Photoreceptive Abiotrophy of the Retina in the Elkhound

Transcription

Path. vet. 2: 101-128 (1965)
From the Howe Laboratory of Ophthalmology, Harvard University
Medical School and the hfassachusetts Eye and Ear Infirmary, Boston
Photoreceptive Abiotrophy of the Retina
in the Elkhound
DAVIDG. COGANand TOICHIRO
I<UWABAR-4
Idiopathic degeneration of the retinal photoreceptive layer, here
termed photoreceptive abiotrophy of the retina, is that hereditary
abnormality which in human beings is familiarly known as retinitis
pigmentosa. In mice and rats, the animal species in which it has been
most thoroughly documentedl-6, the disease begins within the first
few weelis of life and progresses to blindness within a month or two.
In dogs, where it is usually known as progressive retina1 atrophy7-10,
it has been reported to produce blindness at a few weeks of age in
some breeds and at 1-2 years in other breeds79 89 2. It has occurred in
Gordon setters113 12, Irish setters73 12, 9, Labrador retrieverssp 10, and
possibly in poodles13. In man retinitis pigmentosa has a variable onset
and course but usually begins during adolescence with night blindness and leads to blindness in early adult life.
Photoreceptive abiotrophy is transmitted as a recessive mendelian
trait, not necessarily linked with other hereditary abnormalities, and
produces clinical symptoms and pathologic changes most like those of
severe vitamin A deficiency. Yet there is no substantial evidence of
vitamin deficiency in man or animals with this disease. It has been
suggested, therefore, that the pathogenesis resides in the peripheral
utilization of vitamin A in the visual cycle. To explore such a possibility it is necessary to study the condition in a species with sufficiently large eyes for appropriate clinical, pathological and biochemical investigation. The chance occurrence of photoreceptive abiotrophy
in elkhounds gave us an opportunity to explore this possibility and the
present paper is a report of our initial observations on the clinical
and pathological characteristics of the disease.
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COGAN/KUWABARA
The chief clinical signs in dogs have been gradual blindness and
extinction of the electroretinograml4 (ERG), while the chief pathologic
change has been degeneration of the outer retinal layer. Electron
microscopy of retinas with this condition has not been previously reported for dogs but has been reported for rats5 and for human beingsls.
The family of dogs which constitute the substance of this report
(Fig. 1) were elkhounds in which the propositus (Al) was one of two
affected female siblings (out of a litter of six) which became blind at
about one year of age. One of these two was disposed of without
clinical or pathologic investigation but a description of the other
constitutes a part of the present paper. Blindness is said to have
occurred in previous generations and in collateral lines but the details
could not be further documented.
The surviving blind female (Al) was bred to one of her normally
sighted-male sons. This resulted in a litter of four in which two males
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A2ai15 mos) A2b (32mos)
Fig. 1. Chart indicating genetic relationship of affected dogs and (in parentheses)
the times at which they were sacrificed for histologic study.
A b b . 1. Die Tabelle zeigt die genetische Verwandtschaft der erkrankten Hunde
sowie die Zeiten, zu denen sie fur die histologische Untersuchung getotet wurden.
Retinal Abiotrophy in Elkhounds
103
(A2a and A2b) developed the abiotrophy while one male and one
female did not. Attempts to inbreed further by mating one of the
affected males with his affected mother so as to produce a pure strain
of dogs with the abiotrophy have so far been successful in producing
only two pregnancies with two puppies each time but all these puppies
died within a few days after birth. We have, however, obtained a
family of elkhounds related to the propositus in which four of the
puppies were affected. This report is therefore based on the clinical
examination of eight affected dogs and on the pathologic examination
of five.
Case Reports
Case Al. When first examined this female dog was 2 years old
and had been blind for at least 6 months. The owner had observed
Fig. 2. Fundus photograph of propositus (Al) on right and of normal elkhound
o n left. Both show the normally protuberant nerve head but the vessels
of the affected dog are extremely narrow. The tapetum also shows
suggestive mottling at its edges.
Abb. 2.\Rechts,Augenhintergrund eines Probanden (Al) und links, eines normalen
Elchhundes. In beiden Photographien sind die normalvorspringenden Papillen zu sehen, aber die Gefasse des erkrankten Hundes sind ausserst verengert.
Das Tapetum weist ebenfalls an seinen Randern vermutlich Flecken auf.
