Download Kristina Narfstrom, DVM, PhD, DipECVO

Kristina Narfstrom, DVM, PhD, DipECVO
Professor of Veterinary Ophthalmology
III. RETINAL DEGENERATIVE DISEASE
DOG
INHERITED RETINAL AND TAPETAL DYSTROPHIES
All cellular layers of the retina are potentially susceptible to the development of
hereditary abnormalities. However, most of these relate to the parts that are
physiologically most complex, the layers of the photoreceptors and the retinal
pigment epithelium. In the canine there is a broad range and diversity of inherited
retinal diseases that affect these structures. An important reason for this is certainly
the establishment of different dog breeds and the custom to inbreed dogs that has
favored the emergence and expression of recessive genes that cause a wide
spectrum of retinal and tapetal disorders.
Similar diseases also affect man and the canine diseases therefore seem to offer a
convenient basis for comparison. The paucity of knowledge concerning the
underlying biochemical, physiological and morphological disease mechanisms of
man renders dogs with similar diseases especially important as animal models.
Thus, the rat, mouse, chicken, cat, and also the dog, are frequently used for
comparative studies of human tapeto-retinal dystrophies.
Classification of the canine retinal dystrophies.
Canine retina dystrophies can affect the photoreceptors and/or the retinal pigment
epithelium primarily. Since the first well-documented report of an inherited retinal
degeneration in the Gordon Setter was reported in Sweden by Magnusson, 1911, a
large number of dog breeds have been found to be affected by hereditary retinal
dystrophies. To these conditions the general term “progressive retinal atrophy”
(PRA) has been applied. Clinicians have, throughout the years, divided the disease
complex PRA into two types, depending on the ophthalmoscopic appearance of
fundus lesions. In generalized PRA there is generalized hyperreflectivity of the
retina at the end stage of disease, indicating a generalized atrophy of the retinal
structures and clinical blindness. In central PRA (CPRA) there are multifocal
accumulations of pigment within the retina and encircling these changes there are
areas of hyperreflectivity at the end stage. The latter disorder is a primary defect in
the retinal pigment epithelium, a disorder that not always leads to blindness. Thus,
the two disease entities represent completely different disorders. During the last
few decades PRA has been further subdivided into more specific diseases at the
cellular level, for many of the diseases gene symbols are used. The term CPRA is
currently being replaced by the term retinal pigment epitelial dystrophy (RPED),
which more specifically relates to the disease entity.
The classification of hereditary retinal degenerations is an issue of different
opinions and discussions. Since the diseases are so diverse as to structures involved
and pathogenesis, a strict classification is not feasable and perhaps not
scientifically correct. It is, however, possible to subdivide PRA grossly into
developmental and degenerative diseases. The developmental class represents a
large aggregate of genetically distinct disorders which are expressed cytologically
in the postnatal period, at the time that the visual cells are beginning to
differentiate. These developmental disorders represent a dysplasia of the rod and/or
cone photoreceptors and each has its own unique disease course and phenotype, as
assessed by functional and morphological criteria. Typical for the dysplasias is that
they, before the retina is adult-like at about 6 weeks of age in the dog, show rather
severe structural alterations of the photoreceptor cells, while the rate of progression
and, in most cases, loss of cones in the disease process is varied. In contrast, the
degenerative type of diseases represent defects in which photoreceptor cells
degenerate after having differentiated normally. In the latter group, disease occurs
more slowly and is modified by temporal and topographical factors. Different
alleles have been identified at the same gene locus (prcd) and these segregate to
regulate the rate of photoreceptor degeneration.
Within the retinal dysplasia and degeneration groups, the diseases are further
subdivided according to the type of cell that is primarily affected, for example rodcone dysplasia of Irish Setters or cone degeneration of Alaskan Malamutes.
However, for several diseases not sufficient data on morphology or
electrophysiology is available and the expression PRA is then appropriate to use in
relation to the lay public. The generic term retinal dystrophy, which implies
heredity and lack of normal structure, may also be applied to the hereditary retinal
diseases and is particularly useful in describing new disease conditions until a
specific name is substantiated with further research.
Clinical signs of PRA
The clinical manifestations of PRA are often remarkably similar, no matter what
type of disorder at the cellular level. The non-specific features associated with
primary photoreceptor degenerations leading to retinal atrophy will be described in
short. Particular features associated with specific genetic disorders will be further
described later in the text. PRA is always bilateral and always leads to blindness. It
should be emphasized that familiarity with the environment can greatly conceal
severe visual deficits and it is not unusual to obtain animals for diagnosis late in
the disease process, since owners have noticed visual problems after having moved
or refurnished their homes.
Almost always the earliest clinical sign is impaired vision in dim light and
darkness (nyctalopia or night blindness). The reduced visual capacity in darkness
may often be observed by visual testing. This is done by testing the menace
reaction or by using falling cotton balls in front of the dog in a dimly lit room.
Ophthalmoscopically, some change in tapetal reflectivity or hyporeflectivity is
often seen, such as a grayish discoloration mainly in the peripheral tapetal fundus.
A slight vascular attenuation and beading of retinal vessels in the midperipheral
and peripheral parts of the tapetal fundus may be observed at this early stage as
well. With progression of disease the color changes in the tapetal fundus become
more marked and generalized as well as the vascular attenuation. In moderately
advanced and advanced stages of disease there is an increase in reflectivity,
hyperreflectivity of the tapetal fundus, usually most marked in the midperipheral
tapetal fundus. The hyperreflectivity progresses to involve all parts of the tapetal
fundus. There is also depigmentation of the non-tapetal fundus at moderately
advanced and advanced stages of the disease. Vascular attentuation becomes
marked and, especially at the advanced stage, only contours of vessels (ghost
vessels) are observed centrally in the fundus. The area that often appears most
spared late in the disease is the central part, as a discolored streak somewhat dorsal
of and on both sides of the optic disc.
In the non-tapetal fundus funduscopic changes are usually not seen until at the
moderately advanced or advanced stages. Then there is often a patchy distribution
of pigment in the non-tapetal fundus with areas in between that are depigmented.
These changes are often described as “pavementing” of the non-tapetal fundus.
The optic disc often becomes pallid with progression of disease and indistinct
borders are often observed. The reasons for this is the loss of retinal circulation that
occur in the retinal degenerative process, and the specific degeneration of neural
tissue and comparably an increase in myelination at the level of the optic disc.
The pupillary light reflexes become progressively more sluggish in the disease and
the resting pupillary opening is often wider in affected animals than in the normal
population. Often the pupillary light reflexes are not lost entirely in PRA, a feature
that is useful in the differential diagnosis of blindness.
Secondary cataract is almost always present in dogs in advanced stages of disease.
The initial changes tend to occur in the posterior cortex and include vacuolation
and opacification. Often irregular radiations are seen from the posterior pole of the
lens that extend to involve the equatorial cortex and later progress to involve the
entire lens. Mature cataracts, especially in certain breeds, make electroretinography
of utmost importance, in order to rule out retinal degeneration before performing
cataract surgery.
