See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/320918634

Slit Lamp-Based Ocular Scoring Systems in Toxicology and Drug Development: A

Literature Survey

Article in Journal of Ocular Pharmacology and Therapeutics · November 2017

DOI: 10.1089/jop.2017.0021

CITATION READS

1 113

5 authors, including:

Joshua Seth Eaton Sara M Thomasy

Ocular Services on Demand University of California, Davis
13 PUBLICATIONS 28 CITATIONS 77 PUBLICATIONS 918 CITATIONS

SEE PROFILE SEE PROFILE

Christopher J Murphy
University of California, Davis
365 PUBLICATIONS 10,242 CITATIONS

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Mechanobiology of the outflow pathway View project

Translational Science View project

All content following this page was uploaded by Christopher J Murphy on 06 December 2017.

The user has requested enhancement of the downloaded file.

JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS INVITED REVIEW
Volume 33, Number 10, 2017
ª Mary Ann Liebert, Inc.
DOI: 10.1089/jop.2017.0021

Slit Lamp-Based Ocular Scoring Systems

in Toxicology and Drug Development:
A Literature Survey

Joshua Seth Eaton,1,2 Paul E. Miller,1,3 Ellison Bentley,1,3 Sara M. Thomasy,1,2 and Christopher J. Murphy1,2,4

Abstract

Purpose: To present a survey of the features of published slit lamp-based scoring systems and their applicability
in the context of modern ocular toxicology and drug development.
Methods: References describing original or modified slit lamp-based scoring systems for human or veterinary
clinical patients or in investigative or toxicologic research were collected following a comprehensive literature
review using textbooks and online publication searches. Each system’s indications and features were compiled
to facilitate comparison.
Results: Literature review identified 138 original or modified scoring systems. Most (48%) were published for
evaluation of the ocular surface, 34% for the general anterior segment, and 18% for the lens. Most systems were
described for assessment of human patients (50%) and small albino laboratory species such as rabbits (19%),
rats (12%), and mice (8%). Systems described for pigmented laboratory species and for larger species such as
dogs, cats, pigs, and nonhuman primates (NHPs) were comparatively underrepresented. No systems described a
lens scoring scheme specific to the dog, cat, pig, or NHP. Scoring schemes for aqueous and vitreous cells were
infrequently described for laboratory species.
Conclusions: Many slit lamp-based scoring systems have been published, but the features of each differ and
complicate translation of findings between different species. Use and interpretation of any scoring system in
toxicology and drug development must be done with awareness of the limitations of the system being used.

Keywords: slit lamp, scoring, ocular, toxicology, drug development

Introduction of cross-sectional illumination permits clinical examiners

S lit lamp biomicroscopy is a requisite component of
clinical ophthalmic evaluation in physician-based and
veterinary ophthalmology. Introduced by Nobel Prize
Laureate Allvar Gullstrand in the early 20th century, the slit
lamp biomicroscope provides examiners the magnification
required to evaluate the eye’s anterior structures and optical
media in detail and to diagnose ocular disease. The slit lamp
derives its namesake from its capacity to produce a narrow
‘‘slit’’ beam of illumination.
Transmission of this beam through the precorneal tear
film, cornea, anterior chamber (AC), iris, lens, and anterior
vitreous provides the examiner with an in vivo optical sec-
tion of the anterior ocular anatomy (Fig. 1). This technique
to identify and spatially localize important ocular patholo-
gies of the anterior segment such as corneal opacification,
changes in corneal thickness and contour, AC flare, AC cells,
lens opacities, and opacities and cells in the anterior vitreous.
Since its introduction, Gullstrand’s original table-mounted
instrument has undergone numerous adaptations and modi-
fications, improving its range of functionalities and versa-
tility in the evaluation of clinical patients.1 Through these
modifications, today’s instrument delivers superior optics,
provides clinicians a variety of illumination settings, and can
enable capture of high-resolution digital images.
Furthermore, development of compact, lightweight, por-
table handheld instruments, such as the Kowa SL Series,
Keeler Classic PSL Portable Slit Lamp, Reichert PSL

1
Ocular Services On Demand (OSOD), LLC, Madison, Wisconsin.
2
Department of Surgical & Radiological Sciences, School of Veterinary Medicine, University of California–Davis, Davis, California.
3
Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin–Madison, Madison, Wisconsin.
4
Department of Ophthalmology & Vision Science, School of Medicine, University of California–Davis, Sacramento, California.

1
2 EATON ET AL.
FIG. 1. (a, b, c, d). Representative slit lamp
photographs illustrating slit lamp illumination
of the anterior segment in the normal pig-
mented mouse (a), albino rabbit (b), dog (c),
and cynomolgus macaque (d).
Portable Slit Lamp, Haag-Streit 904 Portable Slit Lamp,
and the Zeiss HSO-10, has provided clinical ophthalmol-
ogists and vision scientists additional versatility to examine
a full range of domesticated, laboratory, and wildlife species
(Fig. 2). Handheld slit lamps are often preferred in animals
because many species’ skull conformations, temperaments,
and frequent movements during unanesthetized examinations
make table-mounted units cumbersome and unwieldy.
FIG. 2. A veterinary ophthalmologist using a handheld
Kowa SL-15 to examine an unanesthetized dog.
The fundamental anatomic features of the anterior seg-
ment are similar between humans and other vertebrates,
enabling similar biomicroscopic techniques to be used in
numerous species.2–7 These parallels also present theoretical
advantages in comparative and translational investigations
when comparing ocular responses between laboratory spe-
cies and human patients. Thus, slit lamp examination and
semiquantitative slit lamp-based scoring of examination
findings are essential components of toxicologic and pre-
clinical drug safety evaluations for both ocular and systemic
drugs and ocular devices. Together, they enable detailed
characterization and semiquantitative assessment of ocular
inflammation or other adverse effects, precise longitudinal
monitoring of examination findings, and insurance of animal
welfare.8,9
While no scoring system represents a true ‘‘standard’’ for
use in toxicology and preclinical drug development, systems
like the Standardization of Uveitis Nomenclature (SUN;
Supplementary Table S1; Supplementary Data are available
online at www.liebertpub.com/jop)10 and those of Draize
(Supplementary Table S2),11 McDonald-Shadduck,12 and
Hackett-McDonald13 are widely used.8,9 However, these sys-
tems were derived through a diversity of methodologies and
for a variety of indications, and each is associated with its own
unique limitations in the preclinical setting.
The SUN system, for example, was developed to stan-
dardize clinical evaluation of human patients with naturally
occurring uveitic disease,10 whose spectrum of ocular in-
flammation may differ from those of laboratory species. Al-
though the Draize system has been used widely in regulatory
SLIT LAMP SCORING IN PRECLINICAL DRUG DEVELOPMENT 3

