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2005 American College of Veterinary Ophthalmologists

Veterinary Ophthalmology

(2005)

8

, 4, 253258

Blackwell Publishing, Ltd.

Canine goniodysgenesis-related glaucoma: a morphologic review of
100 cases looking at inammation and pigment dispersion

Christopher M. Reilly,* Rebecca Morris and Richard R. Dubielzig

*

Department of Pathology, Veterinary Medical Teaching Hospital, University of California, Davis, CA 95616, USA;


Department of Pathobiological Sciences,
School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA

Abstract

Purpose

To investigate the role of pigment dispersion and inammation in the
pathogenesis of goniodysgenesis-related glaucoma (GDRG).

Procedures

Cases of GDRG were selected when the duration of the disease was specied
and there was not any confounding pathology. Cases were grouped into


7-day (acute),
and > 7-day (chronic) durations, based on the time required to effect end-stage retinal
damage. Acute cases were further divided into < 4-day and 47-day groups to assess
peracute changes. Slides were evaluated for four individual signs of pigment dispersion:
segmental loss of posterior iris pigment epithelium, clumping of posterior iris pigment
epithelium, pigmented cells in the trabecular meshwork or anterior chamber and
preferential settling of pigmented cells in the ventral aspect of the iridocorneal angle.
Slides were also evaluated for the presence of neutrophils and/or lymphoplasmacytic
cells in the trabecular meshwork (TM). Differences between groups were analyzed
statistically.

Results

Of 100 cases evaluated, 34 were


7-days (acute) (14 < 4-day and 20 47-day) and
66 were > 7-days (chronic) in duration. Of all globes examined, 96% had at least one sign
of pigment dispersion, with no signicant difference between groups. Two or more signs
of pigment dispersion were present in 76% of all globes. The 47-day group was
signicantly more likely than the < 4-day group to have at least two signs. The difference
was not signicant between


7- and > 7-day groups. Neutrophils were present in the
TM of 86% of < 4-day and 50% of 47-day cases. Cases in the


7-day group were
signicantly less likely than > 7-day cases to have neutrophils in the TM, with 15 and
65% positive cases, respectively. Lymphoplasmacytic inammation was present in 53%
of all cases, with no signicant difference between groups. Cases in the


7-day group
were signicantly more likely than > 7-day cases to have both types of inammation.

Conclusions

Our results indicate that both acute inammation and pigment dispersion
may be key factors in the pathogenesis of GDRG. Pigment dispersion is prevalent at all
time points and increases during the rst 7 days. The nding of iris pigment epithelial
loss supports the theory that pupillary block associated with iris-lens touching may be
important in the pathogenesis of GDRG.

Key Words:

canine, glaucoma, goniodysgenesis, inammation, pathology, pigment

dispersion

Address communications to:
Dr Richard R. Dubielzig
Tel.: (608) 2639805
Fax: (608) 2634958
e-mail:
dubielzr@svm.vetmed.wisc.edu

INTRODUCTION

Goniodysgenesis (GD), also referred to as pectinate ligament
dysplasia ( PLD), refers to a range of congenital abnormalities
of the iridocorneal angle ( ICA), which predispose to the
development of glaucoma. Many terms (primary angle closure
glaucoma (PACG), open-angle closed-cleft glaucoma, adult-
onset glaucoma, etc.) have been used to describe the glau-
coma resulting from these abnormalities.

113

A more general
term, goniodysgenesis-related glaucoma (GDRG), is used in
the present study to apply across breeds and without regard
to the specic conguration of the ICA or ciliary cleft. GD
254

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2005 American College of Veterinary Ophthalmologists,

Veterinary Ophthalmology

,

8

, 253258

results from failure of rarefaction of the uveal tissue that
spans the angle at birth.

1

Histopathologically, it is recog-
nized in the mature dog as a sheet of iris-like uveal tissue that
extends from the iris base to the terminus of Descemets
membrane (DM), which itself is often abnormal (Fig. 1).

11

GD is recognized in many breeds, including the American
and English Cocker Spaniels, English and Welsh Springer
Spaniels, Bassett Hound, Labrador Retriever, Golden Retriever,
Flat Coated Retriever, Siberian Husky, Samoyed, Bouvier
des Flanders, Dachshund, Chow-Chow, and occasionally in
mixed-breed dogs.

113

The abnormalities in the develop-
ment of the ICA are congenital; however, glaucoma typically
does not develop until middle age (i.e. 48 years).

1,9

In many
instances, the history or clinical progression supports the
theory that a series of transient pressure spikes may precede
sustained glaucoma.

1,2,14

Once glaucoma develops in one eye,
the fellow eye may develop clinical glaucoma within weeks
to years, sometimes within a matter of days.

