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Sudden acquired retinal degeneration syndrome (SARDS) - a review and proposed strategies toward a better understanding of pathogenesis, early diagnosis, and therapy

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Abstract

Sudden acquired retinal degeneration syndrome (SARDS) is one of the leading causes of currently incurable canine vision loss diagnosed by veterinary ophthalmologists. The disease is characterized by acute onset of blindness due to loss of photoreceptor function, extinguished electroretinogram with an initially normal appearing ocular fundus, and mydriatic pupils which are slowly responsive to bright white light, unresponsive to red, but responsive to blue light stimulation. In addition to blindness, the majority of affected dogs also show systemic abnormalities suggestive of hyperadrenocorticism, such as polyphagia with resulting obesity, polyuria, polydipsia, and a subclinical hepatopathy. The pathogenesis of SARDS is unknown, but neuroendocrine and autoimmune mechanisms have been suggested. Therapies that target these disease pathways have been proposed to reverse or prevent further vision loss in SARDS-affected dogs, but these treatments are controversial. In November 2014, the American College of Veterinary Ophthalmologists' Vision for Animals Foundation organized and funded a Think Tank to review the current knowledge and recently proposed ideas about disease mechanisms and treatment of SARDS. These panel discussions resulted in recommendations for future research strategies toward a better understanding of pathogenesis, early diagnosis, and potential therapy for this condition. © 2015 American College of Veterinary Ophthalmologists.
REVIEW ARTICLE
Sudden acquired retinal degeneration syndrome (SARDS) a
review and proposed strategies toward a better understanding of
pathogenesis, early diagnosis, and therapy
Andr
as M. Kom
aromy,*,Kenneth L. Abrams,John R. Heckenlively,§Steven K. Lundy,
David J. Maggs,** Caroline M. Leeth,†† Puliyur S. MohanKumar,‡‡ Simon M. Petersen-Jones,*
David V. Serreze§§ and Alexandra van der Woerdt¶¶
*College of Veterinary Medicine, Michigan State University, 736 Wilson Road, East Lansing, MI 48824, USA; School of Veterinary
Medicine, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA 19104, USA; Eye Care for Animals, 42 Benefit Street, Warwick, RI02886,
USA; §Kellogg Eye Center, University of Michigan, 1000 Wall Street , Ann Arbor, MI 48105, USA; Division of Rheumatology, Department of Internal
Medicine, University of Michigan, 300 North Ingalls Building, Ann Arbor, MI 48109, USA; **Department of Surgical and Radiological Sciences, School of
Veterinary Medicine, University of California-Davis, 1 Shields Avenue, Davis, CA 95616, USA; ††Department of Animal and Poultry Sciences, College of
Agriculture and Life Sciences, 175 West Campus Drive, MC 0306, 3280 Litton Reaves Hall , Virginia Tech, Blacksburg, VA 24061, USA; ‡‡Department
of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA; §§The Jackson
Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA; and ¶¶The Animal Medical Center, 510 East 62nd Street, New York, NY 10065, USA
Address communications to:
A. M. Kom
aromy
Tel.: (517) 353-5420
Fax: (517) 355-5164
e-mail: komaromy@cvm.msu.
edu
Abstract
Sudden acquired retinal degeneration syndrome (SARDS) is one of the leading causes
of currently incurable canine vision loss diagnosed by veterinary ophthalmologists.
The disease is characterized by acute onset of blindness due to loss of photoreceptor
function, extinguished electroretinogram with an initially normal appearing ocular fun-
dus, and mydriatic pupils which are slowly responsive to bright white light, unrespon-
sive to red, but responsive to blue light stimulation. In addition to blindness, the
majority of affected dogs also show systemic abnormalities suggestive of hyperadreno-
corticism, such as polyphagia with resulting obesity, polyuria, polydipsia, and a sub-
clinical hepatopathy. The pathogenesis of SARDS is unknown, but neuroendocrine
and autoimmune mechanisms have been suggested. Therapies that target these disease
pathways have been proposed to reverse or prevent further vision loss in SARDS-
affected dogs, but these treatments are controversial. In November 2014, the Ameri-
can College of Veterinary Ophthalmologists’ Vision for Animals Foundation orga-
nized and funded a Think Tank to review the current knowledge and recently
proposed ideas about disease mechanisms and treatment of SARDS. These panel dis-
cussions resulted in recommendations for future research strategies toward a better
understanding of pathogenesis, early diagnosis, and potential therapy for this
condition.
Key Words: autoimmune retinopathy, blindness, canine, endocrinopathy,
hyperadrenocorticism, sudden acquired retinal degeneration syndrome
INTRODUCTION
In 2013, the American College of Veterinary Ophthalmol-
ogists’ Vision for Animals Foundation (ACVO-VAF) sur-
veyed the ACVO membership by e-mail about the
ophthalmic disorders where focused research funding and
efforts would probably result in significant improvements
in the diagnostic and therapeutic management of animal
patients. Very clearly, supported by 83% of the respon-
dents, sudden acquired retinal degeneration syndrome
(SARDS) was the most commonly reported condition
requiring further investigation. Subsequently, the VAF
Board of Directors organized and funded a Think Tank of
clinicians and basic scientists to develop recommendations
©2015 American College of Veterinary Ophthalmologists
Veterinary Ophthalmology (2016) 19, 4, 319–331 DOI:10.1111/vop.12291
for future research strategies that will enhance our knowl-
edge and help improve early diagnosis and treatment of
SARDS. On November 14, 2014 members of the Think
Tank held a 1-day meeting at the Westin Hotel, Detroit
Metropolitan Airport in Michigan (USA). This article is a
comprehensive review of the current literature on SARDS
(Table 1) and a summary of the Think Tank’s recommen-
dations.
WHAT IS SARDS?
The first formal reports of SARDS emerged in the United
States in the early 1980s, when the condition was also
referred to as ‘toxic metabolic retinopathy’ and ‘silent ret-
ina syndrome’.
15
The syndrome has also been described
in other parts of the world.
68
Based on our observations,
we suspect that SARDS has become a leading cause of
currently incurable vision loss in dogs. When first con-
fronted with a diagnosis of SARDS, most pet owners tend
to be devastated by the news of irreversible blindness in
their dogs, and many are desperate to seek treatment to
help the animal’s condition. The acute loss of sight, which
is frequently combined with systemic abnormalities and
age-related health issues, often results in deteriorated
quality of life for the dog and owner, at least during the
initial adjustment period.
911
Affected dogs tend to be
more cautious, less playful, and more lethargic.
11
SARDS typically affects middle-aged to elderly and
often moderately overweight dogs.
35,1113
The reported
mean or median ages of affected dogs range from 7 to
10 years.
35,1118
Between 60 and 90% of affected dogs
are female; the majority of them are spayed.
35,1117
A
genetic predisposition for SARDS has not been docu-
mented and any breed can be affected, with the disease
diagnosed most commonly in mixed-breed dogs. However,
small breeds including the dachshund, miniature schnau-
zer, pug, Brittany, bichon fris
e, beagle, Maltese, American
cocker spaniel, Pomeranian, and possibly shih tzu are
reported to be most commonly affected.
5,8,1121
Typically, dogs affected with SARDS are presented for
assessment of rapid vision loss that develops over a period
of days to weeks.
15,11,14,16
Histology of a limited number
of affected eyes showed a loss of photoreceptor outer
segments, resulting in an extinguished electroretinogram
(ERG), which, when seen in conjunction with a clinically
normal appearing fundus, is considered the hallmark of
SARDS and allows differentiation from other, neurologic
causes of acute vision loss, such as optic neuritis and intra-
cranial neoplasia, where the ERG is generally not
affected.
15,14,19,20,2226
Typically, patients with SARDS do
not show obvious neurologic signs; however, in our expe-
rience, some exhibit agitation potentially due to acute
vision loss or related to systemic involvement. Initially,
ophthalmic examination findings are normal or insufficient
to explain the degree of visual impairment. Specifically,
the ocular fundus appears normal or is affected by subtle
degenerative or vascular changes inconsistent with the
magnitude of visual impairment.
15
More obvious ophthal-
moscopic signs indicative of generalized retinal degenera-
tion/atrophy, such as a hyper-reflective tapetal fundus
(resulting from retinal thinning), attenuation of the retinal
vasculature, and pallor of the optic nerve head, are typi-
cally seen several months after the onset of SARDS.
15,27
In the majority (~90%) of SARDS-affected dogs the
pupils are mydriatic with diminished response to bright
white light.