evaluations of industrial products,11 it has frequently been
criticized for its inconsistent reproducibility and questionable
relevance across all industries, particularly the pharmaceuti-
cal industry; and some suggest that the numerous modifica-
tions made to this system throughout the late 20th century
underscore its inherent shortcomings.14 Publication of the
ocular irritation scoring systems of McDonald–Shadduck and
Hackett–McDonald provided expanded criteria for anterior
segment evaluation, but like the Draize system, the criteria
comprising each were designed only with respect to albino
rabbits. Furthermore, none of the aforementioned systems
contains a full complement of the scoring criteria required for
toxicologic studies or safety evaluations in modern drug de-
velopment (Table 1).
The lack of standardization for ocular scoring systems in
ocular drug and device development, apparent lack of cri-
teria developed for laboratory species other than albino
rabbits, and the limitations of today’s most commonly used
systems prompted our group to survey the available litera-
ture. Specifically, our goal was to identify, if possible,
scoring systems or schemes with applicability to a wider
range of species or those with greater pertinence to the
needs of modern drug development. Herein we present a
comparative analysis of the results of this survey.
Methods
Original or modified slit lamp-based scoring systems (in-
cluding systems using slit lamp-derived photographic stan-
dards or those citing or recommending slit lamp-assisted
magnification) were identified following a comprehensive
literature review using textbooks and online publication sear-
ches, including PubMed, MEDLINE, Google Scholar, and
Scopus. Keywords or terms searched included ‘‘slit lamp
scoring (grading),’’ ‘‘ocular scoring (grading),’’ ‘‘ocular
scoring (grading) system,’’ ‘‘slit lamp evaluation,’’ ‘‘eyelid
scoring (grading),’’ ‘‘adnexal scoring (grading),’’ ‘‘conjunc-
tival scoring (grading),’’ ‘‘corneal scoring (grading),’’ ‘‘ante-
rior segment scoring (grading),’’ ‘‘uveitis scoring (grading),’’
‘‘aqueous (anterior chamber) scoring (grading),’’ ‘‘aque-
ous (anterior chamber) flare scoring (grading),’’ ‘‘aqueous
(anterior chamber) cell(s) scoring (grading),’’ ‘‘ocular irri-
tation scoring (grading),’’ ‘‘ocular inflammation scoring
(grading),’’ ‘‘lens scoring (grading),’’ ‘‘lens opacity scoring
(grading),’’ ‘‘vitreous cell(s) scoring (grading)’’ ‘‘cataract
scoring (grading),’’ ‘‘dry eye scoring (grading),’’ ‘‘ocular
surface scoring (grading),’’ ‘‘ocular fluorescein scoring
(grading),’’ and ‘‘ocular surface stain scoring (grading).’’
References were included if they cited or described a
scoring system for use in human or veterinary clinical pa-
tients or in investigative or toxicologic research involving
laboratory species. The indications, methodologies, scoring
parameters and schemes, and techniques associated with
each system were compiled to facilitate comparison.
Scoring systems were subdivided into 3 anatomical cate-
gories: (1) general anterior segment, describing scoring criteria
for uveitis/anterior segment inflammation or ocular irritation;
(2) lens systems, describing scoring criteria for lens opacities
and cataracts; and (3) ocular surface systems, indicated pri-
marily for scoring of the adnexa, corneoconjunctival/scleral
surface, or tear film. Systems were further stratified according
to the species for which they were primarily described, as well
as general indication (ie, clinical, investigative, or toxicologic/
preclinical). The ocular anatomical structure(s) and parameters
clinically evaluated by each system were analyzed; and, when
specified, the method of validation and slit lamp settings or
specifications were also evaluated.
Results
At the time of the survey, 138 published slit lamp-based
scoring systems were identified; 47 (34%) describing criteria for
the general anterior segment, 25 (18%) for the lens, and 66 (48%)
for the ocular surface. Analysis of all systems with respect to
species and general indication is presented in Table 2. Across all
systems, most were described for human patients (69 [50%]),
followed by rabbits (26 [19%]), rats (16 [12%]), and mice (11
[8%]). Among the systems described for rabbits, rats, and mice,
the majority (23/26 [88%], 15/16 [94%], and 6/11 [55%], re-
spectively) specified criteria for evaluation of albino strains.
Scoring systems designed for evaluation of larger animal species
were less frequently described, with only 6 for the dog, 2 for the

Table 1. Comparison of Parameters and Species Examined by Common Slit Lamp-Based Scoring
Systems in Toxicology and Drug Development
McDonald– Hackett– Standardization of Uveitis
Shadduck12 McDonald13 Draize11 Nomenclature (SUN)10
Conjunctival congestion X X X
Conjunctival swelling X X X
Conjunctival discharge X X X
Corneal opacity (Severity) X X X
Corneal opacity (Area) X X X
Fluorescein stain (Severity) X X
Fluorescein stain (Area) X X
Pannus (corneal vascularization) X X
AC flare X X X
AC cell X
PLR (Pupillary light reflex) X
Iris involvement/iritis X X X
Lens X
Vitreous cells
Original species described Albino rabbit Albino rabbit Albino rabbit Human patient
A ‘‘X’’ indicates that the above system contains scoring criteria for the corresponding parameter at the left.
AC, anterior chamber.
4 EATON ET AL.

Table 2. Number of Scoring Systems (According to Anatomical Category)

According to Species Examined and General Indication
General anterior segment Lens/cataract Ocular surface All scoring
systems8,10–13,26,32,34–73 systems74–98 systems99–164 systems
Species examined
Fish 0 1 0 1
Mouse 1 3 7 11
Rat 8 3 5 16
Rabbit 17 1 8 26
Cat 1 0 1 2
Dog 3 0 3 6
Pig 1 0 1 2
Sheep 0 3 0 3
Nonhuman primate 1 0 0 1
Multiple laboratory species 1 0 0 1
Human patient 14 14 41 69
General indication
Clinical—Human 14 14 41 69
Clinical—Veterinary 1 1 4 6
Investigative 16 8 14 38
Toxicology/preclinical 16 2 7 25

cat, 2 for the pig, and 1 for the nonhuman primate (NHP). Of
these systems published for larger species, none were compre-
hensive, typically containing only a small number of parameters
for evaluation of the anterior segment, or the ocular surface or
cornea.
Among the 47 general anterior segment scoring systems,
17 (36%) were described for the rabbit (16 for albino
strains), 14 (30%) for human patients, and 8 (17%) for the
rat (7 for albino strains). However, systems scoring the lens
and ocular surface were much more commonly described for
human patients (14/25 [56%] and 41/66 [62%], respective-
ly). Also of note, no systems were found describing a lens
scoring scheme specific to the dog, cat, pig, or NHP.
Clinical assessment of human patients was the most common
indication for development of a scoring system, accounting for
approximately half of all systems (69/138). Of these, the ma-
jority (41 [59%]) were systems described for evaluation of the
ocular surface. Scoring systems were also commonly described
for investigative studies (38 [28%]) or toxicologic or preclinical
drug evaluations involving small or large laboratory species (25
[18%]). Among those described for preclinical drug evaluations,
however, only 4 were published for larger species (2 for the pig,
1 for the dog, and 1 for the cynomolgus macaque). Six systems
were described for clinical evaluation of veterinary patients (3
for the dog, 2 for the cat, and 1 for fish).
All systems were analyzed according to the ocular
structure(s) for which they had scoring criteria, with respect
to primary species and general indication (Table 3). Among
all systems, attributes of the conjunctiva and cornea/sclera
were most commonly scored (51/138 [37%] and 53/138
[38%], respectively), the majority of which were from sys-
tems described for human patients or rabbits (38/51 [75%]
and 33/53 [62%], respectively).
Scoring schemes for AC flare and AC cells were com-
monly described for human patients (9/24 [38%] and 13/21
[62%], respectively), but only one scheme for AC cells was
reported in the rabbit. Conversely, systems scoring iritis and
general aqueous humor findings such as infiltrate, hypopyon,
or hyphema were seldom described for human patients, but
more commonly reported for the rabbit and rat. Schemes for
vitreous cells were rarely cited, primarily described for
human patients (3/5), and also in the NHP (1/5) and pig (1/
5). Scoring schemes for ocular surface vital staining (ie,
fluorescein and Rose Bengal) were most commonly de-
scribed for human clinical patients.
It is noteworthy that statistical analyses of inter- or in-
traobserver variability or reproducibility were only described
or cited in 18/138 systems (13%; 6 for general anterior seg-
ment, 6 for lens, and 6 for ocular surface). Of these 18 systems,
12 were described for clinical evaluation of human patients
and 6 for toxicologic/preclinical studies (4 in the albino rabbit
and 2 in the pigmented mouse). Furthermore, slit lamp settings
and/or descriptions of examination technique were only spec-
ified in 24/138 (17%) systems (10 for general anterior segment,
7 for lens, and 7 for ocular surface).
Discussion
The present survey identifies a large number of published slit
lamp-based scoring systems, widely distributed across the lit-
erature, describing criteria for evaluation of the anterior seg-
ment in humans and animals. Ocular scoring systems, like
those used in other medical fields, are accessible and attractive
clinical tools. Specifically in ocular toxicology and drug safety
evaluation, these systems enable investigators and vision sci-
entists to accurately identify and reliably assess the magnitude
and duration of adverse effects, compare examination findings
between study groups, determine optimal dosing regimens, and
swiftly ensure the welfare of animals used in studies.
Often in question, however, is the precision of published
systems in the context of modern ocular drug and device
development and, therefore, their applicability and trans-
latability. Reproducibility of any system in a population
other than the one used for its development is modest at
best15,16; and system’s subjective criteria may also be
influenced by study-specific objectives or even institutional
bias, complicating applicability in other studies or pro-
grams.17 This survey and review of the literature found that
evaluations of precision, namely intra- and/or interobserver
reproducibility, were rarely reported in slit lamp-based
SLIT LAMP SCORING IN PRECLINICAL DRUG DEVELOPMENT 5

Inflammation
scoring systems developed for animals. In part, this may
General
Ocular
help to explain the industry-wide popularity of the systems

0
0
0
0
0
1
0
0
0
0

0
1
0
0

1
of McDonald–Shadduck and Hackett–McDonald, which
Number of Scoring Systems Containing Parameters for Various Ocular Structures, According to Species and General Indication

were published in tandem with reproducibility assessments.