1,11,15

Despite
this, there is evidence in some models of glaucoma that the
retinal and optic nerve damage may progress in the face of
IOP that has returned to normal.

1

The exact pathogenesis of
GDRG, however, is not well understood nor extensively
studied.
The histopathologic changes seen in spontaneous canine
glaucoma have previously been described.

2123

Of impor-
tance to this study is the rapid progression of degenerative
changes in the ICA in globes with elevated IOP. The TM is
reported to be markedly atrophied within 4 days, and is
Figure 1. Iridocorneal angle from a normotensive Bassett Hound
with goniodysgenesis. Note the band of iris-like tissue extending from
the iris base (arrow) and the easily recognizable corneoscleral TM
(asterisk). H&E, 10.
Figure 2. (a) Superior iridocorneal angle and (b) dependent
iridocorneal angle from a Cocker Spaniel with GDRG. Note the
increased pigment accumulation in the dependent iridocorneal angle
(arrow). H&E, 10.
Figure 3. Anterior segment from a Cocker Spaniel with acute
(<3 days) GDRG. Note the region of iris pigment epithelial loss (arrow)
and pigmented cells free in the anterior chamber (arrowhead). H&E,
2.5.
2005 American College of Veterinary Ophthalmologists,

Veterinary Ophthalmology

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8

, 253258

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255

indiscernible within 12 days.

23

It is well documented that
the degenerative changes that affect the retina are rapidly
progressive, with advanced retinal atrophy and optic nerve
pathology developing in as little as 3 days after the onset of
clinically recognized glaucoma. Within 1 day of the onset of
clinical signs, hypereosinophilic, necrotic ganglion cells can
be recognized in H&E sections.

20,22

With increased chro-
nicity, the proportion of ganglion cells undergoing apoptotic
death increases. The rapid progression of sight-threatening
retinal and optic nerve degeneration highlights the impor-
tance of early and specic therapy targeting the mechanisms
that facilitate GDRG to maintain vision and, ideally, prevent
the onset of glaucoma in eyes determined to be at risk.
Through the case accessions received at the Comparative
Ocular Pathology Laboratory of Wisconsin (COPLOW),
two trends were noted in the histopathology of globes with
GDRG. First, it was noted that pigment dispersion was
present in many globes enucleated for GDRD. Second,
neutrophils were present in the TM in some acute cases of
GDRG. The aim of the present study is to investigate the
possible role of pigment dispersion and inammation in the
development of GDRG.

MATERIALS AND METHODS

Records from pathology submissions to the COPLOW
between 1983 and 2003 were reviewed. Of 7360 canine sub-
missions, 2905 cases of glaucoma were identied. Cases with
a primary histopathologic diagnosis of goniodysgenesis were
selected. Evisceration specimens, mixed-breed dogs, cases
with signicant inammatory, neoplastic or other disease,
and cases where the duration of clinical signs was not given
were excluded. Breeds for which there were less than three
cases were excluded. Cases that were not cut in the vertical
meridian were excluded. The total number of cases included
was 100. Slides were reviewed and evaluated for four criteria
of pigment dispersion and for the presence of inammatory
cells in the ICA by the same veterinary pathologist (RRD),
who was blinded to chronicity of the cases. Globes were rst
evaluated for the ability to predict the dependent side of
the eye based on the distribution of pigment in the anterior
chamber and ICA. The aspect of the angle that contained
the most displaced pigment, whether in the peripheral aspect
of the anterior chamber or within the TM, was assigned as
the ventral aspect (Fig. 2). If there was no difference between
the two aspects of the ICA in a slide, or if there was no
evidence of pigment accumulation, the globe was considered
negative for this criterion. Once a determination was made,
accuracy was assessed using the tapetum as a point of reference
for the superior aspect of the globe. Only cases in which the
dependent aspect could be accurately predicted were con-
sidered positive. Next, the posterior iris surface was evaluated
for the absence of pigment epithelial cells from the posterior
iris surface. The presence of clusters of pigmented cells in
the posterior chamber was evaluated as an independent cri-
terion of pigment dispersion, as this feature can be observed
in slides without overt absence of posterior pigment epithe-
lium. The presence or absence of pigmented cells in the
anterior chamber/iridocorneal angle was also evaluated as a
sign of pigment dispersion (Fig. 3). The number of signs of
pigment dispersion seen in each globe was also recorded.
Globes were evaluated further for the presence or absence of
inammatory cell inltration in the TM or, in chronic cases,
the inner sclera at, and immediately adjacent to, the level of
the iris base. If present, this inltrate was classied as
neutrophilic, lymphoplasmacytic (LP), or both, and the
intensity of each was graded on a scale of 13 (1 + = mild,
2 + = moderate, 3 + = severe). Cases were classied into groups
based on the number of days between the onset of clinical
signs and enucleation:


7 days (acute) and > 7 days (chronic).
Acute cases were further divided into < 4 day and 47 day
groups to assess early changes. Interbreed differences were
not evaluated due to small case numbers from most breeds.
Differences between groups were analyzed for signicance
with the exact Pearsons chi-square test, with a

P

-value
of


0.05 considered signicant.