15,27,28
This aspect of the disease phenotype
has been explored in more detail over the last few years by
Grozdanic et al.
28
and resulted in the recommendation
that chromatic pupillary light reflexes (PLRs) may serve as
a practical diagnostic tool to assess the canine visual path-
ways. In addition to electroretinography, loss of photore-
ceptor function can be verified clinically by observation of
the lack of a PLR following stimulation with a bright
(200 kcd/m
2
) red light of 630 nm wavelength which pri-
marily stimulates the cone photoreceptors.
2832
Because
retinal ganglion cells (RGCs), including the melanopsin-
expressing intrinsically photosensitive RGCs (ipRGCs),
3335
are initially not affected by SARDS, PLRs are retained
when eyes are stimulated with a bright (200 kcd/m
2
) blue
light of 480 nm wavelength that corresponds to the peak
spectral sensitivity of melanopsin,
27,28
whereas red light
with a wavelength of 630 nm does not overlap with the
melanopsin absorption spectrum.
28,34,35
Chromatic PLR
testing is easily performed, can be performed on an unse-
dated animal, and complements electroretinography in the
diagnosis of SARDS.
21,27,28
Light and electron microscopic examination has been
performed in only a few SARDS-affected eyes and has
shown that, in eyes examined within 3 weeks following
the onset of blindness, pathology is limited to the rod and
cone photoreceptors manifest as extensive panretinal loss
of photoreceptor outer segments.
3,4,20,25,26
Subsequently,
photoreceptor inner segments are also shortened, followed
by apoptosis of rods and cones, leading to thinning of the
outer nuclear layer.
1,3,4,19,25,26
Slow degeneration of the
inner retina, including bipolar, amacrine, and ganglion
cells, follows loss of rods and cones and occurs over sev-
eral months to years.
3,4,26
All retinal regions appear to be
equally affected, although central retinal cells may be lost
more gradually than those in the peripheral retina.
3,4,26
While inflammation is not considered an important fea-
ture of SARDS, variable numbers of macrophages were
found in the interphotoreceptor matrix.
4,20
The presence
of intraretinal antibody-producing plasma cells has also
been proposed.
27
Even with increasing availability in veterinary ophthal-
mology,
36
optical coherence tomography (OCT) has not
yet been performed on a sufficiently large number of
patients with SARDS to permit firm conclusions; however,
preliminary reports describe initial thinning of the nerve
fiber layer and total retinal thickness, especially in the
inferior retina.
27,37,38
©2015 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology,19, 319–331
320 kom
ar o m y ET AL.
Despite investigations performed over more than three
decades, etiopathogenic aspects of SARDS are still not
understood and remain quite controversial. In part, the
absence of knowledge and consensus regarding these criti-
cal features relates to lack of peer-reviewed investigations,
but knowledge and consensus is also hampered by contro-
versy about whether the SARDS diagnosis is being used
to describe diseases of multiple different etiopathogeneses.
For example, although the acronym itself and initial
reports describe a sudden onset of vision loss, some own-
ers report that weight gain, polyphagia (PP), polyuria
(PU), polydipsia (PD), and sometimes evidence of sus-
pected visual deficits were present weeks or months before
acute, complete vision loss.
3,4
This may represent a sepa-
rate disease phenotype or an early more gradual manifes-
tation of ‘classic’ SARDS. Likewise, variable presence of
coincident systemic signs has also led to some confusion
regarding etiologic classification systems. As many as 85%
of SARDS-affected dogs are presented with systemic clini-
cal signs, and up to 75% of SARDS-affected dogs have
laboratory abnormalities consistent with those seen in cer-
tain endocrinopathies.
35,8,11,12,14,16,39
These systemic
signs may precede vision loss or occur at approximately
the same time. Although PP can increase in severity for at
least 1 year following the diagnosis of SARDS, in many
dogs systemic signs decrease over months leaving only
blindness as the remaining clinical sign.
11,14,39
It is not
known how these systemic signs may be linked to photo-
Table 1. Summary of publications regarding sudden acquired retinal degeneration syndrome (SARDS)
Publication
Number of
SARDS cases Investigations used Peer reviewed
Vainisi et al.
2
18 Clinical exam, serum biochemistry, protein and lipids, endocrinologic assessment,
vitamins and selenium, ERG, FA, tests for autoimmune disease
N*
Acland et al.
4
26 Clinical exam, obstacle course, CBC, serum biochemistry, lead levels, urinalysis
(incl. amino acids), endocrinologic assessment, CSF analysis, ERG, FA, necropsy,
light and electron microscopic examination of the retina
N*
Bellhorn et al.
52
5 Circulating AAbs (ELISA, Western blot, complement fixation assay) Y
Riis
26
1 Light and electron microscopic examination of the retina N*
Van der Woerdt et al.
5
36 Clinical exam, ERG, CBC, serum biochemistry, urinalysis, endocrinologic assessment Y
O’Toole et al.
20
2 Clinical exam, ERG, CBC, serum biochemistry, endocrinologic assessment,
immunoglobulins, light and electron microscopic examination of the retina
Y
Mattson et al.
39
1 Clinical exam, ERG, CBC, serum biochemistry, urinalysis, fecal examination,
thoracic and abdominal radiographs, endocrinologic assessment,
ultrasonography (adrenal gland and liver), CT (brain/pituitary and adrenal gland),
liver biopsy, CSF analysis
Y
Miller et al.
19
3 Clinical exam, ERG, serum biochemistry, endocrinologic assessment, light
microscopic examination of the retina, incl. TUNEL
Y
Holt et al.
15
38 Clinical exam, ERG, serum biochemistry, urinalysis, endocrinologic assessment N*
Abrams et al.
12
Surveys completed by dog owners and veterinary ophthalmologists N*
Van der Linden et al.
10
24 Questionnaires for dog owners to assess quality of life N*
Gilmour
9
18 Clinical exam, ERG CBC, serum biochemistry, thoracic radiography,
ultrasonography (adrenal glands), CT (brain, pituitary gland),
survey for dog owners to assess quality of life
N*
Levin
44,45
4 Endocrinologic assessment and therapy N*
Gilmour et al.
17
17 Clinical exam, ERG CBC, serum biochemistry, thoracic radiography,
ultrasonography of adrenal glands, CT of pituitary glands,
circulating AAbs (Western blot)
Y
Keller et al.
18
13 Clinical exam, ERG, circulating AAbs (Western blot and ELISA) Y
Braus et al.
8
24 Clinical exam, ERG, serum biochemistry, circulating AAbs (Western blot, ELISA) Y
Grozdanic et al.
28
5 Clinical exam, ERG, chromatic pupillometry Y
Grozdanic et al.
27
19 Clinical exam, ERG, chromatic PLR, OCT of retina, light microscopic
examination of the retina, incl. IHC
N
Grozdanic et al.
37
12 Clinical exam, ERG, chromatic PLR, OCT of retina, behavioral vision
testing, retinal microarray, light microscopic examination of the retina, incl. IHC
N*
Montgomery et al.
14
120 Clinical exam, ERG, CBC, serum biochemistry, urinalysis, serological
testing for Lyme disease, MRI of brain, CSF analysis
Y
Carter et al.
16
13 Clinical exam, ERG, CBC, serum biochemistry, urinalysis,
endocrinologic evaluation, blood pressure
Y
Stuckey et al.
11
100 Clinical exam, ERG, questionnaire completed by dog owners Y
Heller et al.
13
495 Clinical exam, ERG, effect of breed and body weight N
*Conference abstracts.
AAbs, antiretinal antibodies; CBC, complete blood count; CSF, cerebrospinal fluid; CT, computed tomography; ELISA, enzyme-linked immu-
nosorbent assay; ERG, electroretinogram; FA, fluorescein angiogram; IHC, immunohistochemistry; OCT, optical coherence tomography; MRI,
magnetic resonance imaging; PLR, pupillary light reflex; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.
©2015 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology,19, 319–331
sards review and research strategies 321
receptor loss and acute blindness or whether, when pres-
ent, they represent a variant of SARDS. Loss of olfaction
is also reported in some SARDS-affected dogs, resulting
in difficulty detecting food even when it is in close prox-
imity to their noses
12
; however, it is not known how loss
of olfaction is possibly linked to the retinal disease.
Causation also remains undetermined despite numerous
epidemiological studies suggesting some correlative risk
factors. For example, some authors have suggested a sea-
sonality of disease incidence, with peaks in December and
January in the northeastern United States.