Late-onset retinal degenerations
Progressive rod-cone degeneration (prcd) of the Poodle
Hereditary degenerations of the dog retina have since long been termed
“progressive retinal atrophy” (PRA). During the past years, however, this disease
complex in various breeds has been further subdivided and specified. Thus, the
term “progressive rod-cone degeneration” (prcd) today refers not only to classical
PRA but also to a specific photoreceptor disorder with several characteristics:
bilateral late onset disease of the rods primarily, then of cones, typical ERG
findings in affected animals, and a typical spatial distribution of disease seen
morphologically. Genetic homology has been found for prcd so far in a total of 19
breeds, among which are: Toy and Miniature Poodle, American and English
Cocker Spaniel, Labrador Retriever, Chesapeake Bay Retriever, and the
Portuguese Water Dog. The list of prcd breeds gets longer for each year! There is
today a mutation detection test available for the defect.
Structural and functional abnormalities in progressive rod-cone degeneration
(prcd) of the Toy and Miniature Poodle do not become evident until after the visual
cells have developed normally. The disorder is inherited as an autosomal recessive
gene. Of the degenerative group of hereditary retinal diseases recognized in dogs,
mutations at the prcd gene locus account for all of the autosomal diseases
recognized to date (Aguirre Exp Eye Res 46:663, 1988). The prcd gene and the
different mutations responsible for the defined allelic variants that occur in dog
breeds (see below) are not yet identified. So far the peripherin/rds, opsin and
PDEbeta genes have been excluded as causative (Acland Invest Ophthalmol Vis
Sci 36:S891, 1995 and Wang Invest Ophthalmol Vis Sci 36:S772, 1995).
The frequency of prcd in the Poodle breed has been high over the years, and
appears to be still rather high; the prevalence being 8% of the Miniature Poodles
examined in Sweden during a 20-year period (Statistics from the Swedish Kennel
Club, Jan 1,1996).
Night blindness is the first behavioral sign observed in affected dogs, usually at the
age of 3-5 years, but there is considerable variation in debut. Imparied vision does
usually not become obvious to the owner earlier unless the dog is placed in an
altered environment and furniture or other obstacles in the home are rearranged.
Affected dogs may be apprehensive of the dark and experience particular difficulty
in negotiating stairs. Night blindness is followed by reduced vision also in daylight
and finally complete blindness, at a variable age, usually between 5-7 years. The
rate of progression is believed to be faster in dogs that become affected at a young
age compared to those that develop the disease later in life. The development of
secondary cataract may exacerbate vision loss and therefore influence the age at
which the condition first becomes apparent to the owner. It is not unusual that
owners have only noticed the marble-like, white, opacified lenses and want a
cataract extraction to be done. This is where ERG plays an important part, in order
to rule out retinal degeneration, before even reflecting on performing surgery.
Ophthalmoscopic fundus changes are usually prevalent by the time the owners
have noticed visual problems. Often, affected dogs are found during routine
ophthalmoscopic examination. Usually a change in tapetal coloration is seen, into
grayish discolorations, most prevalent in the midperipheral and peripheral tapetal
fundus, near the border of the non-tapetal fundus. This is followed by a progressive
attenuation of the retinal vessels commencing with the small arterioles. Loss of
pigment is usually not seen until the disease has progressed to a more advanced
stage. A change in tapetal reflectivity and hyperreflectivity is then observed,
mainly in the midperipheral and peripheral tapetal fundus. At the advanced stage of
disease radial striae are seen in many cases, in the midperipheral and peripheral
fundus, caused by the choroidal vasculature, underneath the atrophic neural retina.
The vasculature is severely attenuated at this advanced stage. Eventually the retinal
vessels virtually disappear and the optic nerve head atrophies, becoming pallid and
irregular in outline, and later reduced in size.
ERG studies in affected Poodles have shown a normal maturation of retinal
function. At 28 weeks of age, however, affected dogs had ERG responses that
failed to increase in amplitude with dark adaptation, and the dark-adapted
responses were lower in amplitude than normal. With progression of disease the
response amplitudes decreased. By 18 months only small b-wave amplitudes were
recorded in response to red and white stimuli. Another group of researchers have
failed to detect abnomalities of rod and cone responses until 10 months of age. The
variation in results could be due to differences in ERG procedures or in the
phenotype of dogs. There is usually a rather great variation as to disease debut and
progression. However, in practical terms, ERGs from dogs less than 10 months are
unlikely to be meaningful in the early detection of PRA in the breed.
Light microscopically the photoreceptors of affected dogs develop normally, but at
14.5 weeks there was disorganization of some outer segment lamellae, observed by
ultrastructure as well as vesicular profiles in the sclerad half of the outer segment
layer. Cone photoreceptors were morphologically normal at this early age. At 30
weeks, there were distinct abnormalities in rod outer segments, evident also by
light microscopy. In young prcd affected dogs there is a central to peripheral
gradation of disease severity.
There is a highly characteristic sequence of disease in prcd that has been staged as
to structure into 3 major phases: 1) early disease (stage 1-1), 2) degeneration
(stages 2-4), and 3) atrophy (stages 5-8). Starting at the age of 12-14 weeks, all
photoreceptors cells begin to develop the stage-specific pathology characteristic of
the disease, but the rate of progression is dependent on topographic factors.
Pathology is always more severe in the inferior quadrants, while the visual cells in
the superior and temporal retinal quadrants are spared until later in the disease
process. So far, no specific properties have been identified in the inferior retinal
quadrant that selectively predisposes this area to earlier and more severe disease.
Moreover, the rate of progression of disease is not influenced by the presence or
density of pigmentation of the retinal pigment epithelium. Throughout the three
phases, the pigment epithelium remains normal in affected animals. Only in very
advanced disease the pigment epithelium will show non-specific atrophic changes
and sometimes also migratory responses.
Cone pathology is not obvious until later, after rods have begun to degenerate, e.g.,
stage 2 and later stages. Because of structural differences between the disc
membranes of rod and cone outer segments, renewal by membrane addition cannot
be followed in cones. The label in this type of photoreceptor diffuses laterally and
longitudinally throughout the entire cone disc membrane domain. Because of this,
the early phases of renewal in prcd using retinal explants were performed to
evaluate the transfer of newly synthesized protein label from the photoreceptor
inner to the outer segments. In this in vitro study, the renewal defect was observed,
as previously, in rods but not in cones. Thus, the disease in cones certainly appears
to be secondary to a primary defect in rod photoreceptors.
Using the techniques of lectin immunocytochemistry, the molecular components of
the insoluble interphotoreceptor matrix have been studied in order to determine if
abnormalities are present in prod-affected retinas. With the exception of the late
atrophic stages of the disease, the lectin specificity remains normal, indicating that
the photoreceptor specific insoluble interphotoreceptor matrix constituents are not
primarily involved in prcd.
Autoradiographic studies of affected retinas following intravitreal injection of
tritiated leucine or tritiated fucose have shown a reduced rate of rod outer segment
renewal, a finding shown to precede the appearance of structural changes. This
hallmark abnormality identified in prcd rods is a uniform decrease in renewal,
initially of 30-35%, that is associated with disease stage 1. Thereafter, renewal
decreases further and rod disease and degeneration progresses. The transition from
stage 1 to stage 2 marks the end of renewal by membrane addition and only low
levels of diffuse label are present in the rod outer segments in stage 2 and later.
Associated with stage 1 and 2 transition is a decrease in the expression of opsin
mRNA transcripts and immunoreactivity. It is interesting to find that all rods
demonstrate the same changes in opsin mRNA and immunoreactivity as well as the
renewal deficits regardless of their topographic position.