Despite their importance in preclinical drug development
programs, this review identifies noteworthy limitations of the
Height

most commonly used ocular scoring systems for laboratory

Film
Tear

0
0
0
0
0
0
0
0
0
0

2
0
0
0

2
species when applied to studies in modern preclinical drug
and device safety evaluation (summarized in Table 4). A
principal limitation of common systems like those of Draize,
Conjunctival

McDonald–Shadduck, and Hackett–McDonald is that their

Corneal/

Staining

scoring criteria are designed specifically with respect to ocular

0
0
0
1
0
0
0
0
0
0

17

17
0
0
1

18
anatomic features of albino rabbits. Current regulatory stipu-
lations, however, require preclinical evaluation in at least 2
nonhuman species18; and for many models of human ocular
disease, larger species like the dog and NHP are considered
Vitreous
Cells

more ideal for translating findings to the human condition.19,20

0
0
0
0
0
0
1
0
1
0

3
0
0
2

5
With only a small number of published systems describing
criteria specific to larger species, rabbit-specific systems are
often modified or applied as surrogate systems for species like
Lens

1
3
3
3
1
0
0
3
0
0

9
1
9
4

23
NHPs or dogs. This approach, however, fails to account for the
substantive differences in ocular morphology between these
species (ie, lack of distinctly perilimbal conjunctival vascula-
Iris

0
1
5
14
1
0
1
0
0
1

2
0
9
14

25

ture in nonrabbit species and presence of iridal pigment) and

the possible effect on scoring precision and accuracy. Fur-
thermore, ocular melanin, present in the eyes of most human
Pupil/
PLR

0
0
5
5
1
1
1
0
0
0

1
0
7
6

14

patients, can influence drug pharmacokinetics and pharmaco-

dynamics, distribution, and efficacy.21–23 Therefore, use of
pigmented strains and species as models for drug distribution,
Cells
AC

efficacy, and toxicity in human eyes is a requisite consideration

0
0
4
1
0
0
0
0
1
2

13

13
0
5
3

21

in preclinical drug evaluation and also necessitates accurate

scoring.
Flare

Also lacking from the aforementioned systems (and the

AC

0
0
4
5
1
2
1
0
1
1

9
1
8
6

24

majority of those described for examination of animals) are

standardized instrument settings, critical factors when evalu-
ating the repeatability or reproducibility of any slit lamp-
(General)
Aqueous
Humor

based scoring system. When using a slit lamp biomicroscope

0
1
7
9
1
2
0
0
0
0

1
0
15
5

21

to examine the eye’s clear media, dimensions such as slit

beam height and width and angle of illumination determine
the optical section volume sampled. Variations in these pa-
Cornea/

rameters will change the volume examined and potentially

Sclera

0
6
6
18
1
4
2
0
0
1

15

15
2
20
16

53

confound semiquantitative scoring of findings such as AC or

vitreous cells.
Egress of inflammatory cells into the aqueous humor is a
Conjunctiva

common clinical feature of anterior uveitis in any species,

and scoring of cell severity aids longitudinal monitoring of
0
3
2
18
2
4
1
0
0
1

20

20
3
13
15

51

disease and response to therapy. This parameter is not in-

cluded in the aforementioned rabbit-specific systems; so
instead, the human SUN system is commonly utilized as a
surrogate in preclinical studies24 and unlike those systems,
Periocular

SUN does specify slit lamp settings. However, the cell

Eyelid/

0
3
0
3
0
0
0
0
0
0

0
3
3
13

13

19

scoring (based on total number of cells identified in the

volume of aqueous sampled by the slit beam) specified by
the SUN system’s scoring scheme is not directly transpos-
able to those observed in species with markedly differing
Total number of systems
Toxicology/preclinical

AC volumes and geometries.

Clinical–Veterinary
Multiple laboratory
Nonhuman primate

Our group recently published a mathematical analysis

Clinical–Human
General indication
Species examined

Human patient

demonstrating the consequences of a species’ varying an-

Table 3.

Investigative

terior segment geometry on AC cell count using, among

species

others, the SUN system.18 As SUN enumerates the cells

Rabbit
Mouse

Sheep

present in the total volume of aqueous sampled by its

Fish

Dog
Cat
Rat

Pig

1 · 1 mm slit lamp beam, geometric modeling of the AC and

optical section volume of different species yielded widely
6 EATON ET AL.

Provides standardized slit lamp settings and scoring criteria for human

Widely used in clinical ophthalmology and preclinical ocular drug and

differences in anterior segment geometry and anatomy in laboratory

differing results. In dogs and cats and other species with

Does not include scoring criteria inclusive of hypopyon or hyphema

Exact slit lamp settings, as published, can be difficult to reproduce
deeper AC depths, much larger optical section volumes are

adequate capture of differential responses in laboratory species

Aqueous cell density scoring peaks at values that may not allow
sampled by the slit beam compared to humans. This results

Aqueous cell scoring and slit lamp settings do not account for
in identical SUN cell scores representing very different cell
densities (cells/unit volume). A given score in a dog or cat
with larger volumes of aqueous being optically sampled
would overpredict a score in humans (assuming identical #

Does not specify scoring criteria for vitreous cells

Nomenclature (SUN) system10

cells/unit volume). Conversely, because AC depth is com-

Standardization of Uveitis

paratively much smaller in rodents, SUN’s 1 mm-wide slit

patients with naturally occurring uveitis

beam samples a much smaller aqueous volume, yielding

Key Attributes and Limitations of Commonly Used Slit Lamp-Based Ocular Scoring Systems

counts that would greatly underpredict human values (as-

suming identical # cells/unit volume).18
Of course, contributing to the translatability of scores

using handheld instruments

obtained in any species would be the relative reactivity of
the eye to a given test article or implanted device. Un-
fortunately, there is an appreciable knowledge gap with
device development

regard to this important issue. For example, rabbits represent

for Laboratory Species in Ocular Toxicology and Drug Development

Published in 2005

a terrestrial prey species with prominent and wide-set globes

and are inherently at higher risk of ocular trauma and are
generally held to possess greater sensitivity to ocular injury
species.

characterized by a rapid and dramatic breakdown of the

blood–ocular barriers.25 Conversely, foraging and/or arbo-
real species like the NHP with deeper set eyes and a much
greater requirement for maintaining visual acuity possess
Do not specify scoring criteria for AC or vitreous
Expanded upon the limited scoring criteria offered

comparatively less AC activity.25

Provide ocular scoring criteria specific to ocular

this complicates scoring in pigmented strains

McDonald–Shadduck and Hackett–McDonald

ocular anatomical features of albino rabbits;

Do not specify standardized slit lamp settings

Furthermore, even in laboratory species yielding values

Scoring schemes and criteria are designed to
Validated through evaluation of intra- and

that overpredict human values (eg, dogs), interspecies in-

Published in 1977 and 1996, respectively

and other relevant laboratory species

flammatory reactivity can vary considerably. Therefore, even

SUN scores corresponding to the highest values of AC cell
Scoring systems12,13

number in a human may ‘‘max out’’ at values that do not

interobserver reproducibility

allow adequate capture of differential responses in toxico-

logic investigations using other laboratory species possessing
deeper ACs (and thus sampling larger optical volumes).
by the Draize system
toxicologic studies