3,4
However,
this winter peak is not supported by studies from other
geographic regions.
11
Dogs from rural or urban environ-
ments can be affected by SARDS,
3,4
and no environmental
risk factors have been identified so far.
3,4,12
However, con-
cerns have been raised on internet sites and e-mail discus-
sion groups that SARDS could be triggered by stressful
situations, such as general anesthesia, grooming appoint-
ments, kennel stays, household changes, use of certain an-
tiparasiticides, or vaccination. Glutamate excitotoxicity has
also been proposed as a possible mechanism of photore-
ceptor death in SARDS.
26,40
Increased glutamate concen-
trations were reported in vitreous samples collected from
SARDS-affected dogs.
40
However, since the vitreous sam-
ples were submitted for amino acid analysis within the lab-
oratory of E. Dreyer at Harvard Medical School and this
researcher was later convicted of scientific misconduct by
the United States Department of Health and Human Ser-
vices, the integrity of analyses on these samples should be
questioned (grants.nih.gov/grants/guide/notice-files/NOT-
OD-01-006.html).
Taken together, this wide variation in syndromic signs
and the lack of proven causation have led to much contro-
versy regarding etiopathogenesis and whether SARDS is a
single disease entity. This has also led some to assign
diagnostic ‘labels’ originally used for human conditions
such as immune-mediated retinitis (IMR), autoimmune
retinopathy (AIR), and cancer-associated retinopathy
(CAR) to various clinical presentations in dogs.
21,27,37
These are discussed more fully below. It remains unclear
whether the conditions seen in dogs are sufficiently similar
to those described in humans to permit such diagnoses.
Regardless of cause, SARDS remains a devastating diagno-
sis with up to one quarter of SARDS-affected dogs being
euthanized as a result of real or perceived deterioration in
quality of life due to some combination of acute, complete
vision loss, associated systemic abnormalities, or other
age-related health issues.
911
ENDOCRINOPATHIES ASSOCIATED WITH
SARDS
In a majority of SARDS-affected dogs, vision loss is seen
in conjunction with systemic signs (PP, PU, PD, weight
gain, apparent anxiety, panting, etc.) and/or laboratory
abnormalities (lymphopenia, neutrophilia, elevated serum
alkaline phosphatase (ALP), aspartate aminotransferase
(AST), alanine aminotransferase (ALT), or cholesterol, as
well as reduced urine specific gravity and/or proteinuria)
consistent with those seen in certain endocrinopathies
such as hyperadrenocorticism.
15,8,12,14,16,17,20,39
Recent
work has also assessed changes in circulating sex hormone
concentrations. Carter et al.
16
reported that over 90% of
SARDS-affected dogs have elevated adrenal sex hormone
and/or cortisol serum concentrations, before and/or after
stimulation with adrenocorticotropic hormone (ACTH).
The sex hormones most commonly elevated are 17-hy-
droxyprogesterone and progesterone, followed by estra-
diol, androstenedione, and rarely testosterone.
16
These sex
hormones can exhibit glucocorticoid-like activity.
16,41,42
For example, 17-hydroxyprogesterone and progesterone
are major precursors to the production of cortisol and
androgens in the steroid pathway.
16
It is possible that ele-
vated steroid hormones trigger photoreceptor apoptosis in
SARDS-affected dogs.
19
Similarly, pre-ACTH stimulation
cortisol levels have been inversely correlated with visual
function as measured by ERG, and SARDS-affected dogs
have altered blood flow in the ophthalmic artery and vein
as measured by Doppler ultrasonography.
24
Carter et al.
16
suspected pituitary abnormalities in the majority of their
patients with SARDS based on the normal to high circu-
lating ACTH values, which were considered inappropriate
combined with the documented adrenal hyperactivity. In
addition to abnormal ACTH response test, ~60% of
SARDS-affected dogs may also have abnormal results
from a dexamethasone suppression test.
35
Therefore, it
has been recommended that dogs with SARDS and clini-
cal signs suggestive of hyperadrenocorticism should be
further evaluated, using techniques such as pituitary and
adrenal gland imaging.
15,16,39
Despite indications of adre-
nal cortical hypersecretion, only about 20% of SARDS-
affected dogs are diagnosed with typical hyperadrenocor-
ticism,
1,35,15,39
and unlike Cushing’s syndrome in dogs,
the systemic signs in dogs with SARDS without typical
hyperadrenocorticism often resolve (although the blind-
ness does not).
35,15,16,39
Also, despite hyperadrenocortic-
ism being relatively prevalent in middle-aged to older
dogs, we are aware of only two reports documenting
development of SARDS in dogs with confirmed preexist-
ing hyperadrenocorticism.
20,24
Thus, a causal relationship
between SARDS and hyperadrenocorticism remains con-
troversial.
Others have suggested that the atypical hyperadren-
ocorticism seen in patients with SARDS represents a
physiologic response to stress such as sudden vision
loss.
1,35,15,39,43
However, similar signs are not seen in
patients with other diseases causing apparently rapid onset
of vision loss, such as optic neuritis, and to the authors’
knowledge, a comparable syndrome has not been
described in other species including humans. Finally ,
some have claimed that, because the initially elevated
serum cortisol concentrations in patients with SARDS
©2015 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology,19, 319–331
322 kom
ar o m y ET AL.
subsequently decline, and are accompanied by increased
adrenal sex hormone concentrations and subnormal thy-
roxin concentrations, this may represent a form of ‘adrenal
gland exhaustion’. Therefore they have recommended the
term ‘atypical cortisol estrogen imbalance syndrome’ or
the eponymous ‘Plechner’s syndrome’ for this condition
(drplechner.com ).
44,45
As a result, glucocorticoid and thy-
roid hormone replacement therapy for patients with
SARDS by these authors following detailed serum cortisol
and adrenal sex hormone measurements. However, there
are no controlled, peer-reviewed studies supporting
successful treatment outcomes.
The systemic clinical signs and loss of olfaction noted
in many patients with SARDS may also be suggestive of a
neuroendocrine disorder. The olfactory bulb houses dopa-
mine neurons, which are known to be involved in the reg-
ulation of olfactory function.
46,47
The role of dopamine
neurons in the olfactory bulb in SARDS-induced loss of
olfaction has not been explored. The retina is home to the
retinal dopaminergic system whose function still remains
unclear.
48
Whether there is any relationship between the
loss of olfaction noted in SARDS to any possible changes
observed in dopaminergic neurons in the retina has not
been investigated. A similar relationship between dopami-
nergic systems in the olfactory bulb and the nigrostriatal
dopamine neurons in Parkinson’s disease has been
explored.
4951
IS SARDS A FORM OF AUTOIMMUNE
RETINOPATHY?
Autoimmunity as a potential etiology for SARDS has been
investigated many times over the last
30 years.
8,17,18,21,27,37,38,5254
Recently, there have been
claims of prevention or reversal of vision loss following
aggressive immunosuppressive therapy.
21,27,37,38
However,
these claims remain controversial because they have not
yet undergone peer review or been repeated by other cli-
nicians. The failure of patients with SARDS to reliably
respond to immunosuppressive therapies that are typically
effective for other autoimmune diseases fails to support
the purported autoimmune pathogenesis. The following
paragraphs provide a comprehensive review of human AIR
with an emphasis on investigations that are urgently
needed to assess the role of autoimmunity in canine
SARDS.
Similar to SARDS, many forms of AIR in humans are
characterized by an unexplained sudden (typically within
weeks to months) and progressive loss of vision with mini-
mal change in the appearance of the ocular fundus in the
early stages, severe attenuation or loss of ERG amplitudes,
apoptosis of photoreceptors, and lack of intraocular
inflammation.
5567
Comparable to SARDS, AIR occurs
twice as commonly in females as it does in males, and the
disease is typically diagnosed in middle-aged individuals
between the ages of 50 and 70 years.
5658,60,61,68,69
About
6070% of patients with AIR have a family history of
other autoimmune disorders, such as rheumatoid arthritis,
lupus, thyroid disease, or asthma.
55,58,61,66
The condition
presents either as the primary autoimmune condition non-
paraneoplastic AIR (npAIR) or associated with various forms
of nonocular neoplasia where it is defined as either cancer-
associated retinopathy (CAR) or melanoma-associated retinopa-
thy (MAR).
5557,66,6876
Because concurrent cancer cannot
always be diagnosed at the time AIR is diagnosed, a diag-
nosis of npAIR may subsequently be converted to CAR or
MAR.