Several other photoreceptor-specific proteins have been studied in prcd by using
immunocytochemical techniques. The change in immunoreactivity for each one
has been found to be unique. The most stably expressed protein appears to be
IRBP, which demonstrated sustained labeling of the interphotoreceptor matrix
even after most of the photoreceptors had been lost.
In the search for systemic markers in human retinitis pigmentosa and animal
models of the disease, several research groups have investigated the level of
plasma lipids in affected individuals. In Miniature Poodles, significant lower levels
of plasma docosahexaenoic acid (22:6n-3) have been found when affected dogs
were compared to normals. The effects of supplemetation of 22:6n-3 on
polyunsaturated fatty acid metabolism were furthermore determined in normal and
affected dogs. The results showed that there certainly is a defect in 22:6n-3
metabolism in prcd-affected animals. It is not clear yet if there is any correlation
between the reduced renewal rate of photoreceptor outer segments, the lower
22:6n-3 levels and retinal degeneration in prcd-affected dogs, however.
Progressive rod-cone degeneration (prcd) in the English Cocker Spaniel
Crossbreeding experiments with prcd-affected Miniature Poodles and retinal
degenerate English and American Cocker Spaniels have shown that the gene
mutation in each breed is at the same (prcd) locus. In pure-bred English Cocker
Spaniels, however, the disease differs phenotypically in the rate of progression of
disease and in the topographical distribution of disease in the retina.
Clinically, prcd in the Enligh Cocker Spaniel is phenotypically expressed late in
life with funduscopic alterations indicative of retinal degeneration usually not
prevalent until between the age of 4-8 years. Moreover, the fundus appearance in
affected dogs may be quite variable. In some cases there are changes as those
described earlier for the disease, although in others, the retinal alterations vary
greatly in severity in different areas of the fundus. Thus, hyperreflective streaks
can be seen centrally on either side of the optic disc, while other areas are
brownish-gray in appearance and other quite normal appearing. Secondary
cataracts are usually found early in the disease process.
Diagnosis by ERG is also not possible until comparably late, in some cases at the
age of 1 year, while in others not until after the age of 1.5 years. A few cases may
have ERG-responses that are indistinguishable from normal dogs up to 2-2.5 years.
Early ERG changes consisted of mild decreases in the b-wave amplitude to
scotopically balanced red and blue light stimuli and white light stimuli, with
normal b-wave implicit times. Flickering light stimuli at different frequencies
readily differentiated rod and cone responses and showed unequal functional
deficits. Rod components were affected earlier and became non-recordable earlier
than cone components. Isolated rod signals could not be elicited at a time when
cone signals were still distinct. It was shown that prcd affected Miniature Poodle
lost b-wave function at approximately twice the rate as affected English Cocker
Spaniels.
Morphological findings corroborated the clinical findings, especially in cases of
advanced disease. In early disease, changes were limited to rod outer segments and
mainly seen as disorganization of outer segment lamellae. Later, degenerative
changes were seen in outer and inner segments as well as in photoreceptor nuclei
of rods. Phagocytic cells were often present in the subretinal space at this
degenerative stage. In late atrophy the inner retinal layers were affected as well. By
light microscopy, the changes appeared similar to those described for prcd of
Miniature Poodles. At the ultrastructural level, however, the pathology was
somewhat different and, importantly, the temporal and spatial distribution of visual
cell lesions varied between the two breeds. In the English Cocker Spaniel,
vesicular profiles were absent or present in only small numbers in early stage of
disease. Also, there was a varying distribution of disease that was readily observed
in spatial maps constructed. Disease was more severe in inferior than superior,
temporal or nasal meridians, although there was a great variation as to severity of
degenerative changes within meridians. Moreover, not all locations degenerated at
the same rate. Older animals showed a “mosaic” of different disease stages across
a meridian. The most significant difference in English Cocker Spaniel prcd
compared to Miniature Poodle prcd was in the rate of degenerative changes and
confirmed the results of the ERG observations.
Progressive rod-cone degeneration (prcd) in the American Cocker Spaniel
Test-breeding studies have shown that prcd of American Cocker Spaniels is
genetically similar to prcd of Miniature Poodles and English Cooker Spaniels.
Again, there are differences in retinal degeneration phenoptype between the
breeds, which could represent different mutations at the prcd locus or that the same
mutation is present although the disease modified or regulated by the genetic
background of the animal.
Clinically-affected dogs become night blind at the age of 3-5 years. There is also a
successive reduction of visual capacity in daylight and within 1-2 years they
are blind. Secondary cataracts are prevalent, often from the moderately advanced
stage. Ophthalmoscopically, early changes may be seen from the age of 2.5-3 years
or later. Most often there is a generalized change in tapetal reflectivity with a slight
vascular attenuation. With time, the tapetal fundus becomes hyperreflective, first in
the midperipheral and peripheral tapetal area. The central parts of the fundus are
usually spared late in the disease process as seen by ophthalmoscopy.
There are some difficulties in the diagnosis of fundus changes in the American
Cocker Spaniel that need to be discussed. It is not unusual that individual animals
have a thin and uneven peripheral tapetal border. In this area there is often a gray
to brownish sheen that may look like an early stage of prcd. Also some dogs may
have focal, circular but most often curvilinear, folds in the peripheal tapetal fundus.
With time these lesions may become pigmented and even have hyperreflective
parts, which is indicative of scar formation. Because of these aberrations it is not
unusal to have to perform ERG in order to rule out prcd in the American Cocker
Spaniel. Just as in the Miniature Poodle, an early diagnosis of prcd is possible in
the American Cooker Spaniel at the age of 9-10 months. Also, morphologic studies
have shown alterations that are comparable to Miniature Poodle prcd.
Progressive rod-cone degeneration (prcd) in the Labrador Retriever
Progressive rod-cone degeneration (prcd) has been a significant problem in the
Labrador Retriever in Scandinavia for more than 20 years, although this finding
did not attract much attention until rather recently. Studies have shown the disease
to be genetically similar to prcd in the Miniature Poodle, English and American
Cocker Spaniel and the Portugese Water Dog, which indicates that the diseases in
each breed are at the same locus on the chromosome.
Clinically-affected animals become night blind rather late, usually between the age
of 4-6 years. There is a slow progression of the visual problems, and affected dogs
have severe visual impairment at the age of 6-8 years. There are, however,
considerable variations to this finding. In solitary cases, visual impairment has
been observed as early as at the age of 2.5 years and blindness has prevailed only 2
years later. Ophthalmoscopically, changes are usually seen in the midperipheral
and peripheral fundus, as a change in tapetal reflectivity. Often a horizontal streak
on both sides of the optic disc in the tapetal area is seen with a marked grayishbrown discoloration. The changes in the midperipheral area progress to complete
hyperreflectivity of the tapetal fundus, and severe vascular attenuation is the end
stage. In many cases, the central fundus is somewhat spared late in the disease,
with the grayish streak still observed on either side of the optic disc.
ERG studies have shown a successive reduction of scotopic b-wave amplitudes.
Rod function is severely reduced while cone function is spared until late in the
disease. Definite diagnosis by ERG is possible by 15 months using an ERG under
stable recording conditions. However, a recent study by Kommonen showed that
by using a sensitive DC-ERG system, significant differences were found between
affected and normal dogs as well as between dogs heterozygous for the defect and
normal dogs by the age of 3-4 months.
