unique in reporting a statistically
significant inverse correlation between symptoms and signs
in dry eye, specifically that symptoms lessened as lissamine
green staining increased.102 A similar trend was also reported
for fluorescein staining, but this did not attain statistical
significance. The authors cautioned against unconditional
acceptance of this conclusion, because the sample size of
Sjogren syndrome patients was small. This restricted sample
would have made its correlation coefficients vulnerable
to distortion, both through variance restriction and by
outliers, and limits its applicability to less severe dry eye.
Moreover, while the study assessed symptoms with three
different methods (12-item Ocular Surface Disease Index,
8-item Symptom Severity of Discomfort scale, and a single
question regarding the overall severity of dry eye), statistical
significance was only achieved for data based on the single
question, which is expected to be the least reliable method

Table 4. Proportion of individuals with positive symptoms of dry eye in groups of patients who either pass or fail objective
tests of dry eye.
Percent with +ve symptoms
Pass test Fail test
Study Sample, n Criteria for +ve symptoms Test ž non-dry ž dry eye P-value
Lactoferrin 9% 4%* P > 0.05
R/ST 4% 33% P > 0.05
N, 50
Schirmer 6% 0%* P > 0.05
TBUT 6% 6% P > 0.05
Bjerrum90 Presence of dryness†
Lactoferrin 86% 84% P > 0.05
R/ST 78% 88% P > 0.05
DE, 50
Schirmer 55% 92% P < 0.05‡
TBUT 50% 85% P > 0.05
Presence of ≥ 1 symptom
Hay et al97 N & DE, 341 Schirmer 25% 27% P > 0.05
Chosen from list of 3 symptoms
Frequency of symptoms F/S 33.6% 33.9% P = 0.91
Lin et al69 N & DE, 1361 8 items, 0–4 scale Schirmer 30.4% 36.1% P = 0.03‡
+ve when score ≥ 3 on ≥ 1 item TBUT 34.4% 33.6%* P = 0.79
F/S 9% 33% P < 0.01‡
Frequency of symptoms
McCarty N & DE, R/ST 8% 20% —
6 items, ordinal 0–3 scale
et al98 771-838 Schirmer 9% 12% P = 0.23
+ve when score = 3 on ≥ 1 item
TBUT 8% 18% —
F/ST 34.9% 50% P = 0.45
PRT 35.2% 66.7% P = 0.79
Frequency of symptoms
R/ST 35.8% 42.9% P = 0.41
Nichols et al4 DE, 75 5 items, ordinal 0–3 scale
Schirmer 33.9% 46.7% P = 0.34
+ve when score ≥ 2 on ≥ 3 items
TBUT 33.3% 37.5% P = 0.99
TMH 40% 35.2%* P = 0.79
Severity of discomfort Lactoferrin 54% 67% P > 0.05
Yolton et al96 N & DE, 49 4 it ems, ordinal 0–3 scale R/ST 54% 75% P > 0.05
+ve when sum ≥ 3 TBUT 38% 75% P < 0.05‡
Symptoms are typically more common in groups in which objective tests indicate dry eye.
*exception to this general trend.
N = Non-dry eye subjects; DE = Dry eye subjects.
F/S = Fluorescein staining (cornea); F/ST = Total fluorescein staining (cornea and conjunctiva); PRT = Phenol red thread;
R/ST = Total rose bengal staining (cornea and conjunctiva); TBUT = Tear breakup time; TMH = Tear meniscus height.
† indicates that the study looked at more than one symptom, but for consistency only data on dryness is shown. ‡ indicates a statistically
significant result, with Type 1 error set at 5%.

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 ASSOCIATION OF SYMPTOMS AND SIGNS IN DRY EYE / Johnson

Table 5. Correlation of symptoms with objective tests of dry eye.

Study Sample, n Method of symptom assessment Test Correlation P-value
OSDI; Multiple domains
12 items, ordinal 0–4 scale L/S –0.23r* P = 0.20
Percentage of max. score
SSD; Multiple domains
Adatia et al102 DE, 18 8 items, ordinal 0–4 scale L/S –0.27r* P = 0.12
Percentage of max score
Severity of discomfort P = 0.20
1 item, ordinal 1–4 scale F/S –0.22r*
L/S –0.43r* P = 0.01‡
Percentage of max score
Multiple domains
Afonso et al63 N & DE, 80 12 items, variable ordinal scale Schirmer –0.39 ρ P < 0.001‡
Summed total 0–56 Tear clearance 0.65 ρ P < 0.001‡