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COGAN/KUWABARA
Fig. 3. Fundus photograph of dog A1 showing clumping of pigment in nontapetal area. (This clumping is not seen in the normal dog nor in the affected dog during the first year of the disease).
A b b . 3. Augenhintergrund von Hund A1 mit Pigmentklumpen ausserhalb des
Tapetum. (Eine derartige Klumpenbildung wird weder beim normalen
Hund noch beim kranken im ersten Jahr der Erkrankung gesehen).
an abnormally gray reflex from the eyes but it was not apparent
whether this was attributable to a primary color change in the eyes
or to the fact that the pupils were dilated.
On examination the dog was found to be completely blind with
dilated pupils that constricted slightly when bright light was shone on
the temporal side of the retinas. The lenses were clear except for a
few peripheral opacities at the equator. The vitreous of both eyes
showed the white, reflectile particles known as asteroid hyalitis.
The fundi showed normally protuberant discs but extreme narrowing
of the arteries and veins (Fig. 2). Toward the periphery and away
from the tapeta the arteries were converted into thin white lines.
The tapeta had approximately normal appearances but the edges may
have been unusually fragmented. The pigment in the periphery of the
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fundi also appeared abnormally clumped and mottled (Fig. 3), in
comparison with normal elkhound fundi, but there was none of the
bone-corpuscle pigmentation nor invasion of the retina such as we
see in human retinitis pigmentosa.
By retinoscopy the eyes were found to be no more than one
diopter myopic. Electroretinography gave no response whereas control observations on normal dogs gave good responses.
No change in appearance of the fundi occurred over an observation period of two years. The animal was disposed of at the age
of four years for histologic, histochemical, and electron microscopic
study. Portions of the retinas (and other parts of the eyes) were fixed
in formalin or alcohol for paraffin embedding while other portions
were fixed with osmium for epoxy embedding and still other portions
were used fresh for study of dehydrogenases and glycogen synthesis
according to methods we have previously usedl6-18.
Sections stained with hematoxylin and eosin (Fig. 4) or PAShematoxylin showed complete loss of the rods and cones. The retina
was best preserved adjacent to the nerve head but even here the photoreceptors and outer nuclear layer were completely absent and the
ganglion cells were reduced in number (Fig. 5). Away from the disc
the retina showed extensive gliosis with distortion, rarefaction, and
loss of identity of the bipolar and ganglion cell layers although
individual ganglion cells were recognizable even in the most gliotic
areas (Fig. 6). In places, the entire retina was thinned to a tenuous glial
strand or to actual hole formation. These holes were often bridged
by an accessory strand of pigment epithelial cells or, over the tapetum,
by a lamina or two of non-pigmented epithelial cells (Fig. 8). PAS
stains of these bridging cells showed them to be abnormally filled
with glycogen granules. Toward the periphery of the retina pigment
epithelial cells had migrated into the retina forming islands of single
cells or clusters and sometimes free extracellular pigment (Fig. 7).
Similarly non-pigmented cells had migrated into the retina overlying
the tapetum and could be differentiated from glia by the sheet-like
arrangement.
Along with its migration into the retina and apparent focal proliferation the pigment epithelium had disappeared from much of its
normal position behind the retina or had been so severely attenuated
in places that it was no longer recognizable. The choriocapillaris was
also unrecognizable except in the region about the disc. The optic
nerve appeared normal and the tapetum was normal.
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CO G A N / K U W AB A R A
.
.
4
5
Fig. 4. Posterior portion of eye through optic foramen showing intact but thinned
retina; dog Al. The outer retinal layers are missing. H. & E.
Fig. 5. Area adjacent to nerve head of same showing intact nerve fiber layer,
preservation of some ganglion cells, an intact but distorted bipolar layer,
and an absent outer nuclear and photoreceptive layer. H. & E.
107
Flat mounts of the retinal vessels, prepared by trypsin digestiodg,
showed severe acellularity and occlusion of all the smaller vessels with
extensive pigment ensheathing of the veins (Fig. 9).
Lactic acid diaphorase activity was high in the gliotic tissue and
showed the large clumps of nitro blue tetraaolium such as we have
associated with non-mitochondria1 enzyme localization. Succinic diaphorase activity was also high but showed the granular type of
activity such as we have associated with mitochondrial activity. Thus
there appeared in these retinas no dearth of either mitochondrial or
non-mitochondria1 activity-in fact, these appeared greater than in
normal retinas.