Analysis of retinal morphology in the disease has shown changes already at a
comparably early age. As early as the age of 1 month, distinct alterations were
found in the rod outer segments of the central tapetal fundus, whereas the
midperipheral and peripheral areas were normal until at least the age of 5 months.
Light- and electron microscopy have shown degenerative changes in
photoreceptors at the age of 5 months in affected dogs. After this age there is a
slow progression of disease, as described for prcd in the Miniature Poodle.
Progressive rod-cone degeneration (prcd) in the Portugese water dog
This breed of dog has recently been described as having prcd. The diseases in these
prcd breeds are genetically similar and inherited as a simple autosomal recessive
trait. The ophthalmoscopic diagnosis in the Portugese water dog is possible to
make between the age of 3-6 years and ERG is diagnostic at 1.5 years.
Hereditary retinal degeneration (XLPRA) in the Siberian Husky and in the
Samoyed.
Hereditary retinal degeneration in the Siberian Husky and in the Samoyed has been
described in clinical cases as PRA. There seemed to be an excess of affected male
dogs with the disorder and further studies including test-breeding schemes showed
that there is an x-linked transmission for the disease. In fact, these are the first xlinked retinal degenerations described in an animal.
Clinical signs of the disease are usually observed at the age of 2-4 years, including
initial night blindness and early ophthalmoscopic sign of retinal degenerative
disease. ERG findings in affected dogs include diminished rod-mediated function
as described for progressive rod-cone degeneration of other breeds. Morphologic
evidence for XLPRA are also comparable with that of the previously described
affected dog breeds, although details at the ultrastructural level have so far not
been published.
Progressive retinal atrophy in the Tibetan Terrier
PRA in the Tibetan Terrier was first described in Sweden and later in England. An
autosomal recessive inheritance for the defect was established through a testbreeding scheme and the disease was further investigated using electrophysiologic
and morphologic techniques. Recently, molecular genetic studies examining the
opsin gene for polymorphism have been performed in the Tibetan Terrier as well
as in the Miniature Schnauzer, the Irish Setter, the Miniature Poodle, the Labrador
Retriever, and the English Cocker Spaniel dog breeds. Two polymorphisms were
found. One segregating within the Tibetan Terrier population, but not in the other
breeds, was a synonymous transition at nuoleotide position 780 in exon 3.
Inheritance of this polymorphism suggests that opsin is unlikely to contain
mutations causative of PRA in this breed.
The clinical signs of disease in affected Tibetan Terriers are rather early, compared
to prcd affected dogs. Night blindness is often found well before the age of 1 year.
The disease has a fast progression and blindness is not unusual before the age of 2
years. At this early age, the pupillary light reflexes are slow and incomplete.
Bilateral cortical and then complete cataracts are often seen to develop after the
age of 4 years. Typical funduscopic signs of disease are grayish tapetal
discoloration in the midperipheral and peripheral fundus and very soon also a
slight vascular attenuation. The discoloration changes toward hyperreflectivity as
the degenerative disease progresses further, especially in the peripheral tapetal
fundus. These alterations spread centrally to involve all tapetal areas and especially
prominent around the optic disc, which becomes pale and devoid of its normal
vasculature. The end stage is a generalized atrophy also observed in the non-tapetal
fundus, where depigmented areas surround hyperpigmented spots.
ERG findings include a reduction of the scotopic b-wave at about the age of 10
months but normal timing characteristics at this age and normal sensitivity of the
b-wave responses. After the age of 30 months the ERG is non-recordable.
Light-microscopy did not show any major aberrations at 10 weeks of age in
affected dogs. However, at 8 months the neural retina had thinned considerably
and at 24 months there was a generalized atrophy of the retina and the outer
nuclear layer was reduced to only 3-4 rows of photoreceptor nuclei. By
ultrastructure, distinct alterations were observed in rod and cone outer segments as
early as 10 weeks of age in affected dogs. Interspersed between normal rod and
cone outer segments were others (both rod and cone) outer segments that were
severely disorganized and disoriented. Numerous vesicular profiles were seen in
the interphotoreceptor space at this early age. Also, the changes were seen in all
sections from different areas of the retina.
Progressive retinal atrophy in the Tibetan Spaniel
Cases of PRA have been found during the past years in several countries, including
England, Sweden, Norway and the U.S. The clinical findings in the disease were
recently described. Ophthalmoscopic signs of disease have been recorded from the
age of 3-5 years. Affected dogs lose vision thereafter rather quickly and are
severely visually impaired already after another year. Funduscopic changes are the
classical ones for the late onset type of PRA: hyperreflectivity of the peripheral
tapetal fundus and severe attenuation of retinal vessels. The retinal atrophic
changes spread inwards towards the optic disc. Secondary cataract is seen in older
affected dogs but does not seem to be an early finding. Due to variation in tapetal
distribution and size, the fundus of the Tibetan Spaniel is highly variable, causing
difficulties in obtaining an early ophthalmoscopic diagnosis. ERG is an invaluable
aid under these circumstances. Electrophysiologioal and histopathological data are
not yet available.
Progressive retinal atrophy in the Miniature Longhaired Dachshund
A form of progressive retinal atrophy, unlike other previously recorded canine
retinal degenerations, has been reported in the Miniature Longhaired Dachshund.
Segregation patterns in litters from matings involving affected individuals were
consistent with simple autosomal recessive inheritance. The earliest
ophthalmoscopic signs appearing at about the age of 6 months and coinciding in
some cases with the onset of night blindness. Early funduscopic changes consisted
of a granular appearance of the tapetal fundus followed by a generalized tapetal
hyperreflectivity and vascular attenuation. With progression there was an irregular
loss of pigment in the non-tapetal fundus and optic disc atrophy. At the onset of
ophthalmoscopic sign, the pupils appeared partially dilated and the pupillary light
reflexes slugish and incomplete. There was a marked variation in the age of onset
and also in progression of disease, also in a single litter.
ERG showed a normal waveform at 10 weeks, while at 9 months the ERG
amplitudes were markedly reduced and even non-recordable in some dogs. Results
of recent ERG studies have, however, shown that the defect in this breed is a cone
rod dystrophy. The genetic mutation has been found and a mutation detection test
has recently become available.
Morphologically, no definite changes were found by light-microscopy at the age of
6 weeks. However, by 10.5 weeks, there was reduction in thickness of the outer
nuclear layer, indicating a photoreceptor loss. Rod outer and inner segment were
irregular in form and there was disorganization of outer segment lamellae. With
progression of disease there was advanced degeneration of photoreceptor outer
segments and atrophy of inner segments. Not only was the photoreceptor cell layer
diminished but also the outer plexiform layer. It appeared that the changes in the
central retina were less severe than those of the peripheral retina.
In Norway, cases of a retinal dystrophy in the Wiredhaired Dachshund have also
been found during recent years. The disease appears to be a cone rod dystrophy
with early functional defects such as day blindness. Initial, funduscopic alterations
are found between the age of 3-5 years and there is a slow progression of the
disease. A generalized change in tapetal reflectivity is seen with discoloration and
severe mottling of the retinal pigment epithelium is found. ERGs are most often
diagnostic for the defect and show low amplitude cone responses initially. A
generalized retinal atrophy is found within 2-3 years after initial clinical findings.