IC 0.84 ρ P< 0.01‡

Schirmer –0.71 ρ P< 0.01‡
Cennamo et al104 N & DE, 45 Method unclear SEM 0.80 ρ P< 0.01‡
Tear ferning 0.81 ρ P< 0.01‡
TBUT 0.48 ρ P< 0.01‡
Multiple domains IAI 0.27 ρ P < 0.01‡
de Paiva et al101 N & DE, 90 11 items, variable ordinal scale SAI 0.24 ρ P = 0.02‡
Summed total 11–59 SRI 0.31 ρ P < 0.01‡
Frequency of symptoms F/S 0.24 ρ P = 0.08
Gulati et al51 N & DE, 53 2 items, ordinal 1–4 score R/S 0.00 ρ P = 0.99
Summed total 2–8 Schirmer –0.34 ρ P = 0.01‡
TBUT –0.38 ρ P < 0.01‡
IC 0.28c P < 0.01‡
Jackson & Perrigin99 N & DE, 104 Presence of dryness Tear ferning 0.07c P = 0.46
Multiple domains F/S 0.47 ρ P < 0.01‡
Macri & Pflugfelder64 N & DE, 99 11 items, variable ordinal scale Schirmer –0.34 ρ P < 0.01‡
Summed total 0–48 Tear Clearance 0.35 ρ P < 0.01‡
Multiple domains F/S 0.50 ρ P < 0.01‡
Macri et al100 N & DE, 125 11 items, variable ordinal scale Schirmer –0.44r P < 0.01‡
Summed total 10–48 Tear Clearance 0.46 ρ P < 0.01‡
F/ST 0.15 ρ P = 0.21
PRT –0.24 ρ P = 0.05
Nichols et al4 DE, 75 Frequency of symptoms R/ST 0.18 ρ P = 0.15
5 items, ordinal 0–3 scale Schirmer –0.09 ρ P = 0.46
TBUT –0.05 ρ P = 0.68
TMH –0.09 ρ P = 0.47
F/ST 0.09 ρ P = 0.47
McMonnies PRT –0.09 ρ P = 0.47
Nichols et al95 DE, 75 Multiple domains R/ST 0.09 ρ P = 0.45
14 items, variable ordinal scales Schirmer –0.13 ρ P = 0.28
Summed total 0–45 TBUT –0.19 ρ P = 0.11
TMH 0.07 ρ* P = 0.56
OSDI; Multiple domains Schirmer –0.182r P = 0.14
Özcura & Helvaci103 N & DE, 68 12 items, ordinal 0–4 scale P = 0.01‡
Percentage of max. score TBUT –0.296r

Severity of discomfort F/S 0.54 ρ P < 0.01‡

Visual analogue scale, 0–100 mm Schirmer –0.51 ρ P < 0.01‡
TBUT –0.33 ρ P > 0.05
Tuisku et al93 N & DE, 30
OSDI; Multiple domains F/S 0.56 ρ P < 0.01‡
12 items, ordinal 0–4 scale Schirmer –0.47 ρ P < 0.01‡
Percentage of max. score TBUT –0.32 ρ P > 0.05
OSDI; Multiple domains Schirmer 0.04 ρ* NS
12 items, ordinal 0–4 scale TBUT 0.06 ρ* NS
Percentage of max. score L/ST 0.19 ρ NS
Vitale et al73 DE, 42
NEI-VFQ; Multiple domains Schirmer –0.04 ρ NS
25 items, ordinal 1–5 scale TBUT 0.24 ρ* NS
Percentage of max score L/ST 0.20 ρ NS
Lactoferrin –0.28r P < 0.05‡
Severity of discomfort
Yolton et al96 N & DE, 49 R/ST 0.24r P > 0.05
4 items, ordinal 0–3 scale TBUT –0.27r P < 0.05‡
There is typically a worsening of signs with worse symptoms, positive or negative correlation coefficient depending on the test.
*exception to this general trend; N = Non-dry eye subjects; DE = Dry eye subjects.
NEI-VFQ = National Eye Institute Visual Function Questionnaire; OSDI = Ocular Surface Disease Index; SSD = Symptom Severity of Discomfort scale.
F/S = Fluorescein staining (cornea); F/ST = Total fluorescein staining (cornea and conjunctiva); IAI = Irregular asymmetry index; IC = Impression cytology;
L/S = Lissamine green staining (cornea); L/ST = Total lissamine green staining (cornea and conjunctiva); NS = Not statistically significant;
SAI = Surface asymmetry index; SRI = Surface regularity index; PRT = Phenol red thread; R/S = Rose bengal staining (conjunctiva);
R/ST = Total rose bengal staining (cornea and conjunctiva); SEM = Scanning electron microscopy; TBUT = Tear breakup time; TMH = Tear meniscus height.
Correlation coefficient abbreviations: r = Pearson; ρ = Spearman; c = Contingency.
‡ indicates a statistically significant result, with Type 1 error set at 5%; NS = Not statistically significant (undefined).