76
Alternatively, cancer may be diagnosed months to
years prior to AIR.
68
A connection between SARDS and
cancer has been ruled out in dogs
14,17
; however, this
notion has recently been challenged by Grozdanic and
colleagues.
38,53,54
Because the ocular fundus of patients with AIR tends to
appear fairly unremarkable, the use of additional diagnos-
tic tools is needed. In addition to visual field deficits,
which cannot be easily determined in dogs, severely
decreased ERG amplitudes are also often observed in
human patients with AIR.
55,56,6164,66,67,69,77
The discrep-
ancy between the normal appearance of the ocular fundus
and the results of functional tests is explained by initial
immune-mediated retinal damage with delayed death of
retinal cells.
55
Since it is well accepted that AIR is mediated by auto-
immune mechanisms associated with antiretinal antibodies
(AAbs), serum antibody analysis is an important part of
the diagnostic evaluation of human patients.
56,61,64,69,72,78
It is believed that AIR is either triggered by molecular
mimicry between retinal and other, mostly unknown pro-
teins that may be expressed by microorganisms, or by reti-
nal proteins that are misexpressed in cancer cells.
56,79
The
result is an autoimmune reaction against retinal pro-
teins.
56,79
AAbs can penetrate from the blood stream into
the retina and affect the function of their target antigens/
proteins, resulting in retinal dysfunction and cell death
through activation of apoptosis.
65,69,76,8086
Serum antibody analysis is typically performed by a
combination of Western blot, immunohistochemistry
(IHC), and enzyme-linked immunosorbent assay
(ELISA).
61,87
For the Western blot technique, proteins
extracted from a normal retina are separated into discrete
bands according to their molecular weight by gel electro-
phoresis and then transferred to a membrane that is subse-
quently incubated with the patient’s serum.
87
A tagged
secondary antibody (anti-human or anti-dog immunoglob-
ulin depending on the patient species being tested) binds
and marks any of the patient’s AAbs bound to the retinal
proteins on the membrane.
87
For IHC, histologic sections
of normal retina are incubated with the patient’s serum
and any antibodies binding to the retina will be identified,
as for Western blot, with tagged secondary antibodies.
58,87
This technique allows identification of the specific retinal
cells being targeted by the AAbs. The principles of ELISA
are very similar to those of IHC and Western blot analy-
©2015 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology,19, 319–331
sards review and research strategies 323
sis: small wells are coated with specific retinal proteins
and then incubated with the patient’s serum.
87
Any AAbs
bound to the retinal protein in the well will be detected
with a tagged secondary antibody and a colorimetric reac-
tion which is measured with a spectrophotometer.
87
The
ELISA technique allows measurement of titers by testing
serially diluted serum samples. Titers of relevant AAbs are
higher in patients with AIR compared to normal controls,
and a decrease intiter in response to therapy is sometimes
considered clinically relevant.
8791
The interpretation of serum antibody analysis can be
quite difficult, mostly because AAbs can also be found at
some level in over half of normal humans and are there-
fore not always pathogenic or clinically relevant.
66,87,92
Thus, mere presence of AAbs in an individual’s serum is
insufficient to establish a diagnosis of AIR.
87,92
Typically,
more proteins are targeted by AAbs, and the staining
intensity stronger when comparing Western blots of AIR
patients with normal controls.
66
Since many AAbs are
benign, it has to be verified that identified AAbs are truly
pathogenic, for example, by intravitreal injection into a
normal animal.
78,81,87,9294
Only a few of the many AAbs
found in patients with AIR have been proven to cause reti-
nal degeneration, and the clinical manifestation can vary
depending on the retinal protein and cell type tar-
geted.
56,68,78,9597
Antibodies directed against multiple specific retinal anti-
gens have been identified in patients’ sera; only antirec-
overin and anti-a-enolase will be discussed in detail
here.
65,66,68,69,78,82,91,98100
These two AAbs have been
most frequently found in patients with AIR (both npAIR
and CAR) and induce apoptosis of photoreceptors, bipolar
cells, and retinal ganglion cells.
56,59,63,64,69,7174,76,78,81
83,85,86,89,9395,100116
Furthermore, antirecoverin and anti-
a-enolase AAbs are not typically found in the normal pop-
ulation and, when present in healthy individuals, usually
target different epitopes and do not induce apopto-
sis.
55,56,64,80,81,85,9597
Recoverin is primarily expressed in
photoreceptors where it plays a regulatory role in photo-
transduction.
81,117,118
However, it can also be aberrantly
expressed by tumors of patients with CAR, suggesting that
antibodies formed against the tumor’s recoverin cross-
react with photoreceptors.
73,79,81,104,105,119,120
Enolase is a ubiquitously expressed glycolytic enzyme
with three isoforms: a-enolase, found in many tissues; b-
enolase, found predominantly in muscle; and c- or neu-
ron-specific enolase (NSE), found in neurons, neuroendo-
crine tissues, and photoreceptors.
121
Antibodies against
NSE, not anti-a-enolase antibodies as in human patients
with AIR, were found in six of 24 dogs studied with
SARDS, whereas none of the normal control dogs tested
had detectable NSE autoantibodies.
8
This finding repre-
sents the strongest indication to date of an autoimmune
pathogenesis for at least some cases of SARDS. Other
studies have also documented AAbs in SARDS-affected
dogs, but their results were not conclusive.
17,18,38,52
Therefore, a clear relationship between the presence of
serum AAbs and the development of retinal disease still
needs to be established for SARDS. Based on the lessons
learned from human AIR studies, a similar autoimmune
pathogenesis in SARDS cannot be ruled out simply
because AAbs were not found in some affected dogs or
were also found in normal control dogs.
8,17,18,37
Similar to SARDS, AIR is not associated with any clini-
cal signs of intraocular inflammation.
61,66,80,107
Except for
a few macrophages in the regions of retinal cell loss, no
significant inflammation is seen histologically within AIR-
affected retinas.
81,122
However, T and B lymphocytes
probably contribute to the disease process as suggested by
documented activation of the complement system.
78,123
This is further supported by the recent IHC detection of
immunoglobulin-rich plasma cells, T lymphocytes, and
activated microglia embedded within the SARDS-affected
retina and an increase in expression of genes associated
with antigen presentation, immunoglobulin synthesis,
complement, apoptosis, and pro-inflammatory mediators
by microarray analysis.
27,37,53,54
This resulted in the novel
proposition of intraretinal AAbs production.
27
Our review
of the literature on SARDS and AIR confirms that the
potential role of cellular autoimmunity urgently requires
investigation.
Several treatment strategies are used in patients with
AIR, including steroids, intravenous immunoglobulins
(IVIg), immunosuppressive drugs, such as cyclosporine,
azathioprine, mycophenolate mofetil, and cytolytic anti-
bodies, such as rituximab and alemtuzumab that target
specific lymphocyte subpopulations.
55,57,58,66,89,124
Long-
term immunosuppressive treatment for at least 3
4 months is needed to achieve a therapeutic effect; how-
ever, treatment is not always effective, especially when
there is already severe loss of retinal cells.
5658,66,76
If
treatment is effective, it may need to be continued for
years in order to prevent recurrence.
66
Disease parameters
routinely screened to assess treatment outcome include
visual function, ERG amplitudes, and AAbs titer.
57,63,66,87
90,108,125
Assuming SARDS and especially the proposed
early phenotype IMR are autoimmune diseases, Gro-
zdanic and colleagues began immunosuppressive therapy
using high doses of systemic steroids, intravenous or intra-
vitreal administration of human IVIg, and systemic immu-
nosuppressive therapy, such as leflunomide and
cyclosporine in some affected dogs.
21,27,37,38
They
described positive treatment outcomes in a number of
dogs, but these remain controversial due to the lack of
peer-reviewed reports and because others have not repli-
cated their work.
11
RECOMMENDATIONS FROM THE THINK TANK
REGARDING REQUIRED RESEARCH
Because the pathogenesis of SARDS remains poorly
understood and no effective treatments exist, Think Tank
©2015 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology,19, 319–331
324 kom
ar o m y ET AL.
members believe that research strategies and data collec-
tion remain essential. Since the term SARDS has been
applied more widely in recent years than the original defi-
nition was, well-defined inclusion and exclusion criteria
for patients with SARDS will be critical in future studies.