Progressive retinal atrophy in the Akita
Progressive retinal atrophy in the Akita dog has been described as a variable
disease as to first appearance and type of initial clinical symptoms. In this
recessively inherited disease night blindess occurs between 1 and 3 years of age,
with complete blindness developing between 3 and 5 years of age.
Ophthalmoscopically, two patterns of initial funduscopic changes have been
described: the most common involves a hyperreflective horizontal band in the
central tapetal fundus, first seen in the area centralis region and then extending
horizontally on either side of the optic disc; the other pattern is characterized by
retinal alterations, indicative of retinal thinning, in the peripheral tapetal fundus.
With progression of both patterns there is a generalized hyperreflectivity of the
entire tapetal fundus, vascular attenuation and atrophy of the optic nerve head.
Early ERG findings include significant reductions of the scotopic b-wave
amplitudes in dogs less than a year. Dark adaptation curves are abnormal but there
appears to be both rod and cone dysfunction. Since there appears to be a great
variation as to electrophysiologic changes in the disease, a definite diagnosis by
ERG is not obtained until the age of 1.5 to 2 years.
Progressive retinal atrophy in the Papillon dog
Progressive retinal atrophy has recently been described in the Papillon breed of
dog in Sweden. In a study of 707 dogs, 5% were affected with a retinal
degenerative disease. The disease appears to be inherited by an autosomal
recessive gene, and has a late onset and slow progression of clinical symtoms.
Clinically-affected dogs very seldom show evidence of visual impairment, even at
a late stage of disease. Night blindness is, however, a symptom that may be found
in some middle-aged dogs upon visual testing in dim light and in darkness.
Blindness is prevalent at a late stage, usually not until after the age of 7-8 years.
Ophthalmoscopic findings as well as progression of disease is similar to what has
been described for prcd in the Miniature Poodle. Secondary cataracts have, so far,
NOT been a prevalent finding in affected dogs, as is found in most other dog
breeds affected with PRA.
There is a great variability in extent and coloration of the visible tapetum in the
Papillon breed. Some dogs lack visible tapetal cells and some dogs have
subalbinotic eyes. These variables often render diagnosis difficult. ERG is
extremely useful in such eyes but also for the early diagnosis of disease in dogs
with the more common fundus appearance.
Groups of Papillons have been evaluated using ERG. Full-field Ganzfeld ERG was
used to test outer retinal function in 45 young normal and affected Papillons.
Eleven specific responses were recorded, plotted into graphs and evaluated using
age-matched groups of dogs. A severely decreased retinal function in 8 Papillons,
the youngest at the age of 1.2 years, was found. Amplitudes of responses mainly
originating from the rod system were severely reduced when the cone responses
were only slightly reduced or even normal. The results showed that early diagnosis
using ERG may be confidently performed by the age of 1.5 years in the Papillon
breed of dog using techniques previously described.
Morphologic studies corroborate the ERG findings. In a 7-year-old affected dog
there was a generalized retinal degeneration of rods, primarily with less obvious
degenerative changes in cones. There was a regional variation of severity of
disease in that the inferior non-tapetal retina was more severely affected than the
superior tapetal area.
Dominant Progressive Retinal Atrophy
In the Old English Mastiff and in Bullmastiff dogs, a specific retinal disease unlike
those previously described has recently been found. When discovered the disease
displayed an ambiguous mode of inheritance and therefore out-cross matings were
performed in order to elucidate the specific mode of inheritance for the disorder.
This was shown to follow a dominant pattern and the defect found is the first opsin
mutation described for dogs. The gene defect is a T4R mutation, indicating a
different cause of PRA than previously described in other breeds of dogs.
Clinical examination in early disease by ophthalmoscopy and OCT showed a
variably sized and located area of retinal thinning in the central fundus, clearly
demarcated from surrounding clinically normal retina around the age of 6 months.
Through clinical ERGs the disease was defined as a progressive retinal
degeneration. ERG rod and cone-mediated responses were not significantly
different between 2-month-old normal and affected dogs. By 12-18 months of age,
however, affected dogs had severely reduced b-wave amplitudes. Defective dark
(or bleaching) adaptation was also found in affected dogs. The non-uniform
degeneration of photoreceptors detected was verified morphologically. The
photoreceptors developed normally and were indistinguishable from normal at 9
weeks of age. In young affected adult dogs the regional distribution of disease was
striking: normal appearing photoreceptors could be seen or showed different
gradations of disease. In general, more severe disease was observed surrounding
the optic nerve head but centered in the temporal tapetal region of the fundus.
Beyond this there was an abrupt transition zone beyond which photoreceptors were
structurally and quantitatively normal. Advanced retinal degeneration was
observed at the age of 4.5-11 years.
The disease is distinctly different from other canine retinal degenerations and the
differences are exactly the similarities it shares with certain human rhodopsin
mutations. The defect in dark adaptation and the focal initiation of photoreceptor
degeneration characterize both this canine disease and human patients with
Retinitis Pigmentosa (RP), due to class B1 rhodopsin mutations.
An intriguing recent finding is that environmental light appears to contribute to the
regional variation of early disease. It was found that modest light levels (such as
used in routine clinical practice when performing retinal photography) dramatically
accelerated the retinal degeneration. These findings do not immediately lead to
modifications in clinical examination procedures. However, retinal photography
should not be standard in human patients with rhodopsin mutations, retinal
examinations should be of short duration and light exposure during intraocular
surgery should be reduced. Similar recommendations also certainly appear valid
for dog patients with the rhodopsin mutation.
Progressive retinal atrophy in other dog breeds
Progressive retinal atrophy has beed described in many other breeds of dog. They
have, however, not been reported in detail in the scientific literature.
Retinal pigment epithelial dvstrophy (RPED)
The term central progressive retinal atrophy (CPRA) has been used over the years
for a group of conditions having ophthalmoscopic changes that can be
characterized by an accumulation of irregular foci or light brown pigment spots in
the central tapetal fundus. With time, these foci increase in size and become
distributed throughout the tapetal zone. At this stage there are also atrophic
changes, e.g., hyperreflectivity around the pigment foci, which indicate atrophy of
the overlying neural retina. The nontapetal fundus shows similar foci with
hyperpigmentation and depigmented areas in between.
The term CPRA was used in order to differentate the condition from generalized
PRA. For many years it has been clear that CPRA affects the RPE primarily with
secondary effects on the neural retina and that the condition is quite different from
PRA, which affects the photoreptor layer primarily. It is the general opinion
amongst veterinary ophthalmologists today that at least in those breeds, in which
the defect has been established microscopically, the term “retinal pigment
epithelial dystrophy” (RPED) is preferred to CPRA.
RPED has been recognized in many breeds all over the world but perhaps most
prevalent in England. In particular, cases have been recorded in Labrador and
Golden Retrievers, Border Collies, Rough and Smooth Collies, Shetland
Sheepdogs, the English Cocker Spaniel, English Springer Spaniel, Chesapeake Bay
Retriever, among others. In the Briard, an unusual high frequency of the disorder
was reported. In recent years, however, the condition is more rarely observed in the
various breeds, including Briards, even in England.