O n the other hand, glycogen was abnormally scanty, as determined by the periodic acid-Schiff staining of alcohol-fixed tissue, and
the retina was lacking in its capacity to synthesize glycogen when incubated in media containing glucose or uridine diphosphoglucose
(UDPG).
Electron microscopy has its usual limitations in that only a portion of the retina and pigment epithelium could be examined. The
areas selected were from the posterior portions of the globe but not
in the region of the tapetum. Sections were stained with uranyl
acetate and lead. Those from a normal retina are shown in Figures
13 and 14. The pigment epithelium appeared normal except that it
contained more glycogen particles than normal and its villi lacked
the orientation usually provided by the photoreceptors (Fig. 19).
Bruch’s membrane was abnormally thick but less dense than usual.
The choriocapillaris was absent. The retina was very much thinned
and showed complete loss of photoreceptors with no vestige of rod
or cone segments (Fig. 20). The remainder of the retina consisted
chiefly of glial cells with occasional desmosomes and in the outer portion of the retina a stratum of terminal bars that were interpreted as
remains of the outer limiting membrane.
C a m A 2 a and A26. These were the two male offspring (of
Case Al) which ultimately developed the abiotrophy. One was sacriAbb. 4. Durch das Foramen opticum gesehener Augenhintergrund rnit intakter,
aber verschrnalerter Retina; Hund A l . Die Aussenschichten der Retina
fehlen.
A b b . 5. Umgebung der Papille (siehe Abb. 4) mit intakter Nervenfaserschicht,
einigen erhaltenen Ganglienzellen und einer intakten aber verzerrten
Schicht der bipolaren Zellen; die aussere Kern- und Lichtrezeptorenschicht fehlt.
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COGAN/KUWABARA
Fig. 6. Peripheral portion of retina overlying edge of the tapetum; dog A l .
Noteworthy are the ganglion cells, the distorted and rarified bipolar layer,
and the total absence of photoreceptive layer. The choriocapillaris and
pigment epithelial layers are not recognizable. H. & E.
109
Fig. 8. “Hole” in retina bridged by a double layer of epithelium; dog A l . The
granular material giving rise to the dark stain in the epithelium is glycogen.
PAS-hematoxylin.
A b b . 8. ((Loch))in der Retina, das von einer doppelten Epithelschicht iiberbriickt
wird (Hund Al). Das granulare Material, das die dunkle Farbung des
Epithels verursacht, ist Glykogen. PAS-Hamatoxylin.
Fig. 7. Peripheral area showing severely gliotic retina invaded by pigment cell
clusters and free pigment; dog A l . The underlying pigment epithelium
is intact. H. & E.
A b b . 6. Peripherer, den Rand des Tapetums iiberlagernder Teil der Retina;
Hund A l . Man beachte die Ganglienzellen, die verzerrte und verminderte
Schicht der bipolaren Zellen und das vollkommene Fehlen der Lichtrezeptorenschicht. Die Kapillaren der Chorioidea und die Pigmentepithelschichten sind nicht erkennbar.
A b b . 7. Die periphere Zone zeigt starke Gliose der Retina, die von Pigmentzellklumpen und freiem Pigment durchsetzt wird. Hund A l . Das darunterliegende Pigmentepitbel ist intakt.
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COGAN/KUWABARA
111
ficed at age 15 months and the other at 32 months. One male and one
female sibling did not develop the disease and will not be described
further although they were also examined periodically and served
as controls for the affected dogs.
At three months and six months of age the visual function of all
four dogs in the sibship appeared equal and normal and the vessels,
tapeta, and retinal periphery were normal. The pupils showed full
responsiveness to photic stimulation. At eight months of age, however, the retinal arteries of the two affected puppies were pathologically
narrow and the owner of the dogs observed an abnormally gray
reflex from the fundus (as compared to that from the normal siblings)
although this was not apparent to the examiner. The pupils at this
stage were reactive to light. The tapeta had an equivocally yellow
and washed-out appearance in comparison with the normal. Electroretinography showed diminished or absent responses whereas the
two controls showed good responses to flashes of light.
Periodic observations up t o 15 months of age showed progressive
narrowing of the retinal vessels but the vitreous, tapeta, retinal periphery, and optic nerves remained normal. At this stage one of the
affected dogs (A2a) was disposed of and the eyes studied histologically
in the same manner as described in the foregoing case.