RESULTS

Of 100 cases evaluated, there were 62 Cocker Spaniels, 14
Bassett Hounds, 10 Labrador Retrievers, seven Chow Chows
and seven Huskies. The sex distribution was approximately
two female dogs: one male dog, as described previously.

1,8,13

Thirty-four cases were


7 days in duration (acute), with 14
< 4 day and 20 47 day cases. Sixty-six cases were > 7 day
(chronic). The average duration of clinical signs preceding
enucleation was 53.2 days (range = 8 h


316 days).

Pigment dispersion

At least one sign of pigment dispersion was present in 96%
of all examined globes ( Table 1). There was no signicant
difference between groups. Two or more signs of pigment
dispersion were present in 77% of all examined globes. The
47 day group was signicantly more likely than the < 4 day
group to have at least two signs (

P =

0.022), with 100% (20/
20) and 71.1% (10/14) of cases, respectively. Of individual
signs of pigment dispersion, only the presence of pigmented
cells in the angle was signicantly different between groups
(82.4% of


7 day and 50% of > 7 day,

P

= 0.002; 64.3% of
< 4 day and 95% of 47 day,

P

= 0.032, data not shown). Of
Table 1. Pigment dispersion patterns in eyes with GDRG with respect
to duration of clinical signs. Each P-value compares the group for which
it is listed and the group above it in the table


Duration (n)
At least 1
sign (n) P-value
At least 2
signs (n) P-value
< 4 days (14) 92.9% (13) 71.1% (10)
47 days (20) 100% (20) 0.412 100% (20) 0.022
7 days (34) 97% (33) 88.2% (30)
> 7 days (66) 95.4% (63) 1.000 71.1% (47) 0.078
TOTALS (100) 96 77
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2005 American College of Veterinary Ophthalmologists,

Veterinary Ophthalmology

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8

, 253258

all cases, 84, 57 and 26% exhibited preferential ventral
distribution of pigmented cells, posterior epithelial loss and
clumping of pigmented cells, respectively, with no signicant
differences between groups (data not shown).

Inammation

Neutrophils were present in the TM of 86% (12/14) of
< 4 day cases and 50% (10/20) of 47 day cases (

P =

0.066)
(Table 2). Neutrophilic inammation in the TM or its rem-
nants was more prevalent in acute cases, with 64.7% (22/34)
positive, than in > 7 day cases, with 16.7% (11/66) positive.
This difference was highly signicant (

P =

0.0001). Sixty-four
per cent (9/14) of < 4 day, 60% (12/20) of 47 day, and 32/66
(48%) of chronic cases had lymphoplasmacytic inamma-
tion. Forty-four per cent (15/34) of acute cases, 57% (8/14)
of < 4 day, 35% (7/20) of 47 (day) and 12% (8/66) of chronic
cases had evidence of both types of inammation. The
difference was signicant between acute and chronic cases
(

P =

0.0005). In eyes with acute or chronic inammation, all
had mild to moderate inltrate (1


2 +) and there was no
difference in severity of either type of inammation between
groups (data not shown).

DISCUSSION

These results suggest that both pigment dispersion and
inammation may be important factors in the initiation of
glaucoma in dogs with GD. The overwhelming majority
(96%) of globes had evidence of pigment dispersion at all
time points, and 77% had at least two signs. Although small
sample size limits the statistical power of this study, there
was a clear trend for signs of pigment dispersion to be more
prevalent in 47 day cases than in other groups. This trend
was signicant when comparing the presence of pigmented
cells in the angle, as well as when comparing cases with at
least two signs of pigment dispersion. This trend could be
explained by early accumulation of pigment with subsequent
drainage or redistribution of pigmented cells with chronicity.
Neutrophilic inammation in the TM is signicantly more
common in acute than in chronic cases and there was a trend
(

P =

0.066) for neutrophilic inammation to be more preva-
lent in the rst 3 days of clinical signs than from 4 to 7 days.
Based on these results, it is likely that neutrophilic inam-
mation is a factor in the acute phase of GDRG; however, it
is not clear if it is a primary trigger of glaucoma or if it is sec-
ondary to pigment dispersion or degenerative changes in the
ICA. The signicance of lymphoplasmacytic inammation
is more difcult to interpret, as its prevalence was similar
across all groups. The prevalence of mixed inammation
mirrored the prevalence of neutrophilic inammation.
Several limitations of this study must be considered. The
rst is the inherent difculty in accurately recognizing the
onset of clinical signs in the dog. It likely takes hours to days
for a dog owner to notice the clinical signs of glaucoma (i.e.
corneal edema, conjunctival hyperemia, buphthalmia, overt
pain) after the onset of subtle alterations in visual elds asso-
ciated with early elevations in IOP. Second, the vast majority
of dog owners are reluctant to enucleate a globe at the rst
signs of glaucoma, causing acute cases to be under-represented
in a histopathology-based study. Previous reports have
described the pathologic changes in glaucomatous canine
globes as a function of time.