We note that semiquantitative schemes for vitreous cells

are rarely described. It needs to be recognized that differ-
ences exist between the AC and vitreous with respect to the
dynamics of inflammatory cells. Vitreous inflammatory cells
tend to migrate more slowly from the uveal tissue, at least
cells

partially due to the more gel-like rheologic properties of the

vitreous. For those same reasons, vitreous cells tend to
persist longer than aqueous cells.26 It also needs to be ac-
preclinical ocular drug and device development

knowledged that the posterior extent of the vitreous volume

this complicates scoring in pigmented strains

Does not specify standardized slit lamp settings

Often criticized for inconsistent reproducibility
ocular anatomical features of albino rabbits;
Used widely as a regulatory and governmental

industrial products and other nontherapeutic

standard for evaluation of ocular toxicity of

sampled by a slit beam cannot be accurately defined, with

Scoring schemes and criteria are designed to

the volume sampled varying with magnification, incident

Scoring criteria are limited to the cornea,
and questionable relevance in modern

angle of the beam, beam height and width, pupil diameter,

and other relevant laboratory species

as well as the plane of focus. Despite these limitations,

Draize scoring system11

scoring of anterior vitreous cell provides valuable infor-

mation at decision nodes in the drug development pathway.
It is noteworthy that compared to scoring systems for the
general anterior segment, those for the lens and ocular
Table 4.

conjunctiva, and iris

surface were less commonly described for laboratory spe-

cies. Systems like the Lens Opacities Classification Systems
Published in 1944

(LOCS) or that of the World Health Organization (WHO)

compounds

provide photographic standards of clinically significant pa-

rameters for human lenses, but are less applicable to young
laboratory animals used in toxicologic studies. With the
focus in assessment of laboratory animal lenses being the
identification and characterization of untoward lens toxicity,
Key attributes

previously described schemes for clinical description of lens

toxicology
in ocular
Limitations

opacities or other lesions are still preferred.