Case Ah.Cross sections of these eyes showed complete loss of
all rods and cones but the outer nuclear layer was still partially intact
about the disc (Fig. 10). Elsewhere it was also spottily present but
Fig. 9.
Flat mount of retinal vessels showing extensive acellularity of the small
vessels and adherent pigment clumps; dog A l . PAS-hematoxylin.
Fig. 10. Dog A2a (15 months). Cross section of retina overlying the tapetum in
the vicinity of the nerve head. The ganglion cell layer and bipolar layer
are intact but the outer nuclear layer is greatly rarified and the photoreceptors are completely absent. The underlying pigment epithelium
is normal. H. & E.
A b b . 9. Retina, flach prapariert, die starke Zellverminderung der kleinen Gefasse
und anhaftende Pigmentklumpen aufweist ; Hund A l . PAS-Hamatoxylin.
Abb. 10. Hund A2 (15 Monate alt). Querschnitt durch die Netzhaut iiber dem
Tapetum in Nachbarschaft der Papille. Die Ganglienzellschicht und die
Schicht der bipolaren Nervenzellen sind intakt, aber die aussere Kornerschicht ist erheblich vermindert und die Lichtrezeptoren fehlen vollig.
Das unterliegende Pigmentepithel ist normal.
112
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12
c 0 G A N / I< U W A B A R A
113
greatly distorted by gliosis and clefts. The bipolar cell layer was also
thinned or absent in places but ganglion cells were widely identified.
The irregular loss of these nuclear layers resulted in great variations in
the thickness of the whole retina. The pigment epithelium and the
non-pigmented epithelium over the tapetum were present and appeared normal but the choriocapillaris was not recognized. The
epithelial cells had not migrated into the retina. The optic nerves were
normal.
The retinal vessels visualized as flat mounts showed moderate
capillary acellularity, but much less than in the previous case, and
unaccompanied by pigment ensheathing (Fig. 11).
Some glycogen was present (identified by periodic acid-Schiffamylase) in the inner retinal layers but less than in the normal eyes
and much less than would be expected in view of the extensive
damage to the outer layers. Nor were we able to demonstrate glycogen
synthesis by means which we had previously employed for the retina
and which were successful in showing glycogen synthesis in the normal control.
Case A2b. The second of the affected dogs (A2b) in this litter was
sacrificed at 32 months of age, that is 17 months after the disposal of
its affected sibling. At this time the dog was completely blind and the
ERG was completely extinguished. The retinal arteries were severely
narrow and the periphery showed a splotchy pigment but the nerve
head showed its normal protuberance. The retinas and other ocular
structures were prepared in a manner similar to those of the previous
cases.
F&. 11. Flat mount of retinal vessels showing only moderate acellularity of the
capillaries and n o adherent pigment; dog A2a. PAS-hematoxylin.
Fig. 12. Dog A2b (32 months). Cross section of peripheral retina showing a
thinned and severely gliotic retina but partial preservation of the ganglion
cells and bipolar cells. The rods and cones have disappeared completely
but the pigment epithelium is intact. H. & E.
A b b . 11. Retina, flach prapariert, die nur geringe Azellularitat der Kapillaren und
kein anliegendes Pigment aufweist (Hund A2a, PAS-Hamatoxylin).
Abb. 12. Hund A2b (32 iMonate alt). Querschnitt periphere Netzhaut: die Retina
ist diinn und stark glios, aber Ganglien- und bipolare Zellen sind zum
Teil erhalten. Die Stabchen und Zapfen sind vollkommen verschwunden,
wahrend das Pigmentepithel intakt ist.
9
Path. x t . , Vol. 2, No. 2 (1965)
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COGAN/KUWABARA
Cross sections of the retinas showed complete loss of the rods
and cones from the entire retina and loss of the external nuclear layer
from the entire retina except in the region about the disc where it
was partially preserved. The bipolar and ganglion cell layers were
intact and normal about the disc but became progressively distorted
by gliosis away from the disc (Fig. 12). Except in the immediate
peripapillary area the retina was considerably thinner than normal
and in addition there were foci in which the retina was reduced to
a tenuous glial strand or to actual hole formation. At these latter sites
pigment epithelial cells had migrated into the retina and sometimes
formed bridges connecting two edges of the retina. Similarly nonpigmented epithelial cells sometimes formed bridges or clusters of
glycogen rich cells within the retina overlying the tapetum.