It has been suggested that RPED in the Labrador Retriever is inherited as a
dominant trait with variable penetrans. The reduction in incidence, that has been
accomplished in the Border Collie, through selective breeding is perhaps consistent
with this view. A recessive mode of inheritance was thought likely for the Briard
but has not been proven. Further studies are needed in order to elucidate whether
there is a simple Mendelian inheritance for the defect or not. It is possible that a
genetic predisposition in an individual breed can be modified by environmental
factors. Important in this context is that lesions similar to RPED have been
produced in dogs fed diets deficient of vitamin E, an antioxidant that retards the
intracellular accumulation of lipofuscin pigment. Also, naturally-acquired
retinopathy as a result of vitamin E-deficiency has been described in dogs. The
similarities between CPRA/RPED and vitamin E deficiency may explain its unique
geographic distribution.
The ophthalmoscopic changes described above are often found before there are any
signs of visual impairment in the dog. With progression of disease the pigmented
lesions coalesce into widely spaced irregular patches with hyperreflective tapetal
fundus in between. End stage atrophy includes a more generalized hyperreflectivity
with sparse amounts of pigmented foci and/or stria, the latter findings not always
obvious to the examiner. With these severely advanced changes, the
ophthalmoscopic diagnosis is not always easy and similarities to generalized PRA
may be found. Retinal changes are always bilateral in RPED, just as for PRA, and
more or less symmetrical. ERG is not diagnostic in RPED, although there is a
reduction in ERG amplitudes with progression of disease.
The behavioural signs of RPED are typical. Visual impairment is usually not found
until a moderately advanced stage of disease. Then, because of the relative sparing
of the peripheral, compared to the central, retina, peripheral vision is retained until
late in the disease. Vision tends to improve at low light levels. Also, vision may
appear normal for moving and distant objects but impaired for stationary and
objects near by. Not all affected dogs become blind. Secondary cataracts are most
often seen at the advanced stage of RPED.
In the Briard dog an extremely high frequency of the disease was found in a 5-year
survey. Almost one-third of dogs examined (approximately 70% of the Briard
population in England at the time) that were more than 18 months old were
clinically affected. In this breed the typical pigmentary changes were first seen
towards the periphery of the tapetal fundus temporal to the optic disc before
spreading to involve the whole tapetal zone. There are, however, significant
differences between the funduscopic alterations in the various breeds, which
probably indicates a spectrum of disease entities at the retinal pigment epithelial
level.
In affected Briards, biochemical and morphological studies have been performed
of retinal tissue and blood. These studies have shown that rod outer segment
renewal is normal as well as acid phosphatase activity in the retinal pigment
epithelium. Also some affected dogs have also been described to be
hypercholesterolaemic and systemically deficient of vitamin E and taurine.
Further investigations into the blood biochemistry of normal and affected Briards
in the United Kingdom have shown that there is a hyperlipideaemia in Briards that
is characterized by increased plasma cholesterol but normal triglyceride
concentrations. There was no significant difference in plasma cholesterol
concentrations between affected dogs and those that were ophthalmoscopically
normal. The absence of obvious metabolic derangements associated with
hypercholesterolaemia, suggest that Briards in the United Kingdom may have a
primary abnormality in cholesterol metabolism. The possibility that abnormality in
lipid metabolism might play a role in the development of RPED in Briards is being
further investigated.
Morphologic studies have shown that the earliest recognizable lesions in RPED are
in the retinal pigment epithelium. The cells become hypertrophied and accumulate
a light-brown granular material in the cytoplasm. Opposite the hypertrophied cells,
the photoreceptor outer segments are shortened. With progression of disease, more
cells become hypertrophied. At the end stage, hypertrophic pigment epithelial cells
form multicellular nests. Focal degeneration is then seen of photoreceptors
overlying the hypertrophied cells, followed by complete retinal degeneration with
intraretinal migration of non-melanin containing cells. Diseased pigment epithelial
cells contain autofluorescent lipopigment similar to ceroid or lipofuscin.
Biochemical studies of retinas from affected dogs have shown that the pigment that
accumulate in the disease varies with breed, and appears to be the result of
peroxidation of rod outer segment lipids.
Neuronal ceroid lipofuscinosis (NCL)
Neuronal ceroid-lipofucscinosis (NCL), a group of inherited and progressive lipid
storage diseases, is characterized by retinal degeneration and encephalopathy. They
affects both human and several other animal species. The genetic defect has been
elucidated for the infantile and juvenile forms in humans. A spectrum of apparent
biochemical defects has been implicated in these disorders. The central nervous
system appears to be the main focus of the pathogenetic defect and there are
reasons to believe that this brain-specific abnormality is related to a biochemical
event unique to nervous tissue.
The disease has been described in several breeds of dog such as the English Setter,
Dalmatian, Border Collie, Tibetan Terrier and others. The hereditary characteristic
is mainly autsomal recessive in the breeds studied so far. A common clinical
manifestation in both man and dogs is blindness that occurs together with a broad
spectrum of neurologic abnormalities caused by the accumulation of
autofluorescent lipopigments in neurons and other cells. With some exceptions the
blindess is cortical in origin, since photoreceptor function and structure are
generally preserved. There are some exceptions to this: in the Tibetan Terrier night
blindness occurs in young animals and more severe neurologic abnormalities are
not observed until later in life. Also, in the Polish Owczarek Nizinny (PON) dog
visual dysfunction and tunduscopic alterations occur early in life, often between
the age of 1-2 years. In most cases neurologic symptoms are found simultaneously
or slightly thereafter. Ceroid-lipofuscinosis was also described in the Miniature
Schnauzer. At the age of 3-4 years blindness developed over a 3-month period,
accompanied by neurological signs. Pathology showed severe inner and outer
retinal degeneration and extensive accumulation of fluorescent lipopigment in
central nervous tissue and retina. In the English Setter, retinal function is initially
normal at a time when neurologic abnormalities are present. In this breed clinical
signs usually develop about at one year of age and include progressive blindness,
ataxia, muscle weakness and dementia. The disease is ultimately fatal. The disease
in Tibetan Terriers resembles that of the English Setter but the time course is
longer. In the Tibetan terrier nyctalopia becomes evident as early as 2 months or
age or earlier, but funduscopic changes, with similarities to PRA, do not appear
until 3-4 years of age. The ocular changes appear to represent one part of a more
generalized disease process.
Specific functional and morphological characteristics have been described for
some affected breeds. In the English Setter, ERG responses are normal in young
dogs but become grossly abnormal with time. In advanced cases there c-wave of
the ERG becomes non-recordable and there is a reduction of the standing potential
of the eye. In the PON dog, the scotopic ERG responses were absent and the cone
flicker responses reduced but recordable in a 2-year-old affected dog. The c-wave
was replaced by a slow negative potential indicating a dysfunction of the retinal
pigment epithelium. For the Tibetan Terrier, abnormal ERGs were recorded
already at the age of 7 weeks. There was a complete lack of positivity and a large,
monophasic negativity in the region of the normal b-wave of the ERG. Continued
monitoring of ERGs with increasing age showed age-related changes indicative of
a retinal degenerative process.
Ultrastructurally intracellular inclusions with a granular appearance or containing
membranous fingerprint-like material or curvilinear profiles, resembling ceroid,
have been found in different retinal cells of PON dogs. Also in the English Setter
and Tibetan Terrier breeds, inclusions accumulate in pigment epithelial and other
retinal cells but also in CNS neurons. However, the association between neuronal
lipopigment storage, cell dysfunction and cell death is presently not known. The
genetic mutation has been found for some of the above described breeds and
mutation detection tests are available for these.