Unlike lens anatomy which is relatively well conserved
across species, tear film dynamics, ocular surface physiology,
and ocular surface pathology vary widely between species,27–29
SLIT LAMP SCORING IN PRECLINICAL DRUG DEVELOPMENT
presenting challenges in the identification of ideal animal
surrogates for dry eye disease and other ocular surface disor-
ders. As a result, published ocular surface scoring systems in
animals vary widely, many being described for the evaluation
of a specific species, strain, or experimental model, compli-
cating the generalizability of reported systems.
Scoring systems with criteria for iris involvement and/or
iritis were much more commonly described for albino rab-
bits. Furthermore, scoring of aqueous humor infiltrates (ie,
hypopyon, hyphema) was also more common in the rat and
rabbit. While the original description of the SUN system
mentions hypopyon in human patients, it specifies that this
finding be recorded separately. It is plausible that findings like
hypopyon, while commonly observed and of significance in
laboratory animals with acute experimental uveitis,30–32 are
not as commonly encountered in human patients33 and con-
sidered an outlying finding when scoring naturally occurring
endogenous uveitis.
Interpretation of any ocular scoring system in toxicology
and drug development must always be done critically, keeping
in mind the important influence of instrumentation and set-
tings, as well as species anatomy and physiology. This survey
identifies a wide array of published scoring systems used in
both clinical and laboratory settings. Of the few systems with
proven reproducibility in laboratory species, however, none
specify slit lamp settings and none include scoring criteria for
AC or vitreous cells. Furthermore, there is an underrepresen-
tation of scoring criteria applicable to pigmented strains and
larger laboratory species. The scoring systems used by mem-
bers of OSOD presented as a companion article to this liter-
ature survey, address many of these limitations and seek to
improve the applicability and precision of semiquantita-
tive scoring in modern ocular toxicology and drug and de-
vice development.
Acknowledgments
The authors thank Hugh Wabers and Michael Neider of
Ocular Services On Demand (OSOD), LLC, and Ariana
Marangakis of the Murphy/Russell/Thomasy Laboratory at
the University of California - Davis School of Veterinary
Medicine, for providing representative slit lamp photographs.
Author Disclosure Statement
No competing financial interests exist.
References
1. Gellrich, M.M. History of the slit lamp. The Slit Lamp.
Berlin Heidelberg: Springer; 2014; p. 189–210.
2. Überreiter, O. Die Mikroskopie am lebenden Tierauge.
Wien. tierärztl. Mschr. 43:77, 1956.
3. Überreiter, O. Examination of the eye and eye operations
in animals. Adv. Vet. Sci. 5:1–80, 1959.
4. Martin, C.L. Slit lamp examination of the normal canine
anterior ocular segment. 3. Discussion and summary. J.
Small Anim. Pract. 10:163–169, 1969.
5. Martin, C.L. Slit lamp examination of the normal canine
anterior ocular segment. II. Description. J. Small Anim.
Pract. 10:151–162, 1969.
6. Martin, C.L. Slit lamp examination of the normal canine
anterior ocular segment. I. Introduction and technique. J.
Small Anim. Pract. 10:143–149, 1969.
7
7. Featherstone, H.J., and Heinrich, C.L. Ophthalmic exam-
ination and diagnostics. In: Gelatt, K.N., Gilger, B.C., and
Kern, T.J., eds. Veterinary Ophthalmology, 5th ed. Ames,
Iowa: Wiley-Blackwell; 2013; p. 568–572.
8. Munger, R.J. Veterinary ophthalmology in laboratory
animal studies. Vet. Ophthalmol. 5:167–175, 2002.
9. Wilkie, D.A. The Ophthalmic Examination as It Pertains
to General Ocular Toxicology: basic and Advanced
Techniques and Species-Associated Findings. In: Gilger,
B.C., ed. Ocular Pharmacology and Toxicology. New
York: Springer; 2014; p. 143–203.
10. Jabs, D.A., Nussenblatt, R.B., and Rosenbaum, J.T. Stan-
dardization of uveitis nomenclature for reporting clinical
data. Results of the First International Workshop. Am. J.
Ophthalmol. 140:509–516, 2005.
11. Draize, J.H., Woodard, G., and Calvery, H.O. Methods for
the study of irritation and toxicity of substances applied
topically to the skin and mucous membranes. J. Phar-
macol. Exp. Ther. 82:377–390, 1944.
12. McDonald, T.O., and Shadduck, J.A. Eye irritation. In:
Marzulli, F.N., Maibach, H.I., eds. Advances in Modern
Toxicology, Volume IV: Dermatotoxicology and Phar-
macology. Washington, D.C.: Hemisphere Publishing
Corp; 1977; p. 139–191.
13. Hackett, R.B., and McDonald, T.O. Assessing ocular ir-
ritation. In: Marzulli, F.N., Maibach, H.I., eds. Dermato-
toxicology, 5th Edition. Washington, DC: Hemisphere
Publishing Corp.; 1996; p. 557–567.
14. Wilhelmus, K.R. The Draize eye test. Surv. Ophthalmol.
45:493–515, 2001.
15. Singer, M. Oxford Textbook of Critical Care. New York,
NY: Oxford University Press; 2016.
16. Bouch, D.C., and Thompson, J.P. Severity scoring sys-
tems in the critically ill. Contin. Educ. Anaesth. Critic.
Care Pain. 8:181–185, 2008.
17. Barbini, P., Cevenini, G., Furini, S., and Barbini, E. A naive
approach for deriving scoring systems to support clinical
decision making. J. Eval. Clin. Pract. 20:1–6, 2014.
18. Thomasy, S.M., Eaton, J.S., Timberlake, M.J., et al.
Species differences in the geometry of the anterior seg-
ment differentially affect anterior chamber cell scoring
systems in laboratory animals. J. Ocul. Pharmacol. Ther.
32:28–37, 2016.
19. Gilger, B.C., Abarca, E., and Salmon, J.H. Selection of
appropriate animal models in ocular research: ocular
anatomy and physiology of common animal models. In:
Gilger, B.C., ed. Ocular Pharmacology and Toxicology.
New York: Springer; 2014; p. 7–32.
20. Stewart, W.C., Magrath, G.N., Demos, C.M., et al. Pre-
dictive value of the efficacy of glaucoma medications in
animal models: preclinical to regulatory studies. Br. J.
Ophthalmol. 95:1355–1360, 2011.
21. Sasaki, H., Yamamura, K., Nishida, K., et al. Delivery of
drugs to the eye by topical application. Prog. Retin. Eye
Res. 15:583–620, 1996.
22. Salminen, L., Urtti, A., and Periviita, L. Effect of ocular
pigmentation on pilocarpine pharmacology in the rabbit
eye. I. Drag distribution and metabolism. Int. J. Pharm.
18:17–24, 1984.
23. Urtti, A., Salminen, L., Kujari, H., et al. Effect of ocular
pigmentation on pilocarpine pharmacology in the rabbit
eye. II. Drug response. Int. J. Pharm. 19:53–61, 1984.
24. Munger, R.J., and Collins, M. Assessment of ocular tox-
icity potential: basic theory and techniques. In: Weir,
A.B., Collins, M., eds. Assessing Ocular Toxicology in
8 EATON ET AL.
Laboratory Animals. New York, NY: Humana Press; 2013;
p. 23–52.
25. Bito, L.Z. Species differences in the responses of the eye to
irritation and trauma: a hypothesis of divergence in ocular
defense mechanisms, and the choice of experimental ani-
mals for eye research. Exp. Eye Res. 39:807–829, 1984.
26. Nussenblatt, R.B., Palestine, A.G., Chan, C.-C., et al.
Standardization of vitreal inflammatory activity in in-
termediate and posterior uveitis. Ophthalmol. 92:467–
471, 1985.
27. Barabino, S., and Dana, M.R. Animal models of dry eye: a
critical assessment of opportunities and limitations. Invest.
Ophthalmol. Vis. Sci. 45:1641–1646, 2004.
28. Schrader, S., Mircheff, A., and Geerling, G. Animal
models of dry eye. In: Geerling, G., and Brewitt, H., eds.,
Surgery for the Dry Eye: scientific Evidence and Guide-
lines for the Clinical Management of Dry Eye Associated
Ocular Surface Disease. Vol. 41. Karger Publishers; 2008;
p. 298–312.
29. Leonard, B.C., Yañez-Soto, B., Raghunathan, V.K., et al.
Species variation and spatial differences in mucin ex-
pression from corneal epithelial cells. Exp. Eye Res.
152:43–48, 2016.
30. Hanashiro, R.K., Fujino, Y., Samura, M., et al. Synthetic
lipid A-induced uveitis and endotoxin-induced uveitis—a
comparative study. Jpn. J. Ophthalmol. 41:355–361, 1997.
31. Kost, O.A., Beznos, O.V., Davydova, N.G., et al. Super-
oxide dismutase 1 nanozyme for treatment of eye in-
flammation. Oxid. Med. Cell Longev. 2015.
32. Forrester, J., Worgul, B., and Merriam, G. Endotoxin-
induced uveitis in the rat. Graefe’s Arch. Clin. Exper.