The pigment epithelium was everywhere intact and the retina was
nowhere fused with the choroid. The choriocapillaris was present.
Flat mounts of the retinal vessels showed severe acellularity of all
but the larger vessels and extensive ensheathing of the vessel walls by
pigment.
Electron microscopy showed many of the same changes as noted
in the first case. No trace of the photoreceptors was present and the
retina was reduced to a thin membrane consisting chiefly of glial cells.
Although these glial cells appeared to be arranged in a haphazard
manner terminal bars were identified forming a lamina that corresponded to the outer limiting membrane (Fig. 18). The ultrastructure of
the pigment epithelium was normal although the villi, lacking the
usual arrangement which they have with the photoreceptors, were
much folded on themselves. Bruch’s membrane and the choriocapillaris were normal.
While the foregoing studies were taking place and our interest in
the disease became known, we were shown four night blind Elkhounds from a litter of nine distantly related to the foregoing family.
They were six months old; one was a female and three were males.
Night blindness had been observed for a few weeks. Clinical examination revealed suggestive narrowing of the retinal vessels but no
other ophthalmoscopic abnormality. Electroretinography could not
be done at that time for technical reasons.
Case Bla. One of the night blind dogs was sacrificed and the
tissue prepared in accordance with the preceding methods. Light
microscopy revealed no abnormality. Specifically the retinas including
Auf den elektronenmikroskopischen Abbildungen sind die aufeinander folgenden Stadien der Netzhautabiotrophie des Elchhundes zu sehen. Die auf samtlichen Bildern angegebene Markierung (-) bedeutet ein Mikron.
A b b . 13. Netzhaut eines normalen Elchhundes. Aussensegmente der Lichtrezeptoren mit ihren charaktexistischen Plattchenschichten.
C, Aussenabschnitte der Zapfen. Die anderen Plattchenstrukturen sind Aussensegmente von Stabchen.
Electron micrographs showing successive stages in the development of retinal abiotrophy in the elkhound. The marker
(-) in all pictures indicates one micron.
Fig. 13, Normal elkhound retina. Outer segments of photoreceptors with their characteristically laminated plates. C, outer segments
of cones. The other laminated structures are outer segments of rods.
116
COGANIKUWABARA
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A b b . 16. Innensegmente der Lichtrezeptoren desselben Praparates mit schwacherer Konzentration der Mitochondrien und aussergewohnlich deutlichen Zilien. Fett gedruckte Pfeile seigen die Schlussleisten, die die aussere Grenzmembran darstellen ; fein gedruckte Pfeile zeigen die Zilien.
conspicuous cilia. Heavy arrows indicate the terminal bars representing external limiting membrane; light arrows indicate the cilia.
Fig. 16. Inner segments of the photoreceptors in the same specimen showing reduced concentration of mitochondria and unusually
Abb. 17. Abiotrophie bei einem 11 Monate alten Hund (Blb). Die Aussensegmente der Lichtrezeptoren sind stark fragmentiert und
ihre Plattchen sind desorientiert. Die Innensegmente zeigten starken Mitochondrienschwund. Das Pigmentepithel war normal
mit Ausnahme einer Faltelung seiner inneren Oberflache.
Is, Innensegmente; Os, Aussensegmente; PE, Pigmentepithel; fette Pfeile: aussere Grenzmembran.
Fig. 17. Abiotrophy in dog 11months old (Blb). The outer segments of the photoreceptors are severely fragmented and their laminated
platelets are disoriented. The inner segments showed marked reduction in mitochondria. The pigment epithelium was normal
except for pleating of its inner surface.
Is, inner segments; Os, outer segments; PE, pigment epithelium; heavy arrows, external limiting membrane.
Abb. 18. Abiotrophie bei einem 32 Monate alten Hund (A2b). Die Lichtrczcptoren sind volllcommen verschwunden und die aussere
Grenzmembran, die aus einer Serie von Schlussleisten besteht, liegt direkt auf der gefalteten inneren Oberflache des Pigmentepithels. M, Mullersche Zellen in der Retina; PE, Pigmentepithel; fette Pfeile : aussere Grenzmembran.
Fis. 18. Abiotrophy in dog 32 months old (A2b). The photoreceptors have disappeared entirely and the external limiting membrane,
consisting of a series of terminal bars, lies directly apposed to the folded inner surface of the pigment epithelium. M, Muller
cells in the retina; PE, pigment epithelium; heavy arrows, external limiting membrane.