There is also a clear need for the identification and exami-
nation of SARDS-affected dogs in the acute phase of dis-
ease in order for studies of pathogenesis and etiology to
be more accurate and therapeutic strategies to be more
effective. We recommend that all studies must include
carefully selected normal control dogs, ideally breed, age,
and sex matched, from a similar environment, and avail-
able for extensive examinations and sample collection.
There would be advantages from establishing a national
or international center for data and sample collection and
long-term storage. Existing databases that could serve as
templates are the Immune Tolerance Network (www.im-
munetolerance.org) or the canine eye database maintained
by the Orthopedic Foundation for Animals (www.of-
fa.org). This approach would support multicenter studies
and more efficient collection of larger number of samples
and data that are uniformly handled and stored with the
necessary quality control. Although difficult and costly, we
recommend longitudinal monitoring of potential SARDS
biomarkers as performed in larger human epidemiologic
studies, such as the Beaver Dam Eye Study (www.bdeye-
study.org). This may enable identification of early disease
parameters, thereby permitting earlier SARDS diagnosis
and initiation of therapy prior to photoreceptor death.
Based on proposed disease mechanisms discussed herein,
serum and/or plasma should be collected for detection and
characterization of AAbs, hormones, and cytokines, as well
as whole blood for DNA and lymphocyte isolation. Other
potentially useful samples for similar assessments include
aqueous and vitreous humor; however, collection of these is
more invasive and less practical. Given the diversity of
assays and lability of some parameters assessed, sample col-
lection, handling, and storage would require careful plan-
ning. Detailed histologic and molecular evaluation of tissue
samples is also a high priority; however, because dogs tend
to live several years following diagnosis of SARDS, and
because affected eyes do not need to be enucleated, access
to tissues is limited. Access to appropriate control tissues is
similarly difficult. Sponsored tissue donation and public
awareness programs would be very useful. Until then, eval-
uation of archival tissue samples will be important. Strong
evidence that dysregulated immune interactions with com-
mensal intestinal microbiota play a role in generation of au-
toimmunity
126
led the panel to also consider collection and
storage of gastrointestinal flora, including fecal samples, for
future evaluation of the microbiome of affected and normal
animals. As a general consideration for future studies, inves-
tigators are encouraged to widen the range of possible etiol-
ogies to include nutritional, toxic, and infectious causes.
We recognize that some proposed strategies are ambi-
tious and costly and cannot be realistically performed at
many institutions and that funding for canine-specific con-
ditions also is limited. However, the ACVO-VAF is dedi-
cated to provide initial funds through a special grant
application process. If investigations reveal similar disease
mechanisms in SARDS and human diseases such as AIR,
additional funding options for translational research may
become available through agencies such as the National
Institutes of Health. As a guide for future studies, the
remaining paragraphs contain recommended outcome
measures and minimal databases that should be collected
from SARDS-affected and control animals.
Clinical examination
A thorough clinical history, systemic and ophthalmic
examinations, and standardized data collection and sample
storage methods for SARDS-affected and control animals
are essential for disease characterization. For identification
of genetic and environmental risk factors, historical data
should be collected using a detailed standardized question-
naire that includes questions about recent potentially
stressful events, medications, occurrence of PU, PD, PP,
and weight gain, etc.
12
Signalment data must include age,
sex, neuter status, breed, body weight, and body condition
score. Ophthalmic evaluation must include slit-lamp bi-
omicroscopy, ophthalmoscopy, digital fundus photogra-
phy, chromatic PLR assessment, tonometry, standardized
behavioral vision testing, and high-quality electroretinog-
raphy according to a standardized protocol.
127
As tools for
in vivo high-resolution imaging of the retina such as con-
focal scanning laser ophthalmoscopy, optical coherence
tomography (OCT), autofluorescence imaging, and fluo-
rescein angiography become widely available, they should
be included in clinical phenotyping. The complete physi-
cal examination should include blood pressure measure-
ment and neurologic evaluation. Investigators should
perform thoracic radiographs, abdominal ultrasound, and
magnetic resonance imaging of the brain if indicated to
rule out the presence of neoplasia. Objective assessments
of olfaction such as electroencephalographic and behav-
ioral olfactometry using eugenol and benzaldehyde may be
helpful.
128
Clinicopathologic and endocrinologic evaluation
Results of a complete blood cell count, serum biochemis-
try analysis, and urinalysis should be recorded. Additional
serum/plasma/whole blood samples should be stored at
80 °C for future testing, including DNA analyses, test-
ing for thyroid disease, and hyperadrenocorticism via
serum concentrations of cortisol and adrenal sex hormones
including 17-hydroxyprogesterone, progesterone, and
estradiol before and after ACTH stimulation.
16
To deter-
mine whether increased circulating cortisol is stress-
related, catecholamine assessment should be considered.
Continued testing of these hormones/markers following
diagnosis would also be useful. Collaboration with inter-
nists to arrange measurement of many of these parameters
©2015 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology,19, 319–331
sards review and research strategies 325
in dogs with recent PU, PD, and PP of unknown cause
may also provide useful premonitory information if any of
these dogs subsequently develop SARDS.
Immunologic assessment
Circulating AAbs should be identified and characterized in
dogs with SARDS and compared to an appropriate control
population. These evaluations should include assessment
of IgM and IgG titers, and their ratio. Following the dis-
covery by Braus et al.
8
of anti-NSE antibodies in SARDS-
affected dogs, major efforts should be directed at identify-
ing antibodies found exclusively in patients with SARDS
and characterizing their target antigens and epitopes. Sub-
sequent comparison of titers of AAbs in cases and controls
will be critical, and canine cancers should be evaluated for
expression of identified retinal antigens. Development of
functional assays of AAbs to determine their binding affin-
ities, cytotoxicity, and pathogenic potential would be valu-
able and may necessitate intraocular injection of these
antibodies and/or vaccination with the target antigen in
laboratory animals. An ultimate goal should be develop-
ment of standardized arrays for larger scale AAb testing of
affected and normal canine populations.
Considering that most autoimmune diseases are T-cell-
mediated with secondary formation of autoantibodies,
129
131
detailed investigation of the role of cellular immunity
in SARDS is needed. Quantification of circulating CD4
+
and CD8
+
T, natural killer, and B cells by flow cytometry
would determine whether SARDS dogs have abnormal
profiles of these cellular subsets. Cells isolated from whole
blood could also be functionally tested for responsiveness
to retinal antigens in vitro. Major histocompatibility com-
plex (MHC) profiles, which are skewed in several human
autoimmune diseases, should be compared between
affected and control dogs to further support an immune-
mediated pathogenesis. Comparing cytokine concentra-
tions in blood, aqueous humor, and vitreous between
patients with SARDS and normal controls may also pro-
vide information about the immunologic mechanisms
involved in photoreceptor death. Any immunologic assess-
ments should distinguish between causative autoimmune
mechanisms and immune responses that represent a nor-
mal consequence of retinal destruction.
Genetic studies
Although SARDS is not recognized as an inherited dis-
ease, a genetic predisposition is suggested by high disease
prevalence in breeds such as dachshunds and miniature
schnauzers. Detailed pedigree analyses and genomewide
association studies (GWAS) will provide important data
regarding potential genetic factors and may ultimately per-
mit development of genetic markers for SARDS, thereby
elucidating etiologic and pathogenic mechanisms, as well
as permitting earlier diagnosis. Again, the careful selection
and examination of control animals is critical for the suc-
cess of such a study. Likewise, gene expression studies by
microarray or RNAseq analysis of retinal and circulating
lymphocytes should be expanded.
54
This will be greatly
facilitated by a donor system, which should be developed,
maybe through specific breed clubs. Although, it remains
possible that eyes donated some time after the onset of
SARDS may no longer yield samples appropriate for
immunologic or biochemical testing, genetic analysis
should remain useful.
Pathologic and histopathologic studies
Although detailed histologic and molecular analyses of
multiple organ systems may permit better understanding
of the ophthalmic and systemic characteristics of SARDS,
Think Tank members remain concerned that even the
establishment of a body and tissue donation system will
not produce sufficient useful samples in the acute or pre-
monitory phase of disease and that analysis of archival tis-
sue samples remains the most viable option for histologic
or immunohistochemical studies. Very careful histologic
examination of the central nervous system, including
hypothalamus and pituitary gland, as well as adrenal
and olfactory tissues is warranted to determine whether
cells other than the retinal photoreceptors are being
destroyed.
Therapeutic trials
It is generally believed that vision loss with SARDS is per-
manent and that there is no treatment that can prevent or
reverse SARDS-related blindness,
5,14,19,20
although anec-
dotal reports suggest that this may not be the case.