Ophthalmol. 213:221–233, 1980.
33. Zaidi, A.A., Ying, G.-S., Daniel, E., et al. Hypopyon in
patients with uveitis. Ophthalmol. 117:366–372, 2010.
34. McCormick, C., Caballero, A., Tang, A., et al. Effec-
tiveness of a new tobramycin (0.3%) and dexamethasone
(0.05%) formulation in the treatment of experimental
Pseudomonas keratitis. Curr. Med. Res. Opin. 24:1569–
1575, 2008.
35. Friedenwald, J., Hughes, W., and Herrmann, H. Acid-base
tolerance of the cornea. Arch. Ophthalmol. 31:279–283, 1944.
36. Johnson, M.K., Hobden, J.A., Hagenah, M., et al. The role
of pneumolysin in ocular infections with Streptococcus
pneumoniae. Curr. Eye Res. 9:1107–1114, 1990.
37. Cousins, S.W., Trattler, W.B., and Streilein, J.W. Immune
privilege and suppression of immunogenic inflammation
in the anterior chamber of the eye. Curr. Eye Res. 10:287–
297, 1991.
38. Berdy, G.J., Abelson, M.B., George, M.A., et al. Allergic
conjunctivitis: a survey of new antihistamines. J. Ocul.
Pharmacol. 7:313–324, 1991.
39. Bellot, J.L., Palmero, M., Garcia-Cabanes, C., et al. Ad-
ditive effect of nitric oxide and prostaglandin-E2 synthesis
inhibitors in endotoxin-induced uveitis in the rabbit. In-
flamm. Res. 45:203–208, 1996.
40. Papa, V., Milazzo, G., Santocono, M., et al. Naproxen
ophthalmic solution to manage inflammation after phacoe-
mulsification. J. Cataract. Refract. Surg. 28:321–327, 2002.
41. Ledbetter, E.C., Mun, J.J., Kowbel, D., et al. Pathogenic
phenotype and genotype of Pseudomonas aeruginosa
isolates from spontaneous canine ocular infections. Invest.
Ophthalmol. Vis. Sci. 50:729–736, 2009.
42. Maggs, D.J., Nasisse, M.P., Marrion, R.M., et al. Effects
of intracameral administration of alpha-chymotrypsin on
intracapsular lens extraction and postoperative outcome in
clinically normal dogs. Am. J. Vet. Res. 71:1475–1483,
2010.
43. Kulkarni, P.S., Bhattacherjee, P., Eakins, K.E., et al. Anti-
inflammatory effects of betamethasone phosphate, dexa-
methasone phosphate and indomethacin on rabbit ocular
inflammation induced by bovine serum albumin. Curr.
Eye Res. 1:43–47, 1981.
44. Zheng, X., Yamaguchi, M., Goto, T., et al. Experimental
corneal endotheliitis in rabbit. Invest. Ophthalmol. Vis.
Sci. 41:377–385, 2000.
45. Del Sole, M.J., Sande, P.H., Felipe, A.E., et al. Char-
acterization of uveitis induced by use of a single in-
travitreal injection of bacterial lipopolysaccharide in cats.
Am. J. Vet. Res. 69:1487–1495, 2008.
46. Roze, M., Thomas, E., and Davot, J.L. Tolfenamic acid in
the control of ocular inflammation in the dog: pharma-
cokinetics and clinical results obtained in an experimental
model. J. Small Anim. Pract. 37:371–375, 1996.
47. Rocha, G., Baines, M.G., Deschecnes, J., et al. Trans-
forming growth factor-beta levels in aqueous humor dur-
ing experimentally induced uveitis. Ocul. Immunol.
Inflamm. 1:343–354, 1993.
48. Dunne, J.A., and Travers, J.P. Double-blind clinical trial
of topical steroids in anterior uveitis. Br. J. Ophthalmol.
63:762–767, 1979.
49. Gilger, B.C., Abarca, E.M., Salmon, J.H., et al. Treatment
of acute posterior uveitis in a porcine model by injection
of triamcinolone acetonide into the suprachoroidal space
using microneedles. Invest. Ophthalmol. Vis. Sci. 54:2483–
2492, 2013.
50. Baldwin, H.A., McDonald, T.O., and Beasley, C.H. Slit-
lamp examination of experimental animal eyes. II. Grading
scales and photographic evaluation of induced pathological
conditions. J. Soc. Cosmet. Chem. 24:181–195, 1973.
51. Altmann, S., Emanuel, A., Toomey, M., et al. A quanti-
tative rabbit model of vaccinia keratitis. Invest. Ophthal-
mol. Vis. Sci. 51:4531–4540, 2010.
52. Chambers, W.A., Green, S., Gupta, K.C., et al. Scoring for
eye irritation tests. Food Chem. Toxicol. 31:111–115, 1993.
53. Krzystolik, M.G., Afshari, M.A., Adamis, A.P., et al. Pre-
vention of experimental choroidal neovascularization with
intravitreal antiGCxôvascular endothelial growth factor an-
tibody fragment. Arch. Ophthalmol. 120:338–346, 2002.
54. Russo, P., Papa, V., Russo, S., et al. Topical nonsteroidal anti-
inflammatory drugs in uncomplicated cataract surgery: effect
of sodium naproxen. Eur. J. Ophthalmol. 15:598–606, 2005.
55. Kawashima, H., and Mochizuki, M. Effects of a new
immunosuppressive agent, FK 506, on the efferent limb of
the immune responses. Exp. Eye Res. 51:565–572, 1990.
56. Hoekzema, R., Murray, P.I., van Haren, M.A., et al.
Analysis of interleukin-6 in endotoxin-induced uveitis.
Invest. Ophthalmol. Vis. Sci. 32:88–95, 1991.
57. Okada, A.A., Keino, H., Fukai, T., et al. Effect of type I
interferon on experimental autoimmune uveoretinitis in
rats. Ocul. Immunol. Inflamm. 6:215–226, 1998.
58. Zheng, C., Lei, C., Chen, Z., et al. Topical administration
of diminazene aceturate decreases inflammation in
endotoxin-induced uveitis. Mol. Vis. 21:403–411, 2015.
59. Kaburaki, T., Namba, K., Sonoda, K.H., et al. Behcet’s
disease ocular attack score 24: evaluation of ocular dis-
ease activity before and after initiation of infliximab. Jpn.
J. Ophthalmol. 58:120–130, 2014.
60. Altinsoy, A., Dilekoz, E., Kul, O., et al. A cannabinoid
ligand, anandamide, exacerbates endotoxin-induced uveitis
in rabbits. J. Ocul. Pharmacol. Ther. 27:545–552, 2011.
SLIT LAMP SCORING IN PRECLINICAL DRUG DEVELOPMENT
61. Ruiz-Moreno, J.M., Thillaye, B., and de Kozak, Y.
Retino-choroidal changes in endotoxin-induced uveitis in
the rat. Ophthalmic. Res. 24:162–168, 1992.
62. Bucolo, C., Cuzzocrea, S., Mazzon, E., et al. Effects of
cloricromene, a coumarin derivative, on endotoxin-
induced uveitis in Lewis rats. Invest. Ophthalmol. Vis. Sci.
44:1178–1184, 2003.
63. Mathews, J.D., Crawford, B.A., Bignell, J.L., et al. Aza-
thioprine in active chronic iridocyclitis. A double-blind
controlled trial. Br. J. Ophthalmol. 53:327–330, 1969.
64. Smith, J.R., Hart, P.H., Parish, C.R., et al. Experimental
melanin-induced uveitis in the Fischer 344 rat is inhibited
by anti-CD4 monoclonal antibody, but not by mannose-6-
phosphate. Clin. Exp. Immunol. 115:64–71, 1999.
65. Tugal-Tutkun, I., Cingü, K., Kir, N., et al. Use of laser
flare-cell photometry to quantify intraocular inflammation
in patients with Behçet uveitis. Graefe’s Arch. Clin.
Exp. Ophthalmol. 246:1169–1177, 2008.
66. Hogan, M.J., Kimura, S.J., and Thygeson, P. Signs and
symptoms of uveitis. I. Anterior uveitis. Am. J. Ophthal-
mol. 47(5 Pt 2), 155–170, 1959.
67. Martin, P.L., Miller, P.E., Mata, M., et al. Ocular in-
flammation in cynomolgus macaques following intrave-
nous administration of a human monoclonal antibody. Int.
J. Toxicol. 28:5–16, 2009.
68. Brown, D.M., Kaiser, P.K., Michels, M., et al. Ranibizu-
mab versus verteporfin for neovascular age-related mac-
ular degeneration. N. Engl. J. Med. 355:1432–1444, 2006.
69. Hafezi-Moghadam, A., Noda, K., Almulki, L., et al. VLA-
4 blockade suppresses endotoxin-induced uveitis: in vivo
evidence for functional integrin up-regulation. FASEB J.
21:464–474, 2007.
70. BenEzra, D., Forrester, J.V., Nussenblatt, R.B., et al. Uveitis
Scoring System. Berlin Heidelberg: Springer; 1991; p. 1–2.
71. Kimura, S.J., Thygeson, P., and Hogan, M.J. Signs and
symptoms of uveitis. II. Classification of the posterior
manifestations of uveitis. Am. J. Ophthalmol. 47, 1959.
72. Carpenter, C.P., Smyth, H.F., Jr. Chemical burns of the
rabbit cornea. Am. J. Ophthalmol. 29:1363–1372, 1946.
73. Barnett, R.A., and Aronson, S.B. A biomicroscopic
method for quantitation of ocular and adnexal toxicity.
Fundam. Appl. Toxicol. 3:187–191, 1983.
74. The Age-Related Eye Disease Study (AREDS). System
for classifying cataracts from photographs: AREDS Re-
port No. 4. Am. J. Ophthalmol. 131:167–175, 2001.
75. Sparrow, J.M., Bron, A.J., Brown, N.A.P., et al. The
Oxford clinical cataract classification and grading system.
Int. Ophthalmol. 9:207–225, 1986.
76. Chylack, L.T., Leske, M.C., Sperduto, R., et al. Lens opacities
classification system. Arch. Ophthalmol. 106:330–334, 1988.
77. Chylack, L.T., Leske, M.C., McCarthy, D., et al. Lens
opacities classification system II (LOCS II). Arch. Oph-
thalmol. 107:991–997, 1989.
78. Chylack, L.T., Wolfe, J.K., Singer, D.M., et al. The lens
opacities classification system III. Arch. Ophthalmol.