2123

In as little as 4 days, the
corneoscleral TM is severely atrophied and becomes
unidentiable.

23

As a result, most globes examined have col-
lapsed ciliary clefts and only remnants of TM for examina-
tion. In the present study, attempts to objectively identify
these remnants on the basis of anterior segment anatomy
were made, and are supported in the literature, but have
inherent limitations.

24

Furthermore, normotensive globes
from dogs with clinically recognized GD are not readily
available to serve as controls. As mentioned earlier, it is also
impossible to precisely determine cause and effect in a
histology-based study; that is to say, does neutrophilic
inammation precede and promote the development of
glaucoma, or is it an early sequela of glaucoma, due to pigment
dispersion in the TM and ciliary cleft collapse? Lastly, sparse
historical data, particularly with respect to prior medical
or surgical therapy, are a caveat when interpreting pigment
dispersion, as some treatment modalities may inuence
pigment within the uvea.
Little is known about the pathogenesis of GDRG, beyond
the fact that some extent of iridocorneal angle malformation
is a predisposing factor. Recently, it has been shown that
high-resolution ultrasound (HRUS) biomicroscopy is an
effective diagnostic tool for evaluating the anterior segment
in dogs.

1618

More recent work by Miller

et al

. has shown
that reverse pupillary block, as demonstrated with HRUS,
may play a role in the episodic IOP spikes that lead to
Table 2. Inammation patterns in the TM of eyes with GDRG with respect to duration of clinical signs. Each P-values compares the group for
which it is listed and the group above it in the table


Duration (n) Neutrophils (n) P-value LP (n) P-value Both (n) P-value
< 4 days (14) 85.7% (12) 64.3% (9) 57.1% (8)
47 days (20) 50% (10) 0.066 60% (12) 1.00 35% (7) 0.3
7 days (34) 64.7% (22) 61.76% (21) 44.1% (15)
> 7 days (66) 16.7% (11) < 0.0001 48.5% (32) 0.29 12.1% (8) 0.0005
TOTALS (100) 33 53 23
LP, lymphoplasmacytic.
2005 American College of Veterinary Ophthalmologists,

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sustained glaucoma.

18

In dogs with acute PACG, HRUS
demonstrated a sigmoid iris conguration, with pupillary
block and ciliary cleft collapse. This type of transient pupillary
block may contribute to chang of the posterior iris pig-
mented epithelium and subsequent pigment dispersion in
the iridocorneal angle.

19,20

The nding of iris pigment epi-
thelial loss or stripping supports the theory that pupillary
block associated with touching of the pupillary iris to the
lens is important in the pathogenesis of canine GDRG.
Interestingly, two of the dogs in the acute group were
involved in a dogght within 12 days of the onset of clinical
signs related to glaucoma. While clearly a minority of the
cases reported, this observation may support the theory that
pigment dispersion, due to traumatic iris-lens chang, is a
proximal cause of glaucoma in some dogs with GD.
In humans, pigment dispersion syndrome bears several
similarities to the mechanism proposed in this study.

19,20

In
this syndrome, pigment is rubbed from the posterior iris
surface, by iris-zonule contact, and accumulates to varying
degrees in the anterior segment. If the cells of the TM
become sufciently engorged with phagocytosed pigment,
they die and can no longer perform their function. Pigmentary
glaucoma develops when optic nerve damage, with or without
increased IOP, results. In dogs, a distinct type of pigment-
related glaucoma, best characterized in the Cairn Terrier,
exists.

26

This disease, however, is typied by diffuse, abnormal
deposition of intraocular pigment that leads to glaucoma and
must not be confused with the pigment dispersion described
in this report, despite unclear terminology.
To our knowledge, this is the rst report of pigment dis-
persion or acute inammation as factors in GD-related glau-
coma. The results of this study suggest that clinical research
is needed to more precisely assess pigment dispersion and
inammation in normotensive dogs with GD, as well as in
dogs presenting acutely with GDRG. Therapies directed
at minimizing lensiris contact and pigment dispersion, or
minimizing neutrophil-mediated destruction of ICA struc-
tures in at-risk dogs may be indicated.

ACKNOWLEDGMENTS

The authors would like to thank Ms. Kate Leiber and Ms.
Emily Datta for their technical assistance and Dr Phillip
Kass for his statistical expertise.

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