121
the rods and cones were normal. The pigment epithelium, choriocapillaris and optic nerves were normal. Flat mounts of the retinal
vessels showed normal cellularity. Tetrazolium diaphorase was normal using lactate DPN and succinate substrates and the glycogen
content as well as the glycogeneogenesis were normal.
The electron microscopic findings were, however, interpreted as
abnormal. The laminated discs in the outer segments of the rods and
cones were disarranged (Fig. 15) in comparison to the regular lamination of the controls and the cilia connecting the outer and inner segments were unusually conspicuous and extended anomalously to the
base of the photoreceptors (Fig. 16). The mitochondria in the inner
segments were also less abundant than normal. Within the retina
proper the only abnormality was an increased pleating of the glial
membranes. On the other hand the pigment epithelium and choriocapillaris were normal.
Two of the night blind siblings of the foregoing case were
examined when they were 11 months of age. In the meantime they
had become progressively night blind (as had the third sibling not
examined) and the retinal arteries were interpreted as having become
narrower. Electroretinography at that time showed no recordable
response in one dog and a minimal response in another while a normal control dog showed a good response.
Case BID. One of these siblings was sacrificed (11 months of age)
and the tissues examined by light and electron microscopy.
Hematoxylin and eosin stains showed no definite abnormality
and periodic acid-Schiff stains showed minmal glycogen. Sections
incubated in glucose, however, showed glycogen synthesis in Muller’s
cells that was thought to be approximately normal. Tetrazolium preparations incubated with lactate-DPN and succinate were also interpreted as either normal or only slightly less than normal.
Electron microscopy showed advanced disorganization of the
outer segments of the rods and cones (Fig. 17). Portions of these
outer segments appeared to be detached fragments lying in the subretinal space with irregular arrangement of their lamination. The cilia
were perhaps thickened but were not as elongated as in the preceding
specimen. The pigment epithelium was present but showed excessive
pleating of its inner surface. The synaptic organs in the outer plexiform layer were suggestively decreased in number and the Muller
cells showed a non-specific packing and parallel stratification about the
blood vessels (such as we have seen in retinas with gliosis).
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COGAN/KUWABARA
Fig. 19. Abiotrophy in dog 4 years old (Al). The retina (upper half of picture)
is thin and gliosed. The photoreceptors are entirely absent but a single
terminal bar represents a portion of the external limiting membrane.
The pigment epithelium is normal although its villous processes project
freely in the subretinal space since the photoreceptors are lacking. A
pigment epithelial cell has invaded the retina (right middle). PE, pigment
epithelium; heavy arrow, terminal bar; double arrows, internal limiting
membrane.
123
Comments
The name photoreceptive abiotrophy is suggested as most effectively designating the entity which we are describing in the present
report. Photoreceptive indicates the predominant involvement of the
photoreceptors while abiotrophy refers to the degeneration of a
tissue which has matured normally and then undergone secondary
degeneration. The name seems to us preferable to progressive retinal
atrophy which would etymologically have to include several types of
primary progressive retinal degeneration in addition to the photoreceptive type, and it is certainly preferable to the term retinitis
pigmentosa which is a misnomer by all standards. This latter name is
established in human nosology for historical reasons but use of it can
only lead to confusion if applied to the analogous abnormality in
animals.
The photoreceptive abiotrophy here described appears to be a
mendelian recessive abnormality which produces signs in dogs at
about the sixth to eighth month of life. It thus comes on later than the
comparable abnormality reported in mice but much earlier than that
occurring typically in man. From these few observations it would
appear that the rapidity of onset and course parallel the life span of the
species.
Like retinitis pigmentosa of man and the comparable condition in
mice the characteristic changes in dogs consist of early extinction of
the electroretinogram, predominant degeneration of the rods and
cones, and a paradoxic narrowing and obliteration of the retinal
vessels-paradoxic because these vessels do not supply the photoreceptive layer of the retina. The migration of pigment into the retina
which is such a conspicuous feature in man occurs also in the dog but in
our cases did so only after the condition had been present 1-2 years.