111:831–836, 1993.
79. Wall, T., and Bjerkas, E. A simplified method of scoring
cataracts in fish. Bull. Eur. Assoc. Fish Pathol. 19:162–
165, 1999.
80. Kwon, Y.H., Kim, C.S., Zimmerman, M.B., et al. Rate of
visual field loss and long-term visual outcome in primary
open-angle glaucoma. Am. J. Ophthalmol. 132:47–56, 2001.
81. Robertson, L.J., Morton, J.D., Yamaguchi, M., et al.
Calpain may contribute to hereditary cataract formation in
sheep. Invest. Ophthalmol. Vis. Sci. 46:4634–4640, 2005.
9
82. Lee, H.Y., Morton, J.D., Robertson, L.J., et al. Evaluation
of a novel calpain inhibitor as a treatment for cataract.
Clin. Exp. Ophthalmol. 36:852–860, 2008.
83. Lassen, N., Bateman, J.B., Estey, T., et al. Multiple and
additive functions of ALDH3A1 and ALDH1A1: cataract
phenotype and ocular oxidative damage in Aldh3a1(-/-)/
Aldh1a1(-/-) knock-out mice. J. Biol. Chem. 282:25668–
25676, 2007.
84. Forster, J.E., Abadi, R.V., Muldoon, M., et al. Grading
infantile cataracts. Ophthal. Physl. Opt. 26:372–379, 2006.
85. Chen, B.Y., Lin, D.P., Su, K.C., et al. Dietary zerumbone
prevents against ultraviolet B-induced cataractogenesis in
the mouse. Mol. Vis. 17:723–730, 2011.
86. Xu, G.T., Zigler, J.S., Jr., and Lou, M.F. The possible
mechanism of naphthalene cataract in rat and its preven-
tion by an aldose reductase inhibitor (ALO1576).
Exp. Eye Res. 54:63–72, 1992.
87. Morton, J.D., Lee, H.Y., McDermott, J.D., et al. A macro-
cyclic calpain inhibitor slows the development of inherited
cortical cataracts in a sheep model. Invest Ophthalmol. Vis.
Sci. 54:389–395, 2013.
88. Dynlacht, J.R., Tyree, C., Valluri, S., et al. Effect of es-
trogen on radiation-induced cataractogenesis. Radiat. Res.
165:9–15, 2006.
89. Gwon, A.E., Jones, R.L., Gruber, L.J., et al. Lens regen-
eration in juvenile and adult rabbits measured by image
analysis. Invest. Ophthalmol. Vis. Sci. 33:2279–2283, 1992.
90. Jose, J.G., and Ainsworth, E.J. Cataract production in
mice by heavy charged argon, neon, and carbon particles.
Radiat. Res. 94:513–528, 1983.
91. Worgul, B., Kundiyev, Y., Sergiyenko, N., et al. Cataracts
among Chernobyl clean-up workers: implications regarding
permissible eye exposures. Radiat. Res. 167:233–243, 2007.
92. Klein, B.E., Klein, R., Linton, K.L., et al. Assessment of
cataracts from photographs in the Beaver Dam Eye Study.
Ophthalmol. 97:1428–1433, 1990.
93. Merriam, G.R., Jr., and Focht, E.F. A clinical and exper-
imental study of the effect of single and divided doses of
radiation on cataract production. Trans. Am. Ophthalmol.
Soc. 60:35–52, 1962.
94. Thylefors, B., Chylack, Jr., L.T., Konyama, K., et al. A
simplified cataract grading system The WHO Cataract
Grading Group. Ophthalmic Epidemiol. 9:83–95, 2002.
95. Bron, A., and Brown, N. Classification, grading and preven-
tion of cataract. J. Int. Biomed. Inform. Data. 4:21–47, 1983.
96. Chylack, L.T. Classification of human cataractous change
by the American Cooperative Cataract Research Group
method. In: ciba Foundation Symposium Vol. 106- Human
Cataract Formation. London, United Kingdom: Wiley
Online Library; 1984; p. 3–24.
97. Adamsons, I., Taylor, K., Enger, C., et al. A new method
for documenting lens opacities. Am. J. Ophthalmol. 111:
65–70, 1991.
98. Munoz, B., West, S., Wang, F., et al. Measuring cataract
progression for longitudinal studies. Invest. Ophthalmol.
Vis. Sci. 32:1243–1243, 1991.
99. Frank, G.M., Divito, S.J., Maker, D.M., et al. A novel
p40-independent function of IL-12p35 is required for
progression and maintenance of herpes stromal keratitis.
Invest. Ophthalmol. Vis. Sci. 51:3591–3598, 2010.
100. Lin, C.P., and Boehnke, M. Effect of fortified antibiotic
solutions on corneal epithelial wound healing. Cornea.
19:204–206, 2000.
101. McCluskey, P., and Wakefield, D. Prediction of response
to treatment in patients with scleritis using a standardised
10
scoring system. Aust. N. Z. J. Ophthalmol. 19:211–215,
1991.
102. Ahmed, R.A., and Azzam, S.A. Management of acquired
punctal stenosis in trachomatous patients using single
versus double silicone tube insertion (a pilot study). Kasr.
Al Ainy. Med. J. 22:1, 2016.
103. Babin, M.C., Ricketts, K.M., Gazaway, M.Y., et al. A
combination drug treatment against ocular sulfur mustard
injury. J. Toxicol. Cutaneous. Ocul. Toxicol. 23:65–75, 2005.
104. Kamiya, K., Nakanishi, M., Ishii, R., et al. Clinical eval-
uation of the additive effect of diquafosol tetrasodium on
sodium hyaluronate monotherapy in patients with dry eye
syndrome: a prospective, randomized, multicenter study.
Eye (Lond). 26:1363–1368, 2012.
105. Labcharoenwongs, P., Jirapongsananuruk, O., Visitsun-
thorn, N., et al. A double-masked comparison of 0.1%
tacrolimus ointment and 2% cyclosporine eye drops in the
treatment of vernal keratoconjunctivitis in children. Asian
Pac. J. Allergy Immunol. 30:177–184, 2012.
106. Matsumoto, Y., Sato, E.A., Ibrahim, O.M., et al. The
application of in vivo laser confocal microscopy to the
diagnosis and evaluation of meibomian gland dysfunction.
Mol. Vis. 14:1263–1271, 2008.
107. Yoeruek, E., Ziemssen, F., Henke-Fahle, S., et al. Safety,
penetration and efficacy of topically applied bevacizumab:
evaluation of eyedrops in corneal neovascularization after
chemical burn. Acta Ophthalmol. 86:322–328, 2008.
108. Oh, J.Y., Kim, M.K., Choi, H.J., et al. Investigating the
relationship between serum interleukin-17 levels and
systemic immune-mediated disease in patients with dry
eye syndrome. Korean J. Ophthalmol. 25:73–76, 2011.
109. Aragona, P., Aguennouz, M., Rania, L., et al. Matrix
metalloproteinase 9 and transglutaminase 2 expression at
the ocular surface in patients with different forms of dry
eye disease. Ophthalmol. 122:62–71, 2015.
110. De Paiva, C.S., and Pflugfelder, S.C. Corneal epithelio-
pathy of dry eye induces hyperesthesia to mechanical air
jet stimulation. Am. J. Ophthalmol. 137:109–115, 2004.
111. Den, S., Sotozono, C., Kinoshita, S., et al. Efficacy of
early systemic betamethasone or cyclosporin A after
corneal alkali injury via inflammatory cytokine reduction.
Acta Ophthalmol. Scand. 82:195–199, 2004.
112. Ogawa, Y., Kim, S.K., Dana, R., et al. International
Chronic Ocular Graft-vs-Host-Disease (GVHD) Con-
sensus Group: proposed diagnostic criteria for chronic
GVHD (Part I). Sci. Rep. 3:3419, 2013.
113. Prabhasawat, P., Tesavibul, N., and Kasetsuwan, N. Per-
formance profile of sodium hyaluronate in patients with
lipid tear deficiency: randomised, double-blind, controlled,
exploratory study. Br. J. Ophthalmol. 91:47–50, 2007.
114. Rodriguez, J.D., Johnston, P.R., Ousler, G.W., et al. Auto-
mated grading system for evaluation of ocular redness as-
sociated with dry eye. Clin. Ophthalmol. 7:1197–1204, 2013.
115. Rodriguez, J.D., Lane, K.J., Ousler, G.W., et al. Auto-
mated grading system for evaluation of superficial punc-
tate keratitis associated with dry eye. Invest. Ophthalmol.
Vis. Sci. 56:2340–2347, 2015.
116. Terry, R.L., Schnider, C.M., Holden, B.A., et al. CCLRU
standards for success of daily and extended wear contact
lenses. Optom. Vis. Sci. 70:234–243, 1993.
117. Wu, T.G., Wilhelmus, K.R., and Mitchell, B.M. Experi-
mental keratomycosis in a mouse model. Invest. Oph-
thalmol. Vis. Sci. 44:210–216, 2003.
118. Efron, N. Clinical application of grading scales for contact
lens complications. Optician. 213:26–34, 1997.
EATON ET AL.
119. Abelson, M.B., Chambers, W.A., and Smith, L.M. Con-
junctival allergen challenge. A clinical approach to
studying allergic conjunctivitis. Arch. Ophthalmol. 108:
84–88, 1990.
120. Asano-Kato, N., Fukagawa, K., Tsubota, K., et al. Quantitative
evaluation of atopic blepharitis by scoring of eyelid conditions
and measuring the water content of the skin and evaporation
from the eyelid surface. Cornea. 20:255–259, 2001.
121. Bonini, S., Bonini, S., Lambiase, A., et al. Vernal kerato-
conjunctivitis revisited: a case series of 195 patients with
long-term followup. Ophthalmol. 107:1157–1163, 2000.
122. Bron, A.J., Benjamin, L., and Snibson, G.R. Meibomian
gland disease. Classification and grading of lid changes.
Eye (Lond). 5:395–411, 1991.
123. Bron, A.J., Evans, V.E., and Smith, J.A. Grading of cor-