Mucopolysaccharide (MPS) storage diseases
In both man and animals, mucopolysaccharide (MPS) storage diseases are caused
by the inherited deficiency of lysosomal enzymes and represent generalized
multisystemic abnormalities of which ocular lesions are but one component. The
lysosomal enzymes participate in the degradation of glycosaminoglycans (GAGS).
Morphologic studies show accumulation of intracellular inclusions in secondary
lysosomes in the enzyme deficient retinal pigment epithelium. In dogs, MPS VII
has been described. In the pigment epithelium single cytoplasmic inclusions are
present initially during the early postnatal period. Their number and size increase
during the period of photoreceptor differentiation. The pigment epithelial cells
enlarge and the whole monolayer becomes hypertrophied. In spite of the pigment
epithelial pathology, the neuroretinal structures and functions are preserved and
there is no photoreceptor degeneration in the disorder.
A late-onset lysosomal storage disease has been described in the Tibetan Terrier.
The principal clinical manifestation includes visual loss, progressive cerebellar
ataxia, and dementia. Morphologic studies indicate lysosomal storage of both lipid
and carbohydrates.
Hereditary tapetal degeneration
An autosomal recessively inherited tapetal abnormality of laboratory Beagle dogs
has been described. Affected dogs have a light, uniform choroidal pigmentation
which precludes visualization of the choroidal vessels. Morphologically, there are
normal numbers of tapetal cells at birth but, with time, there is a progressive
degeneration of the tapetal cell layer. The retinal structure and function, however,
remains normal.
SPECIFIC RETINOPATHIES
Uveodermatological / Voat-Koyanagi-Harada (VKH) syndrome
The uveodermatologic or Vogt-Koyanagi-Harada (VKH) syndrome of man
embraces a variety of clinical signs, including uveitis, choroiretinitis,
depigmentation of skin (vitiligo), loss of hair pigment (poliosis), and various
nervous signs. The disease has been reported in dogs as an immune-mediated
syndrome which resembles VKH in man. Several cases have been reported in the
Akita, although numerous other breeds have been affected as well. In dogs, cases
are usually presented with a history of sudden blindness. Ocular examination may
reveal anterior and/or posterior uveitis and serous retinal detachment. The uveitis is
usually granulomatous, with cellular infiltrates of lymphocytes, plasma cells,
epitheloid cells and macrophages containig ingested malanocytes. The cause of the
disease is unknown, although the histopathology is consistent with antimelanocyte
autoimmunity, and the breed incidence, such as in the Akita, suggests the
involvement of genetic factors. Moreover, a relationship between circulating antiretinal antibodies and clinical signs has been found. This could indicate a
breakdown of the blood-retina barrier and exposure to retina-specific antigens and
a secondary production of the anti-retinal antibodies.
Sudden acquired retinal degeneration (SARD)
Sudden acquired retinal degeneration (SARD) is a retinal disorder of unknown
etiology that causes a sudden and permanent blindness in adult dogs. There is no
treatment for the disorder. Clinical signs are characterized by a sudden loss of
vision, usually within days or 1-2 weeks, pupillary dilatation and unresponsive
pupils, absence of ophthalmoscopic fundus abnormalities at the early stage, and an
extinguished ERG. It appears that all breeds may be affected, even cross-breeds,
and often in their middle-age. After several weeks to months, slight funduscopic
alterations may be observed, indicative of a generalized retinal degenerative
process. The end-stage is a generalized retinal atrophy that is indistinguishable
from PRA.
Affected dogs are usually healthy, but in some there is a history of weight gain,
polyuria, polydipsia, and polyphagia. In some cases there have been elevations in
serum alkaline phosphatase, serum amino transferase, serum cholesterol, or serum
bilirubin. Frequently there are signs suggestive of hyperadrenocorticism. There
have been speculations on involvement of faulty fat metabolism in the disorder.
Also implications of an autoimmune mechanism stems from findings that dogs
with SARDS had circulating antiretinal antibodies. Lately, attention has focused on
a possible toxic etiology.
Morphologically, abnormalities are restricted primarily to the photoreceptor cell
layer. There is a rapid loss of photoreceptor outer segments, both rod and cone,
followed by a degeneration of the other retinal layers. Different regions of the
retina are equally affected, in contrast to many of the hereditary retinal
degenerative diseases earlier described in dogs.
Retinal toxicities
Drug-induced retinotoxicity
Compounds can cause retinal damage directly by damaging neuroretinal or retinal
pigment epithelial cells or indirectly by inflammatory reactions that lead to focal or
more generalized cell death. The assessment of retinal integrity is an essential
component of ocular safety evaluation. Usually ophthalmoscopy and
biomicroscopy of treated animals and histo-pathology of retinal tissues are used in
routine toxicological studies. These methods are adequate to detect gross retinal
degenerative changes. They fail, however, to detect minor pathology of the retina,
such changes that involve subtle though generalized structural alterations without
degeneration. Minor morphological changes may be elucidated using improved
methods of tissue fixation and the use of both light- and electron microscopy.
Functional evaluation can be done using electrophysiologic testing, such as ERG
and/or VEP. In order to determine target-tissue specificity and examine
mechanisms of compound associated retinal damage in vitro methods, such as
tissue culturing can be used. Preliminary extended protocols for ocular toxicity
testing have been proposed in some areas of toxicology.
Drug-induced retinopathies are usually characterized by bilateral symmetry. There
is usually a relationship between the duration of administration of the toxic
compound, the dosage and the onset of clinical signs. Some well-known and
representative drug-related retinotoxic compounds are provided below.
-Ethambutol
-Diphenylthiocarbazone (Dithizone)
-Hydroxypyridinethione
-Quinine and some of the cinchona derivates
-Rafoxanide
-Chloroquine is an antimalarian drug that has an affinity for melanin and ocular
tissues containing melanin. In dogs, the earliest changes may be seen in the non-
tapetal fundus as scattered gray-white specks. Histologically, membranous
cytoplasmic bodies are seen in ganglion cells by ultrastructure.
-Azalide is an antibiotic drug that can cause tapetal color changes if administrered
in high doses (100-fold the recommended clinical dise). Ophthalmoscopically there
was a dull white appearance of the tapetal fundus. Microscopic examination of
ocular tissue showed tapetal cells that were swollen and vacuolated and retinal
cells, primarily ganglion cells, that contained lysosomal lamellar bodies. No other
effects were found in the eye or systemically.
-Closantel is an antihelmintic used in domestic ruminants and intoxication has been
described in a dog. Eye examination revealed bilateral mydriasis with absent
pupillary reflexes. Funduscopically the optic discs were swollen and several small
papillary and peripapillary hemorrhages were seen. The tapetal fundus was
diffusely hyperreflective. Retinal vasculature appeared normal. With time there
was progression of the lesions, which resulted in a generalized retinal and optic
disc atrophy. Blindness was irreversible.
Retinopathy induced by light and oxygen
There is an association between high light intensity and retinotoxicity that is well
established. Phototoxicity in the rat model has been extensively studied.
Illumination of the canine fundus with the light from an indirect ophthalmoscope
for 20 minutes may be sufficient to cause ophthalmoscopically visible changes.