21,27,37,38
The goal of the VAF initiative is to rigorously investigate
potential therapies. If affected animals can be diagnosed
before photoreceptors are permanently lost and the disease
process reversed, it may be possible to successfully manage
dogs with SARDS. Although an etiology and pathogenesis
for SARDS must be unequivocally determined, potential
treatments will likely continue to be tested. In order for
these trials and their results to gain wider acceptance,
patient selection criteria, treatment protocols, and outcome
measures must be rigorous and consistently applied, proper
controls are essential, and data must be submitted for peer
review. Because no treatment is available for this disease, a
double-masked, randomized, placebo-controlled study
design would likely be considered ethically responsible pro-
vided that frequent interim data review is conducted during
the study, and rescue criteria are identified a priori.
Undoubtedly, such a study design would present the most
convincing strategy to prove effectiveness of a new treat-
ment. The most important treatment outcomes are objec-
tively assessed restoration of visual performance in
association with improved ERG and PLR parameters.
Although pet owners’ satisfaction is critical, their assess-
ment of visual performance at home is insufficient to docu-
ment successful treatment, especially because dogs adjust to
blindness through increased dependence upon nonvisual
senses.
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326 kom
ar o m y ET AL.
Therapeutic trials could involve already clinically
approved treatment strategies or new classes of drugs.
Specifically, Think Tank members discussed the feasibility
of producing a canine-specific IVIg, which may be more
efficacious and better tolerated than the human product.
Clinically approved drugs/antibodies against B cells, such
as the anti-CD20 drug rituximab (Rituxan
â
; Genentech,
Inc., South San Francisco, CA, USA) were also consid-
ered; however, many human-specific compounds may not
target canine B-cell receptors and versions would have to
be specifically developed for the dog.
132
Treatment of endocrine abnormalities was also dis-
cussed. For example, use of a lignan phytoestrogen and
melatonin combination has been advocated for treatment
of dogs with atypical hyperadrenocorticism, where cortisol
concentration is within reference limits, but levels of adre-
nal sex hormone concentrations are increased and mimic
clinical signs of excess cortisol secretion.
42
These com-
pounds may decrease steroid hormone secretion by the
adrenal gland and could potentially be beneficial for treat-
ing patients with SARDS, depending on how abnormal
sex hormones and loss of photoreceptor function are
linked.
42
SUMMARIZING COMMENTS BY THINK TANK
PARTICIPANTS
The following represent individual Think Tank members’
summary comments on the most critical and central ele-
ments in the ACVO-VAF’s goal to better elucidate predis-
posing factors, etiology, pathogenesis, clinical syndrome,
and treatment options for SARDS in dogs.
(1) Andr
as M. Kom
aromy: ‘Regardless of the research
methods used to investigate the pathogenesis of
SARDS, the careful selection and examination of con-
trol animals is critical’.
(2) Kenneth L. Abrams: ‘Based on clinical and pathologi-
cal findings in SARDS patients over years of original
and review publications, there seems to be a neuroen-
docrine systemic trigger to the disease’.
(3) John R. Heckenlively: ‘There are striking similarities
between SARDS and features seen in AIR. AIR in
humans can present as a paraneoplastic event so it
would help to document in SARDS if neoplasms are
present, and if other systemic diseases co-exist. Mito-
chondrial mutations also can present with abrupt
onsets, and mutational analysis of mitochondrial DNA
from affected canines would be informative even if
negative’.
(4) Steven K. Lundy: ‘As part of a research team that is
studying the immune pathogenesis of human AIR, I
am struck by the similarities in clinical findings
between SARDS and AIR. It is too early to know
whether these two syndromes are closely related in
either immune or neuroendocrine features. Similarities
or differences found between SARDS and AIR could
significantly enhance our understanding of both dis-
eases. Regardless of the cause of pathology, advances
in screening and early interventions will likely be criti-
cal to preserving sight in either species’.
(5) David J. Maggs: ‘At the core of all future investiga-
tions of SARDS in dogs must lie a rational, orderly,
committed, and rigorously standardized characteriza-
tion of the clinical and epidemiological features of the
disease or diseases that we currently group under this
syndromic diagnosis’.
(6) Caroline M. Leeth: ‘Determining the pathogenesis of
SARDS will require a concerted effort to study
appropriate research participants with adequate con-
trols in a systematic manner as this syndrome
appears multi-faceted with the possibility for several
etiologies’.
(7) Puliyur S. MohanKumar: ‘There is a distinct possibil-
ity of neuroendocrine involvement in SARDS which
has not been explored thoroughly. Understanding the
possible role of neurotransmitters in precipitating
some of the co-morbidities observed in SARDS might
provide important insights’.
(8) Simon M. Petersen-Jones: ‘Detailed early assessment
of affected dogs is essential, and we should consider
the possibility that more than one underlying etiology
may be responsible for the SARDS presentation’.
(9) David V. Serreze: ‘As someone outside the veterinary
community, I came away from the Think Tank with a
view that SARDS is a syndromic range of diseases,
and that better subtype stratification based on neuro-
endocrine, and immunological profiles is required to
select optimized treatment strategies’.
(10) Alexandra van der Woerdt: ‘It will require the com-
bined efforts of clinicians to identify affected animals
and appropriate control dogs, and research scientist to
help improve our knowledge about the etiology, path-
ogenesis and treatment of SARDS in dogs’.
ACKNOWLEDGMENTS
Special thanks go to Ms. Jen Gazdacko of the ACVO-
VAF for her administrative support of the SARDS Think
Tank. The authors thank the ACVO membership for pro-
viding strong recommendation that the first ACVO-VAF
Think Tank covers the important subject of SARDS.
Thanks also go to Dr. Sinisa Grozdanic (Animal Eye
Consultants of Iowa) for his assistance in planning the
Think Tank. The SARDS Think Tank and this publica-
tion were generously supported by the ACVO-VAF.
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... Degenerative retinal and optic nerve diseases are the most common causes of irreversible vision loss in dogs and include glaucoma, sudden acquired retinal degeneration syndrome (SARDS), progressive retinal atrophy (PRA), and retinal detachment (RD). [1][2][3][4][5][6] Medical and surgical treatments are available for some of these conditions, such as lowering intraocular pressure (IOP) and reattachment of the retina in canine patients with glaucoma and RD, respectively. Progressive retinal atrophy is a group of genetically heterogeneous diseases with a steadily increasing number of defined mutations. ...
... The reasons for this phenomenon are not fully understood, but likely include oxidative stress, excitotoxicity caused by disproportionate excitatory amino acid release, such as glutamate and aspartate, excessive intracellular calcium, neurotrophin deprivation, inflammation, and reactive gliosis. [2][3][4][9][10][11] In order to optimize treatment outcome and limit, or even prevent, further loss of neurons and eyesight, these complicating factors need to be addressed in addition to the treatment of primary underlying disease mechanisms. Like other mammalian central nervous system (CNS) neurons, retinal neurons do not regenerate and cannot be replaced with the currently available technologies, supporting the need for effective neuroprotection. ...
... Per definition, dogs with SARDS are generally completely blind with no recordable retinal function and rapid loss of photoreceptors. 2 Recent reports suggest that some SARDSaffected dogs may still have limited sight dependent on the time of diagnosis. 11,26 The low rate of neuroprotection recommendation for SARDS is likely based on the general belief that sight cannot be restored in these canine patients. ...
Article
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Objective To investigate veterinary ophthalmologists’ use of presumed neuroprotective therapies for degenerative retinal and optic nerve diseases in dogs. Procedures An online survey was sent to 663 board‐certified veterinary ophthalmologists who were Diplomates of the American College of Veterinary Ophthalmologists (ACVO), Asian College of Veterinary Ophthalmologists (AiCVO), Latin American College of Veterinary Ophthalmologists (Colegio Latinoamericano de Oftalmólogos Veterinarios, CLOVE), or European College of Veterinary Ophthalmologists (ECVO). The survey was created using Qualtrics® software and focused on the prescription of presumed neuroprotective treatments for canine glaucoma, sudden acquired retinal degeneration syndrome (SARDS), progressive retinal atrophy (PRA), and retinal detachment (RD). Results A total of 165 completed surveys were received, representing an overall response rate of 25%, which was comparable across the four specialty colleges. Of all respondents, 140/165 (85%) prescribed some form of presumed neuroprotective therapies at least once in the last five years: 114/165 (69%) for glaucoma, 51/165 (31%) for SARDS, 116/165 (70%) for PRA, and 50/165 (30%) for RD. The three most recommended neuroprotective reagents were the commercial Ocu‐GLO™ Vision Supplement for animals, amlodipine, and human eye supplements. Conclusions Despite lack of published clinical efficacy data, the majority of surveyed board‐certified veterinary ophthalmologists previously prescribed a presumed neuroprotective therapy at least once in the last five years in dogs with degenerative retinal and optic nerve diseases.