The asteroid spots in the vitreous found in one of the dogs does not
occur significantly with retinitis pigmentosa of man but is a nonAbb. 19. Abiotrophie bei einem 4 Monate alten Hund (Al). Die Retina (obere
Halfte des Bildes) ist diinn und glios. Die Lichtrezeptoren fehlen vollig;
eine einzelne Schlussleiste stellt einen Teil der ausseren Grenzmembran
dar. Das Pigmentepithel ist normal, obwohl die villosen Fortsatze frei
in den Raum unterhalb der Retina vordringen, da die Lichtrezeptoren
fehlen. Eine Pigmentepithelzelle ist in die Retina eingedrungen (Mitte
rechts). PE, Pigmentepithel; fetter Pfeil: Schlussleiste; Doppelpfeile :
innere Grenzmembran.
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C O G A N J K UAWB A R A
Fig. 20. Inner portion of retina of same specimen showing portions of glial cells
and part of a single ganglion cell. Nuc, nucleus of ganglion cell; er,
ergastoplasm; ly, lysosomes ; double arrows, internal limiting membrane.
A b b . 20. Innenteil der Retina desselben Praparates mit Gliazellanteilen und Teilen
einer einzelnen Ganglienzelle. Nuc, Ganglienzellkern; er, Ergastoplasma; ly, Lysosomen: Doppelpfeile: innere Grenemembran.
125
specific and relatively frequent finding with various types of retinal
degeneration in dogs. The preservation of the protrusion of the disc
despite extensive retinopathy and blindness is significant in indicating
that the optic nerve and ganglion cell layer are preserved.
The present series of five cases permits a first-order attempt to
reconstruct the sequence of morphologic changes occurring in the
retina. At the onset of symptomatic night blindness the retina shows
no morphologic abnormality by light microscopy nor by histochemical
studies of lactate and succinate diaphorase or glycogeneogenesis.
Electron microscopy, however, reveals disarrangement of the laminated plates in the outer segments of the rods and cones, fragmentation of the outer segments and suggestive abnormalities in the cilia of
the photoreceptors. Similar disarrangement of the outer segments
were reported by DOWLING~
in rats with retina atrophy or with
vitamin A deficiency.
After the night blindness has been present for 1-2 years all the
photoreceptors will have disappeared but remnants of the outer nuclear layer will still be present about the disc and spottily present
throughout the rest of the retina. The entire peripheral retina will
have become thinned and in places it will be reduced to a tenuous
glial membrane. No pigment has migrated into the retina at this stage.
By one or tw-o years after the onset of the night blindness, the gliosis
will have become so severe as to destroy the nuclear lamination of the
retina throughout the periphery although scattered ganglion cells are
still present and the inner layers are still identifiable about the disc.
At this stage pigment epithelial cells in the periphery have migrated
into the retina. These form brown clumps that can be seen with the
ophthalmoscope and cell clusters that can be seen with the microscope, Such clumps are particularly apt to be associated with areas of
thinning or rupture of the retina and to surround the blood vessels.
Similar clusters of non-pigmented epithelial cells occur in the retina
overlying the tapetum. The absence of pigment in these latter cells
permits one to detect their pathologic loading with glycogen granules.
Except for migration of its cells into the retina the pigment epithelium may remain normal even late in the disease. The optic nerves
also remain histologically normal. The smaller retinal blood vessels
become occluded but there is no histologic evidence for this at a
stage when the arterial narrowing is first noted clinically.
Since photoreceptive abiotrophy occurs in mice, dogs, and man
it probably will be found eventually in other species as well. One paper
126
COGANJKUWABARA
describes the condition in cats20 and we incidentally processed the
eyes of a cat which had identical pathologic changes as in the dogs but
we were unable to obtain genealogic or clinical data to corroborate a
possible abiotrophic etiology. We also had occasion to examine the
eyes of several dogs (and human beings) showing loss of photoreceptors in the retinal periphery as a senile manifestation. Evidence does
not permit a conclusion as to whether these senile changes do or do
not have an hereditary basis but they are obviously different from the
present abiotrophy which begins at an early age and involves the
entire retina. Virus infections are frequently cited as causing retinopathy in dogs with blindness similar to that of the inherited disease
but the viral cases we have had an opportunity to study showed patchy
involvement of all layers of the retina, and unlike the abiotrophy, they
had produced acute symptoms within a few days’ time. Finally, there
are several retinotoxic agents in man and animals which produce a
degeneration of the photoreceptors comparable to those of an abiotrophy. Best documented are chloroquine and MellarilB (Thioridazine)
in human beings and iodoacetic acid in animals (rabbits). These
instances are cited to emphasize the importance of making a diagnosis
of photoreceptive abiotrophy only when there is clearcut evidence of
hereditary transmission and typical clinicopathologic findings.