THE OCULAR SURFACE / OCTOBER 2009, VOL. 7, NO. 4 / www.theocularsurface.com 205

 ASSOCIATION OF SYMPTOMS AND SIGNS IN DRY EYE / Johnson
of measuring ocular discomfort. It also used Pearson cor-
relation analyses inappropriately on ordinal data. These
considerations may explain why the results of this study
oppose the general trend reported by others.
V. THEORETICAL CONSIDERATIONS
Theoretical reasons to expect only a partial concordance
between the severity of symptoms articulated by patients
and the results of objective clinical tests are described below.
A. Artificial Test Environment
Symptoms generally refer to experiences in environ-
ments to which patients are habitually exposed, but these
environments differ between individuals and may be very
different from the conditions during testing. For example,
reports of dry eye symptoms in office workers who use
visual display terminals are higher than in non-office work-
ers,107 who presumably have no difference in their predispo-
sition, and an experimental study has found symptoms to
increase with use of a computer.108 These reports are prob-
ably explained by a concentration-related reduction in blink
rate.108,109 Symptoms are likely a time-integrated evaluation
by patients, rather than what they are feeling at a given mo-
ment, whereas clinical tests are generally done at one point
in time. Also, some tests assess the propensity of an individ-
ual to experience dry eye, particularly tests that assess tears
rather than the ocular surface, but the manifestation of the
disease is to some extent dependent on the environmental
challenges to which patients are habitually exposed.34,110-112
B. Nonlinear Sensory Response to Stress
The purpose of ocular surface sensation is likely not to
precisely measure stimulus intensity, but to act as a warning
system to protect the eye from injury and provide feedback
in a homeostatic loop with the lacrimal glands.11,113-117 Such
a system may be expected to have a rapid gain in response
to stimulus stress and quickly be firing maximally. In con-
trast to information on sensory thresholds, experimental
data on the perception of suprathreshold stimuli is sparse.
A gas esthesiometer with variable flow rate can be used to
selectively stimulate the ocular surface with mechanical,
thermal, or chemical stimuli.117 Chemical stimulation is
achieved by varying the mixture of carbon dioxide with
air, which leads to a localized reduction of pH at the eye
through the production of carbonic acid on contact. With
this instrument, perceived intensity, assessed with a vi-
sual analog scale (VAS), has been reported to level off as
mechanical stimulation is increased, consistent with the
reasoning that the response of nerves does not continue
to rise indefinitely.9,118,119 However, in the same group of
studies, a plateau in perceived intensity was not found when
the percentage of carbon dioxide was increased from 0% to
80%, and results were equivocal for temperature changes
ranging from -5n to +3nCelsius. Interestingly, in a similar
experiment, the absence of a plateau and an accelerating
increase in pain was reported as skin temperature was either
warmed or cooled.120
206 THE OCULAR SURFACE / OCTOBER 2009, VOL. 7, NO. 4 / www.theocularsurface.com
It is not possible, however, to make robust conclusions
from these studies. Although the length of the VAS response
is measured on a linear scale, it does not follow that it repre-
sents the latent trait of interest on a linear interval scale, and
so it may distort graphical representations of associations
between data.121 Also, the average VAS scores in these stud-
ies did not exceed halfway on their 0 to 10 cm scales for even
the most intense stimulus. Therefore, the possibility cannot
be excluded that the perception of stimulus intensity for
chemical or thermal insult reaches a plateau and would not
continue to increase if intensity were increased further. It is
noteworthy that in earlier related work on cats, where the
discharge rate of corneal polymodal nerves was monitored
as carbon dioxide stimulus increased from 0% to 100%, fir-
ing rates reached a plateau for the highest concentrations.122
C. Altered Sensory Responsiveness With Time
Ocular surface disease is accompanied by changes to
the responsiveness of its sensory nerves. Responsiveness
can be reduced with sustained stimulation, as occurs dur-
ing the adaptation period of contact lenses,123-125 but, more
typically, when inflammation is present, nerves become
sensitized and develop a lowered threshold for activa-
tion.12,33 Hypersensitivity of the ocular surface has been
reported in dry eye,93,126 although, as explained below, a
hyposensitivity can also develop in the condition. These
changes in responsiveness to peripheral stresses occur both
peripherally and centrally.127
Altered nerve morphology has been observed in dry
eye.128-131 When the connection of the cell body with its
terminal is interrupted, and, hence, connection with the
peripheral target, it is intuitively expected that corneal
sensitivity would be reduced. A raised corneal sensitivity
threshold in dry eye has been reported by several groups128-
133; however, the possibility of altered gradients in the
stimulus-response function of nerves cautions against the
extrapolation of these results to suprathreshold stimuli.