neal and conjunctival staining in the context of other dry
eye tests. Cornea. 22:640–650, 2003.
124. Fenga, C., Aragona, P., Cacciola, A., et al. Meibomian
gland dysfunction and ocular discomfort in video display
terminal workers. Eye (Lond). 22:91–95, 2008.
125. Jain, R., Murthy, S.I., Basu, S., et al. Anatomic and visual
outcomes of descemetopexy in post-cataract surgery des-
cemet’s membrane detachment. Ophthalmol. 120:1366–
1372, 2013.
126. Lemp, A. Report of the National Eye Institute/Industry
workshop on clinical trials in dry eyes. Eye Contact Lens.
21:221–232, 1995.
127. Whitcher, J.P., Shiboski, C.H., Shiboski, S.C., et al.
A simplified quantitative method for assessing kerato-
conjunctivitis sicca from the Sjögren’s Syndrome Inter-
national Registry. Am. J. Ophthalmol. 149:405–415,
2010.
128. Korb, D.R., Baron, D.F., Herman, J.P., et al. Tear film
lipid layer thickness as a function of blinking. Cornea.
13:354–359, 1994.
129. Foulks, G.N., and Bron, A.J. Meibomian gland dysfunc-
tion: a clinical scheme for description, diagnosis, classi-
fication, and grading. Ocul. Surf. 1:107–126, 2003.
130. Sen, H.N., Sangave, A.A., Goldstein, D.A., et al. A
standardized grading system for scleritis. Ophthalmol.
118:768–771, 2011.
131. Hikita, N., Lopez, J.S., Chan, C.-C., et al. Use of topical
FK506 in a corneal graft rejection model in Lewis rats.
Invest. Ophthalmol. Vis. Sci. 38:901–909, 1997.
132. van Bijsterveld, O.P. Diagnostic tests in the Sicca syn-
drome. Arch. Ophthalmol. 82:10–14, 1969.
133. BenEzra, D. Blepharitis and Conjunctivitis: guidelines
for Diagnosis and Treatment: Barcelona, Spain: Editorial
Glosa, SL; 2006.
134. Shoji, J., Inada, N., and Sawa, M. Evaluation of novel
scoring system named 5–5-5 exacerbation grading scale
for allergic conjunctivitis disease. Allergol. Int. 58:591–
597, 2009.
135. Charoo, N.A., Kohli, K., and Ali, A. Preparation of in situ-
forming ophthalmic gels of ciprofloxacin hydrochloride
for the treatment of bacterial conjunctivitis: in vitro and
in vivo studies. J. Pharm. Sci. 92:407–413, 2003.
136. Davis, K., and Townsend, W. Tear-film osmolarity in
normal cats and cats with conjunctivitis. Vet. Ophthalmol.
14 Suppl 1:54–59, 2011.
137. Filipec, M., Phan, T.M., Zhao, T.Z., et al. Topical cy-
closporine A and corneal wound healing. Cornea. 11:546–
552, 1992.
138. Gahl, W.A., Kuehl, E.M., Iwata, F., et al. Corneal crystals
in nephropathic cystinosis: natural history and treatment
 SLIT LAMP SCORING IN PRECLINICAL DRUG DEVELOPMENT
with cysteamine eyedrops. Mol. Genet. Metab. 71:100–
120, 2000.
139. Grau, D.R., Visalli, R.J., and Brandt, C.R. Herpes simplex
virus stromal keratitis is not titer-dependent and does not
correlate with neurovirulence. Invest. Ophthalmol. Vis.
Sci. 30:2474–2480, 1989.
140. Holland, E.J., Chan, C.C., Wetzig, R.P., et al. Clinical and
immunohistologic studies of corneal rejection in the rat
penetrating keratoplasty model. Cornea. 10:374–380, 1991.
141. Jabs, D.A., Wingard, J., Green, W.R., et al. The eye in
bone marrow transplantation. III. Conjunctival graft-vs-
host disease. Arch. Ophthalmol. 107:1343–1348, 1989.
142. Ledbetter, E.C., Kim, S.G., Dubovi, E.J., et al. Experi-
mental reactivation of latent canine herpesvirus-1 and
induction of recurrent ocular disease in adult dogs. Vet.
Microbiol. 138:98–105, 2009.
143. Luchs, J. Efficacy of topical azithromycin ophthalmic
solution 1% in the treatment of posterior blepharitis. Adv
Ther. 25:858–870, 2008.
144. Maggs, D.J., Chang, E., Nasisse, M.P., et al. Persistence of
herpes simplex virus type 1 DNA in chronic conjunctival
and eyelid lesions of mice. J. Virol. 72:9166–9172, 1998.
145. Pan, Z., Chen, Y., Zhang, W., et al. Rat corneal allograft
survival prolonged by the superantigen staphylococcal
enterotoxin B. Invest. Ophthalmol. Vis. Sci. 44:3346–
3351, 2003.
146. Robinson, M.R., Lee, S.S., Rubin, B.I., et al. Topical
corticosteroid therapy for cicatricial conjunctivitis asso-
ciated with chronic graft-versus-host disease. Bone Mar-
row Transplant. 33:1031–1035, 2004.
147. Thompson, P., Xu, D., Brunette, I., et al. Combined effect of
rapamycin and cyclosporine in the prevention of rat corneal
allograft rejection. Transplant Proc. 30:1033–1035, 1998.
148. Xin, M., Wang, T., Shi, W., et al. Experimental efficacy of
mycophenolate mofetil implant on high-risk corneal allograft
rejection and its biocompatibility in the anterior chamber of
rabbits. J. Ocul. Pharmacol. Ther. 28:609–617, 2012.
149. Baradaran-Rafii, A., Ebrahimi, M., Kanavi, M.R., et al.
Midterm outcomes of autologous cultivated limbal stem
cell transplantation with or without penetrating kerato-
plasty. Cornea. 29:502–509, 2010.
150. Dana, M.R., Yamada, J., and Streilein, J.W. Topical in-
terleukin 1 receptor antagonist promotes corneal trans-
plant survival. Transplantation. 63:1501–1507, 1997.
151. de Almeida, D.E., Roveratti, C., Brito, F.L., et al. Con-
junctival effects of canine distemper virus-induced kerato-
conjunctivitis sicca. Vet. Ophthalmol. 12:211–215, 2009.
152. Erhamamci, S., Karalezli, A., Yilmaz, S., et al. The clin-
ical value and histopathological correlation of lacrimal
scintigraphy in patients with primary Sjogren’s syndrome.
Nucl. Med. Commun. 33:689–694, 2012.
153. Moore, J.E., McMullen, T.C., Campbell, I.L., et al. The
inflammatory milieu associated with conjunctivalized
cornea and its alteration with IL-1 RA gene therapy. In-
vest. Ophthalmol. Vis. Sci. 43:2905–2915, 2002.
154. Ozturk, F., Yavas, G.F., Kusbeci, T., et al. Efficacy of
topical caspofungin in experimental fusarium keratitis.
Cornea. 26:726–728, 2007.
155. Schreiber, W., Olbrisch, A., Vorwerk, C.K., et al. Com-
bined topical fluconazole and corticosteroid treatment for
View publication stats
11
experimental Candida albicans keratomycosis. Invest.
Ophthalmol. Vis. Sci. 44:2634–2643, 2003.
156. Sonoda, Y., and Streilein, J.W. Orthotopic corneal trans-
plantation in mice—evidence that the immunogenetic
rules of rejection do not apply. Transplantation. 54:694–
704, 1992.
157. Williams, D., Middleton, S., Fattahian, H., et al. Compar-
ison of hyaluronic acid-containing topical eye drops with
carbomer-based topical ocular gel as a tear replacement in
canine keratoconjunctivitis sicca: a prospective study in
twenty five dogs. Vet. Res. Forum. 3:229–232, 2012.
158. Yamaguchi, M., Kutsuna, M., Uno, T., et al. Marx line:
fluorescein staining line on the inner lid as indicator of
meibomian gland function. Am. J. Ophthalmol. 141:669–
675, 2006.
159. Craven, E.R., Liu, C.C., Batoosingh, A., et al. A ran-
domized, controlled comparison of macroscopic con-
junctival hyperemia in patients treated with bimatoprost
0.01% or vehicle who were previously controlled on la-
tanoprost. Clin. Ophthalmol. 4:1433–1440, 2010.
160. Miyata, K., Amano, S., Sawa, M., et al. A novel grading
method for superficial punctate keratopathy magnitude
and its correlation with corneal epithelial permeability.
Arch. Ophthalmol. 121:1537–1539, 2003.
161. Ehrenberg, M., Zolotariov, E., Loeb, E., et al. Combining
sodium hyaluronate and polyvinylpyrrolidone therapies for
the rabbit Cornea: a new approach to relief of the human
dry eye syndrome. Curr. Eye Res. 40:913–922, 2015.
162. Sotozono, C., Ang, L.P., Koizumi, N., et al. New grading
system for the evaluation of chronic ocular manifestations
in patients with Stevens-Johnson syndrome. Ophthalmol.
114:1294–1302, 2007.
163. Sotozono, C., Inatomi, T., Nakamura, T., et al. Cultivated
oral mucosal epithelial transplantation for persistent epithe-
lial defect in severe ocular surface diseases with acute in-
flammatory activity. Acta. Ophthalmol. 92:e447–453, 2014.
164. Lemp, M.A., and Foulks, G.N. The definition and classi-
fication of dry eye disease. Ocul. Surf. 5:75–92, 2007.
Received: February 14, 2017
Accepted: August 12, 2017
Address correspondence to:
Dr. Christopher J. Murphy
Department of Surgical and Radiological Sciences
School of Veterinary Medicine
University of California–Davis
1 Shields Avenue
Davis, CA 95616
E-mail: cjmurphy@ucdavis.edu
Dr. Joshua Seth Eaton
Ocular Services On Demand (OSOD), LLC
6527 Normandy Lane, Suite 100
Madison, WI 53719
E-mail: seaton@ocularservices.com