... Depending on the location and the pathological and clinical features, GME is classified into focal, disseminated and ocular form. Of these three forms, the ocular form is the least common [4,7]. The optic nerve is surrounded by meninges and subarachnoid space. ...
... Therefore, diseases of the meninges can affect the optic nerve [2]. Because the ocular form of GME involves the optic nerve, it presents with acute onset of vision loss and unresponsiveness to light stimulation [4,7]. On Funduscopic examination, swelling of the optic nerve head, indistinct disc margins, dilated vessels, and, occasionally, retinal hemorrhage or detachment could be revealed. ...
... It is characterized by sudden-onset blindness, completely extinguished retinal electrical responses, and the properties of abnormal chromatic pupil light reflex (cPLR) (no red PLR -good blue PLR). [1][2][3] It has been theorized that SARDs is an autoimmune disease similar to autoimmune retinopathies in humans (AIR), with a strong retinal autoantibody component. [4][5][6][7][8] Autoimmune retinopathies (AIR) are rare but devastating autoimmune diseases in humans, characterized by the sudden onset of severe visual deficits (or complete blindness), extinguished retinal electrical activity, relatively normal fundus appearance, and presence of serum retinal autoantibodies. ...
Article
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Objective To describe functional and structural features of presumed cancer‐associated retinopathy (CAR) mimicking sudden acquired retinal degeneration syndrome (SARDS) in dogs and describe treatment outcomes. Animals Subjects were 17 dogs from 8 eight US states and Canada diagnosed with SARDS or immune‐mediated retinitis (IMR) by 12 ophthalmologists. Nine eyes from seven deceased patients were used for microarray (MA), histology, or immunohistochemical (IHC) analysis. Procedures Dogs underwent complete ophthalmic examination, including retinal photography, optical coherence tomography (OCT), chromatic pupil light reflex testing (cPLR), and electroretinography (ERG), in addition to complete systemic examination. Histology, microarray, and IHC analysis were performed in CAR retinas to evaluate histological and molecular changes in retinal tissue. Results None of the patients evaluated satisfied previously established criteria for diagnosis of SARDS (flat ERG+ no red – good blue PLR), and all were diagnosed with IMR. All patients were diagnosed with a cancer: meningioma (24%), sarcoma (18%), pituitary tumor (12%), and squamous cell carcinoma (12%), other (34%). Median survival time was 6 months from diagnosis (range 1‐36 months). Most frequent systemic abnormalities were as follows: proteinuria (78%); elevated liver enzymes (47%); and metabolic changes (PU/PD, polyphagia – 24%). Immunosuppressive therapy resulted in the reversal of blindness in 44% of treated patients, with 61% of all treated patients recovering and/or maintaining vision. Median time for preservation of vision was 5 months (range 1‐35 months). Conclusions Observed changes are highly suggestive of immune‐mediated damage in IMR‐CAR eyes. A relatively high percentage of patients with CAR responded positively to immunosuppressive therapy.
... SARDS affects middle-aged to elderly dogs and often moderately overweight, aged between 7-10 years [2,3,51,53]. According to the studies, the majority of the affected dogs are spayed females [5,24]. Until now, genetic predisposition has not been documented. ...
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Aging consists of a physiological decline of an organism’s functional activity. During the aging process, the structural and functional changes of the retina can be observed. In most cases, progressive vision loss occurs due to the age related changes of the anterior segment. Retinal diseases, characteristic for senior dogs are: retinal detachment, hypertensive chorioretinopathy, sudden acquired retinal degeneration syndrome (SARDS), progressive retinal atrophy (PRA), glaucoma, retinopathy, cystoid degeneration and neoplasms. The examination of the retina in senior dogs is based on: ophthalmoscopic examination, electroretinography, spectral-domain optical coherence tomography (AD-OCT) and if necessary, histopathological examinations. Comprehensive knowledge regarding the senior dog’s health, significantly increases their quality of life.
Chapter
The fundic examination is the most challenging portion of the ophthalmic examination and, as a result, it is often omitted. However, recognition of fundic abnormalities is extremely important because posterior segment disease has a high potential to result in vision loss, and because changes to the posterior segment may signify underlying systemic disease. This chapter discusses the normal appearance of fundic structures, as well as changes that are indicative of pathology. Specific diseases of the posterior segments are then discussed. Fundic changes suggestive each disease are listed for each disease process, along with recommendations for initial diagnostics and therapeutics.
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Objective: Electroretinography (ERG) is used prior to cataract removal surgery to assess retinal function. We aimed to replicate and improve upon previous studies by performing a full ECVO protocol and by examining the retina post-surgery in all patients. Animals studied: One hundred twenty-seven eyes from 67 dogs were included in the study. Procedures: A full ECVO protocol electroretinography, which includes extensive rod and cone analysis, was performed on all dogs presenting for cataract surgery. Results: Our main findings were that amplitudes, but not implicit times of rod responses decreased with advanced cataracts. Amplitudes of the single flash rod and rod flicker responses were significantly lower in eyes with mature cataracts, and the former also decreased in hypermature cataracts. Cone flicker amplitude responses were also significantly lower in eyes with mature and hypermature cataracts. However, mixed single flash rod-cone and cone responses, with the exception of the mixed rod-cone a-wave amplitude in eyes with hypermature cataracts, were unaffected by cataract stage. The b-wave amplitude of the scotopic, mixed rod-cone, and photopic cone responses were affected by age and decreased by an average of 2.9, 7.5, and 1.5 μV/year, retrospectively (p < 0.01). Conclusions: Lower ERG amplitudes in canine cataract patients may result from aging or the presence of advanced cataracts and may not indicate the presence of retinal disease.
Chapter
Degrees of miosis [constricted pupil], mydriasis [dilated pupil] and anisocoria [asymmetric pupil size] occur in many ocular diseases with or without degrees of blindness. Although our patients are not very frequently presented because of these problems alone, identifying the site(s) of neural damage helps greatly in localizing the lesion and consolidating a diagnosis and prognosis. Horner syndrome and the intricate sympathetic supply to the eye and head is emphasised.
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Objective: To quantitatively and qualitatively characterize the retinal optical coherence tomographic features of sudden acquired retinal degeneration syndrome (SARDS) and SARDS suspect dogs. Animals studied: Fourteen SARDS affected dogs, 11 age-, breed-, and sex-matched control dogs, and two SARDS suspect dogs. Procedures: Spectral-domain optical coherence tomography (OCT) images were used to evaluate the quantitative features, including thickness, intereye asymmetry, and longitudinal changes in retinal layer thickness and the qualitative features, including retinal architecture and vitreous haze. Results: Mean outer retinal layer thickness (ORT), outer nuclear layer thickness (ONL), and photoreceptor layer thickness (PRL) were significantly lower in the SARDS group, whereas mean inner retinal layer thickness was significantly higher in the SARDS group than in the control group. While thickness values of all retinal layers did not differ significantly between paired eyes in each group, the absolute intereye asymmetries in the ORT (p < .0001), ONL (p = .008), and PRL (p < .0001) were significantly higher in the SARDS group than in the control group. Some SARDS patients and SARDS suspects had a greater PRL than the control group, and serial OCT evaluation showed an increase in PRL in one SARDS suspect. Vitreous haze severity was greater in the SARDS group than in the control group (vitreous relative intensity, p = .030). Conclusions: We described the OCT features of SARDS patients and suspects. In particular, PRL thickening in the SARDS suspects might indicate an early change in SARDS. Although further studies are needed, this finding might provide new insights into the pathogenesis of SARDS.
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Endocrine diseases make up a significant percentage of the chronic diseases in small animal patients. Dogs and cats with endocrinopathies are at risk of developing many serious ocular signs that may jeopard ize their quality of life. Most of the endocrinopathies including diabetes mellitus, Cushing's disease, growth hormone imbalance, hypothyroidism, hyperthyroidism etc. have ocular manifestations. A better understanding of such ocular manifestations will help in the early diagnosis of the disease condition as well as to undertake the prompt measures for prevention of their occurrence, slowing down the progress or treatment.