To date it cannot be said that any lead points unequivocally to the
pathogenesis of photoreceptive abiotrophy in man or animals. The
finding of obliteration of the choriocapillaris in some cases was not
borne out in other cases. One might logically expect a missing enzyme
in the vitamin A-retinene cycle but none has been reported. GRAYMORE^^ has found a specific and early defect in a lactic acid dehydrogenase isoenzyme of rat retinas with photoreceptive abiotrophy. A
suggestive finding in the present cases was the unexpected paucity of
glycogen in some of the affected retinas and the absence of the capacity
for glycogen synthesis by the retinal glia but this was not evident early
in the disease.
An idiopathic degeneration involving predominantly the photoreceptors of
the retina occurs in the elkhound similar to that which has been reported in other
breeds of dogs and analogous to that which occurs in mice and men. It is suggested
that the term applied to the comparable condition in man, retinitis pigmentosa, is
inappropriate. A preferred name is photoreceptive abiotrophy of the retina.
127
Photoreceptive abiotrophy in the present eight cases appeared to be a
mendelian recessive trait producing signs at 6-8 months of age consisting of
night blindness, narrowing of the retinal vessels and extinction of the electroretinogram. Pathologically it consists of degeneration of the photoreceptive cells
and paradoxic obliteration of the retinal capillaries. Electron microscopy reveals
disorganization and fragmentation of the outer segments of the rods and cones
and pleating of the inner surface of the pigment epithelium, long before any abnormality is detectable by light microscopy.
The pathogenesis of photoreceptive abiotrophy is obscure but in the early
case here reported n o abnormality was detected in diaphorase activity nor in
glycogeneogenesis although there was a paucity of glycogen in the retinal glia and
an absence of the normal capacity for glycogen synthesis at a later stage.
Zusammenfasssztg
Eine hauptsachlich die Lichtrezeptoren der Retina betreffende idiopathische
Degeneration tritt beim Norwegischen Elchhund auf. Sie ist der bei anderen
Hunderassen beschriebenen ahnlich und analog der bei Mausen und Menschen auftretenden Degeneration. Die Bezeichnung ((Retinitis pigmentosa)) fur die vergleichbare Krankheit des PvIenschen ist nicht passend, so dass die Hundekrankheit
((Abiotrophie der retinalen Lichtrezeptoren)) genannt wird.
Bei den vorliegenden 8 Fallen schien eine Mendelsche rezessive Anlage fur
das Auftreten von Nachtblindheit, Verengerung der Netzhautgefasse und Extinktion des Elektroretinogramms im Alter von 6 bis 8 Monaten verantwortlich zu
sein. Pathologisch handelt es sich um Degeneration der lichtempfindlichen Zellen
und paradoxe Obliteration der Netzhautkapillaren. Elektronenmikroskopisch
liess sich Desorganisation und Zerbrechen der ausseren Anteile der Stabchen und
Zapfen sowie Faltelung der inneren Oberflache des Pigmentepithels lange vor
Sichtbarwerden irgendeiner Veranderung im Lichtmikroskop nachweisen.
Die Pathogenese der Abiotrophie der Lichtrezeptoren ist unbekannt ; jedoch
wurde bei einem der hier beschriebenen fruhen Falle weder eine Anomalie der
Diaphoraseaktivitat noch der Glykogenogenese entdeckt, obgleich zu einem
spateren Zeitpunkt eine Glykogenverarmung der Retina Glia und Fehlen der
normalen Fahigkeit der Glykogensynthese feststellbar war.
AcknowZedgments
This investigation was supported by Fight for Sight Grant-in-Aid#G-263
from the National Council to Combat Blindness, Inc.
The authors wish to acknowledge the enthusiastic cooperation of Miss
ELSIE
HEALEY
for her conscientious care of the dogs and supervision of the breeding program. We would also like to express our appreciation to Drs. Zrv and
C. KUPFER
for assistance with electroretinography and to Dr. D. DONALDSON
for
taking the fundus photographs.
128
COGAN~KUWAB
A AR
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Photoreceptive Abiotrophy of the Retina in the Elkhound

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