Prolonged exposure results in areas of increased granularity in the tapetal fundus,
followed by retinal pigmentation and increased tapetal reflectivity. The non-tapetal
fundus is, however, virtually non-affected, showing the protective effect of
pigmentation. Histologic changes in minor retinopathies include vesiculation and
shortening of photoreceptor outer segments but also vesiculation of the pigment
epithelial cells. More advanced cases show photoreceptor degeneration and
atrophy of the retinal pigment epithelium.
It has been shown that exposure to high oxygen tensions produces selective
damage to the visual cells in dogs. Oxygen administration has been strongly linked
with human retinopathy of prematurity (ROP). Oxidative processes and the
generation of free radicals have been suggested to be important in the development
of the disease. Furthermore, light and oxygen can interact to produce oxygen-free
radicals, a process known as photosensitization. Experimental studies in new-born
Beagles showed clinical and histologic abnormalities in eyes exposed to light in
the presence of rose bengal, a photosensitizing agent. A spectrum of retinal lesions
were obtained including vitreous hemorrhage, fibrovascular and fibrocellular
proliferation with traction on the retina, complete and partial retinal detachment
and retinal dysplasia. The study showed that photosensitization can produce a
spectrum of retinal pathology in dogs that resembles human ROP.
Retinopathy induced by radiation
Radiation-induced ocular injury secondary to treatment of nasal cancer occurs in
humans and animals. In a clinical and histological study, immediate changes were
found, such as blepharitis and keratoconjunctivitis. However, at 3-6 months post
treatment (36-67.5 Gy in fractionated doses given in 4 weeks using a 6 MV linear
accelerator) a degenerative angiopathy of retinal vessels appeared with multifocal
retinal hemorrhage and mild diffuse retinal degeneration, first affecting the outer
retinal layers but then progressing inwards. At 1-2 years post irradiation time, there
was a moderate retinal degeneration with swelling and loss of ganglion cells and,
subsequently, optic nerve axonal degeneration. Even tapetal and choroidal atrophy
was observed. Thus, structures of the canine eye are sufficiently sensitive that even
relatively low total doses of radiation cause significant long-term injury.
Retinopathies of nutritional and general disease processes
Vitamin deficiency
Systemic vitamin A deficiency is characterized by night blindness in several
species. In dogs, systemic diseases causing imparied fat absorbtion could cause
vitamin A deficiency, although this clinical situation is extremely rare.
Vitamin E is an antioxidant with an important function in maintaining the stability
of cell membranes by preventing lipid peroxidation. A deficiency may result in
pathologic changes in muscle, central nervous system, reproductive tract and retina
Experimental studies by Riis, producing vitamin E deficiency, have been
performed in dogs. At weaning, dogs were fed a diet deficient of Vitamin E.
Ophthalmoscopic signs of disease developed early and were described as a mottled
tapetal fundus appearance, particularly centrally, with numerous discrete yellowbrown foci. With time the central fundus became hyperreflective and there was an
attenuation of retinal vessels. The ERG was non-recordable at the age of 4 months.
Histologically, an accumulation of autofluorescent pigment within the retinal
pigment epithelial cells was observed and, at later stages, in migrating cells in all
retinal layers. Photoreceptor damage occurred in areas overlying affected regions
of the pigment epithelium. After the age of 6 months, there was a complete atrophy
of the photoreceptor layer. The obvious similarities between vitamin E deficiency
and hereditary RPED suggest some common etiologic factor.
CAT
Lysosomal storage disease
Inherited enzyme deficiencies or lysosomal storage diseases affect the retina as
well as other body systems, such as the cornea as described earlier. The recessively
inherited diseases include alpha-mannosidosis, manifested as a dull, gray, granular
appearance of the area centralis region and GM1 gangliosidosis, associated with
focal fundus lesions in the form of multiple small spots, which represent
accumulation of glycolipid within the ganglion cells. Another lysosomal storage
disease is mucopolysaccharidosis type VI, where there is a generalized retinal
atrophy in most affected cats. This is also the case in gyrate atrophy, which
represents a systemic ornithine deficiency and also results in blindness.
Chediak-Higashi syndome
As described above Chediak-Higashi syndome (CHS) is an autosomal recessive
disease of cats and other species. Affected kittens have hypopigmentation not only
of iris but also of retinal pigment epithelium (RPE) and changes in the tapetal cells.
The tapetal cells do not seem to reach maturity, and ophthalmoscopically there is a
lack of visible tapetum in affected cats. Ultrastructurally there is a loss of RPE
cells and of tapetal cells with time. A membrane defect has been reported in CHS,
involving an increase in unsaturated fatty acid content. This could lead to increased
peroxidation of both phagosome derived and intracellular CHS-RPE membranes,
making them resistant to lysosomal degradation.
Progressive retinal atrophy (PRA)
PRA was for many years reported in only a few breeds of cats and in few
individuals in each report. Retinal degeneration with a suspected hereditary basis
was described in Siamese Persian and in mixed-breed domestic cats in the U.S. In
only one breed thus far is there hereditary PRA, proven through genetic studies,
and that breed is the Abyssinian. It has also been shown that in the Abyssinian cat
there are two specific types of retinal diseases and each one has a different mode of
inheritance for the defect. Both are bilateral and more or less symmetrical in the
two eyes and progressively lead to blindness.
Progressive rod cone degeneration in the Abyssinian cat is a disease with an
autosomal recessive inheritance. Classical early signs of PRA are found
ophthalmoscopically in affected cats at the age of 1.5-2 years. There are tapetal
color changes and slight changes in tapetal reflectivity and some vascular
attenuation mainly in the midperipheral and peripheral tapetal fundus. With
progression of disease, there are progressively more widespread changes indicating
neuro-retinal thinning, showing as hyperreflectivity and severe vascular
attenuation. The late stage is seen 3-4 years after the initial findings, when there is
a complete bilateral retinal atrophy.
Functionally, it has been shown by using electroretinography (ERG) and
morphologically, by using light- and electron microscopy, that the retina develops
mainly normally in affected cats up to the age when the retina is adult-like, at 5
months in cats. After that age there is a drop out primarily of rod photoreceptors
and much later of cones. The neuro-retinal cell layers are successively lost, starting
in the midperiphery and periphery. The central retina is spared until late in the
disease process.
The pathogenesis of this rod cone degenerative disease is so far not elucidated and
further studies are in progress in order to find the gene defect. Early diagnosis of
affected cats can be made by careful ERG studies at the age of 8 months, well
before retinal changes are diagnosed by ophthalmoscopy. The frequency of the
disease was calculated to be unusually high, up to 45% affected animals in
Sweden, when first found. Through hard work mainly by the breeders in Sweden
and with the help of an effective breeding program, the prevalence of the disease
has been significantly reduced during recent years. The Abyssinian cat has become
a valuable animal model for the study of hereditary retinal degenerative in man
since the cat rod cone degeneration is similar to human Retinitis Pigmentosa (RP).
Taurine deficiency retinopathy
The amino acid taurine is found at high levels in shellfish, liver, and in meat;
essential components in the daily diet of cats. With a lack thereof, a specific
retinopathy develops. Ophthalmoscopically, a band retinopathy develops along the
visual streak and an atrophic lesion is observed in the area centralis region. With
time, the lesions progress and a generalized retinal degeneration is the end-stage of
the retinopathy. Cone-mediated ERG is reduced early in the disease process and
both cone and rod ERGs become non-recordable with time. If taurine is
supplemented early in the disease, the retinopathy can be stopped and some vision
preserved.