It must also be appreciated that any reduction in corneal
sensitivity through injury is not synonymous with nerve
quiescence, because maladaptive changes can produce al-
terations in function, such that nerves fire spontaneously or
in response to normally innocuous stimuli.12,13,127 Ectopic
firing in damaged nerves can produce sensory inflow in
the absence of sensory stimuli or peripheral inflamma-
tion. Moreover, when activated, the afferent nerves of the
cornea can release neurotransmitters and other substances,
including calcitonin gene-related peptide and substance P,
which facilitate production of the inflammatory mediators
from neighboring non-neuronal cells and vascular tissue, a
phenomenon termed neurogenic inflammation.12,13,127,134,135
Nerve injury can also lead to epitheliopathy through re-
duced trophic support.136
It has been postulated that neuropathic pain is an impor-
tant source of symptoms in some individuals complaining
of ocular surface discomfort, most notably following cor-
neal refractive surgery, where the influence of neuropathic
pain may exceed the well-documented reduction in tear
 ASSOCIATION OF SYMPTOMS AND SIGNS IN DRY EYE / Johnson
production.137-141 In these procedures, corneal nerves are
directly damaged during laser ablation, and, additionally
in laser in-situ keratomileusis (LASIK), by the cutting of
a corneal flap.142
D. Duration of Disease
Disease duration may have an influence on the relation-
ship between symptoms and signs. It seems reasonable to
assume that the length of time that an individual has had
dry eye, in combination with the severity of the disease,
determines the extent of altered nerve responsiveness and
damage. Disease duration is expected to be particularly im-
portant with tests that examine tears, because there is a delay
between the onset of tear anomalies and ocular surface inju-
ry, and, therefore, ocular surface nerve stimulation. Further-
more, a growing disconnection between the degree of tear
anomaly and ocular surface injury could develop if tissue
damage occurs at a rate that exceeds its regenerative capacity.
There is currently little experimental information on the
effects of natural progression of dry eye on symptoms and
signs to confirm these suppositions. Published studies that
have investigated longitudinal changes in the disease have
had a retrospective design and have been based on patients
undergoing an assortment of treatments. It is noteworthy
that these studies have had a strong bias toward severe
disease at presentation, with a predominance of Sjogren
syndrome, which limits the applicability of their findings
to less severe disease. Most of these studies have concluded
that dry eye undergoing treatment is a relatively stable con-
dition, with severe disease tending to worsen and moderate
disease tending to improve.143-147
E. Masquerading Disease and Comorbidy
Symptoms of ocular discomfort, including the percep-
tion of dryness, can be misattributed to dry eye. The dis-
criminatory ability of the ocular surface is crude,9,119,148 so
nearly identical perceptions may result from quite different
causes. Dryness of the eyes is commonly experienced, even
on a sporadic basis, by people without dry eye, so it is un-
derstandable that, when the brain receives a similar signal
from the ocular surface, it is perceived and subsequently
articulated as dryness. This is one important reason why,
in making a clinical diagnosis, a physical examination can-
not be replaced by simply asking patients if they have dry
eyes. Other diseases can masquerade as dry eye, and these
may require different management.149-151 Additionally, dry
eye is a heterogeneous disease and ocular examination is
required to clarify the etiological factors in an individual
that will direct treatment.
VI. SUMMARY AND CONCLUSIONS
Inferences on the strength of the relationship reported
between symptoms and signs in dry eye must be interpreted
in the context of similarly poor correlations between dif-
ferent objective tests and, more ominously, less than ideal
agreement between single tests when they are repeated on
different days. Measurement of the strength of association
THE OCULAR SURFACE / OCTOBER 2009, VOL. 7, NO. 4 / www.theocularsurface.com
between two variables is underestimated if either has poor
accuracy or repeatability. It is, therefore, possible that a
clinically significant relationship between symptoms and
signs exists, but is masked by the deficiencies of current
objective tests. This is contrary to the common belief that
untrustworthy patient testimonies are responsible for the
poor association between symptoms and signs. Indeed, it
is, in part, because of the perceived better accuracy of signs
versus symptom assessment that some disease classifica-
tion algorithms are exclusively based on objective tests,
such as the Copenhagen and Japanese criteria for Sjogren
syndrome.152,153 This is despite reports that symptoms are
more repeatable than signs,77,154 and that higher correla-
tions exist between questionnaires than between objective
tests (Table 1 and Table 2).
The notion that the correlation between symptoms and
signs is attenuated by poor objective test accuracy attains
credibility from the fact that the highest correlation coef-