Chapter
The first step to any neurological evaluation of a veterinary patient, is whether the problem facing them is partially or completely neurological. The opening move in making practising vets feel confident that they are approaching potentially neurological problems in a reasonable way is learning how to recognise when a particular presentation may be caused by a disease process somewhere within the central nervous system or the peripheral nervous system. The chapter discusses the scope of neurological disease manifestations that clinicians may be presented with and provides clues to the correct recognition of neurological disorders. It explores the neurological examination and neuroanatomical localisation of specific lesions. Where relevant, non‐neurological disorders that can mimic or also result in these clinical presentations are: seizures, collapse, movement disorder/dyskinesia, mentation change, behaviour change, blindness, deafness, tremor, paresis/plegia, ataxia, abnormality of head position, abnormality of eye position or movements, hypaesthesia, lameness, pain, and disorders of micturition/urination.
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Full-text available
Purpose The purpose of this study was to evaluate a chromatic pupillometry protocol for specific functional assessment of rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs) in dogs. Methods Chromatic pupillometry was tested and compared in 37 dogs in different stages of primary loss of rod, cone, and combined rod/cone and optic nerve function, and in 5 wild-type (WT) dogs. Eyes were stimulated with 1-s flashes of dim (1 cd/m²) and bright (400 cd/m²) blue light (for scotopic conditions) or bright red (400 cd/m²) light with 25-cd/m² blue background (for photopic conditions). Canine retinal melanopsin/Opn4 was cloned, and its expression was evaluated using real-time quantitative reverse transcription-PCR and immunohistochemistry. Results Mean ± SD percentage of pupil constriction amplitudes induced by scotopic dim blue (scDB), scotopic bright blue (scBB), and photopic bright red (phBR) lights in WT dogs were 21.3% ± 10.6%, 50.0% ± 17.5%, and 19.4% ± 7.4%, respectively. Melanopsin-mediated responses to scBB persisted for several minutes (7.7 ± 4.6 min) after stimulus offset. In dogs with inherited retinal degeneration, loss of rod function resulted in absent scDB responses, followed by decreased phBR responses with disease progression and loss of cone function. Primary loss of cone function abolished phBR responses but preserved those responses to blue light (scDB and scBB). Although melanopsin/Opn4 expression was diminished with retinal degeneration, melanopsin-expressing ipRGCs were identified for the first time in both WT and degenerated canine retinas. Conclusions Pupil responses elicited by light stimuli of different colors and intensities allowed differential functional assessment of canine rods, cones, and ipRGCs. Chromatic pupillometry offers an effective tool for diagnosing retinal and optic nerve diseases.
Article
Mouse retinal photoreceptor cell generation and morphogenesis take place in a well-characterized temporal sequence. Both rod and cone photoreceptor differentiation and synaptogenesis occur postnatally, but the relative timing of these events has been difficult to document due to the paucity of cell-specific markers. We have found that antibodies to neuron-specific enolase (NSE) preferentially label a subpopulation of photoreceptors in the outer nuclear layer (ONL) of the mouse retina in addition to labeling ganglion, amacrine, bipolar, and horizontal cells within the inner layers of the retina. The appearance of NSE immunoreactivity in the different classes of retinal neurons during development showed a close temporal relationship to the onset of expression of the synaptic vesicle-associated protein SV2 and clearly preceded the sequential development of synaptic connections in both inner and outer synaptic layers. The NSE-immunoreactive photoreceptors were identified as cones by dual labeling of their inner segments with the lectin peanut agglutinin or by colabeling with antisera to cone photopigments. Axonal extensions of NSE-labeled cone cells were shown to interact with those of differentiating horizontal cells as early as postnatal day 3 (P3). Colocalization of NSE with SV2 indicated that cone cells began to make synaptic contacts with horizontal cell processes several days prior to the development of rod synaptic terminals. Between P4 and P11, cone photoreceptor cell nuclei were observed to be scattered at various levels throughout the ONL and thus appeared to have become displaced from their previous position directly beneath the outer limiting membrane (OLM). By P12, the cone nuclei had migrated sclerad once again and were now observed to be neatly aligned adjacent to the OLM. In the rd mouse mutant, this migratory process was delayed, so that, at P12, positioning of the cone cell nuclei within the ONL was still quite irregular. Thus, we have identified a late migratory phase for cone photoreceptors during the second week after birth that correlates with the timing of maturation of the rod synaptic terminals just prior to eye opening. The types of cues used by maturing cone cells for their eventual sclerad location remain to be elucidated. J. Comp. Neurol. 388:47–63, 1997. © 1997 Wiley-Liss, Inc.
Article
Adult dogs occasionally become suddenly, totally and permanently blind. If examined soon after the onset of blindness, the dogs show no ophthalmologic evidence of disease sufficient to account for their problem and are usually in otherwise good health. The hallmark of this sudden, acquired retinal degeneration (SARD), that establishes it as a retinopathy, and distinguishes it from neurological disease, is the extinguished electroretinogram. The syndrome has been termed "Silent Retina Syndrome" and "Metabolic Toxic Retinopathy". Although uncommon, SARD has been diagnosed with increased frequency in recent years. Little retinal tissue has, however, become available for histopathologic characterization of the disease. This report reviews twenty six cases of SARD examined by the authors at the Veterinary Hospital, University of Pennsylvania (VHUP). The histopathology and ultrastructural morphology of four cases are described.
Article
Purpose: The purpose of this study was to describe breed, age, gender, and weight distribution of dogs affected with sudden acquired retinal degeneration (SARD) and to investigate whether SARD is more common in small breed dogs. Methods: Medical records of dogs diagnosed with SARD confirmed by an electroretinogram were reviewed. Breed, age, gender, and weight were recorded when available. The same data were obtained for dogs with SARD described in the veterinary literature. Results: Three hundred and two dogs were included from the ophthalmology practices and 193 dogs from the veterinary literature. Sixty breeds were present in the study. Mixed-breed dogs were the most common at 108 dogs (21.8%), followed by the Dachshund (68, 13.7%), Chinese Pug (44, 8.9%), Miniature Schnauzer (39, 7.9%), Maltese (23, 4.6%), Cocker Spaniel (22, 4.4%), Bichon Frise (18, 3.6%), Beagle (16, 3.2%), Brittany (15, 3.0%), and Pomeranian (10, 2.0%). Fifty other breeds were represented by 1-9 dogs each. The median age was 9 years (range = 10 months-16 years). The weight was known for 197 dogs. About 60.9% of dogs were less than 25 pounds, 31.5% were between 25 and 50 pounds, and 7.6% were greater than 50 pounds. Gender was recorded in 393 dogs: 217 female dogs and 176 male dogs. Conclusions: As previously reported, SARD is most common in middle-aged to older dogs. Smaller dogs of less than 25 pounds appear overrepresented, while large/giant breed dogs of greater than 50 pounds are infrequently diagnosed. In this study, there was no statistical significance between female and male dogs.
Article
Purpose: Vision loss occurring in association with cancers predominates in patients with small cell carcinoma of the lung (SCCL). The pathogenesis of some types of paraneoplastic retinopathy may be founded in autoimmunity, such as that previously proposed to explain the cause of the CAR syndrome, in which lung cancer cells expressing the CAR photoreceptor autoantigen, are considered the cause of the immune reaction which characterizes this form of cancer-induced blindness. An extended search for similar immunologic connections has uncovered a second example of this phenomenon, involving a cancer culture expressing a novel retinal antigen. This study inquired into the pathologic significance of the expression of this 'tumor-associated retinal antigen', as a possible trigger mechanism for the induction of autoimmune reactions affecting the eye. Methods: Cultures of SCCL (American Type Culture Collection) were evaluated for the expression of retinal antigens by propagation intraperitoneally in Lewis rats and evaluation of the induced immune response. Results: A culture of SCCL was found to be expressing a single retinal antigen, identified by the production of corresponding antibodies by the recipient rats in which the culture was introduced. Histologic examination of eyes of these rats revealed indications of retinal decay. Conclusions: Structural alterations to the retina can be induced experimentally in Lewis rats through the intraperitoneal cultivation of a SCCL recognized to be expressing a retinal antigen. This model of 'Experimental, Cancer Induced Blindness' provides further evidence of an autoimmune pathogenesis in certain forms of paraneoplastic retinopathy, demonstrating an immunologic pathway through which vision loss can occur as a remote effect of cancer, with eyesight declining as a result of a cancer-evoked autoimmune retinopathy.