ficients are reported from studies that have used laboratory
techniques to assess the ocular surface, such as impression
cytology and scanning electron microscopy,104 which the
author believes to be the most dependable objective assess-
ments. In this regard, it is noteworthy that the majority
of clinicians consider the clinical history to be the most
important part of the dry eye examination.155-157
Notwithstanding the issue of poor objective test reli-
ability, deficiencies in our ability to assess the severity of
symptoms experienced by patients also limit our ability to
determine the nature of the association between symptoms
and signs. Symptoms are subjective, so there are inherent
difficulties with their assessment, but poor methodology
introduces avoidable sources of variability. As an aside,
while the use of well-designed questionnaires to measure
symptoms is emphasized here, it should be recognized
that these have a narrow focus and, although ideal for
detecting change in clinical trials or the responsiveness to
management interventions, they are not a substitute for a
conversational history-taking in the clinical setting.
Some patients with dry eye experience discomfort
out of proportion to the threat that their disease poses to
ocular health, and, in this review, it has been postulated
that in advanced dry eye, a neuropathic origin of pain may
be important. This suggests that it may be advantageous
to manage symptoms in selected cases as a chronic pain
disorder, and target the aberrant nerves and pain pathways
diectly.12,158 Such an approach would need to be strictly
limited to patients who remain incapacitated by their symp-
toms after all attempts to improve ocular surface health
have been made, because such treatment would reduce
the patient’s ability to detect and appropriately respond to
new potentially harmful stimuli.
The relationship between the severity of ocular discom-
fort and signs in dry eye is not only relevant to clinicians, but
also to researchers undertaking clinical trials. In advanced
chronic dry eye, alterations to sensory nerve morphology
and responsiveness cause a disconnection between pe-
ripheral stimulation and nerve excitation,128-131 which can
207
 ASSOCIATION OF SYMPTOMS AND SIGNS IN DRY EYE / Johnson
reduce ocular surface sensitivity. Thus, it is possible that
symptoms may lessen when dry eye progresses from moder-
ate to severe.102 Therefore, it is plausible that treatment of
severe dry eye may lead to an initial worsening of symptoms
if the more favorable ocular surface conditions engendered
permit nerve regeneration. However, based on studies done
elsewhere in the body, it is anticipated that corneal nerve
injury is associated with more variable ocular irritation
and a paradoxical increase in pain.12,127 It follows that the
statistical power of clinical trials that monitor symptoms
will be lowered by the inclusion of subjects with the most
severe diseases, but this presents a quandary, because these
are the individuals who most need treatment. An alternative
approach to lessening the impact of symptom variability in
clinical trials is the tracking of the non-discomfort symp-
toms of dry eye, such as fluctuating vision and complaints
of redness. However, it is the author’s opinion that, because
ocular discomfort is the primary complaint in dry eye, it is
inappropriate to ignore it when evaluating treatments.
Fluctuating vision and redness can be objectively as-
sessed and in an automatic manner so as to avoid subjec-
tive variability on the part of the investigator.159-161 This is
appealing, because it may allow for greater measurement
precision. However, it is doubtful whether an external obser-
vation of something truly represents its internal perception
or psychological burden. The scoring of available question-
naires that inquire about either vision or redness in dry eye
combine this information with that acquired on symptoms
of discomfort,7,20,92 which hinders interpretation of the re-
sulting index. These are different symptom domains, and
to avoid ambiguity, they should be measured in parallel.
At this time, it is not possible to confidently make con-
clusions on the nature of the relationship between symp-
toms of ocular discomfort and physical changes to tears or
the ocular surface in dry eye because of limitations in our
ability to measure either individually. In this regard, it must
also be realized that patterns of association pertaining to
specific symptoms and signs may not apply to all symp-
toms and signs. Notwithstanding these limitations, based
on recurring patterns in published data, it can be stated
with reasonable certainty that there is typically a positive
relationship between the severity of symptoms and most
objective tests in dry eye. However, the balance of current
data suggests that the association between symptoms and
the majority of these tests is at best moderate, and, thus, the
severity of symptoms cannot be estimated with an informa-
tive degree of precision from physical signs, or vice versa. It
follows that neither of these facets of dry eye can be ignored
in the dry eye examination, and that requiring both to be
abnormal as a criterion for treatment initiation may deny
treatment to patients who would benefit from it.
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