Focal Light

The eye is both illuminated and inspected from a distance (≈40–60 cm). The light source should be powerful and focal, such as a penlight of good quality, a direct ophthalmoscope, or an otoscope, to allow any vitreal opacities or condensations to be visualized by both direct and indirect illumination (i.e., by light reflected from the tapetal fundus [tapetum fundus]). Because opacities will either partly or completely block the reflected light, they will be seen as dark structures against a bright tapetal reflectivity. Movement of vitreal structures following motions of the globe or lagging behind ocular motions may be determined more easily in this way. As the vitreous becomes more liquefied, opacities can appear unstable with the gel or even settle to the bottom of the vitreal space.

Slit‐Lamp Biomicroscopy

A slit‐lamp biomicroscope is a highly useful and necessary tool for examination of the vitreous, even though such inspection using a slit‐lamp biomicroscope will be limited to the anterior part. A slit‐lamp biomicroscope is therefore especially useful to evaluate disorders at the lens/vitreous interface, such as persistence of parts of the tunica vasculosa lentis posterior, persistent hyaloid artery (PHA), persistent hyperplastic tunica vasculosa lentis (PHTVL)/persistent hyperplastic primary vitreous (PHPV), and posterior lental pathology. Examination of the posterior vitreous requires the Hruby contact lens with slit‐lamp biomicroscopy and can provide magnifications from 5× to 50× of the vitreous structure.

Medical Treatment

Because the vitreous is avascular in adult dogs, penetration of systemically administrated drugs is poor. When the blood–aqueous barrier is compromised, such as occurs in uveitis, accessibility of the vitreous for drugs increases. Hence, systemic administration of drugs, even though relatively safe, is of limited use in reaching the vitreous medically. The most direct way to achieve high drug concentrations in the vitreous is by intraocular injection. The globe only tolerates rather low doses and volumes, however, and large doses may produce severe ocular damage. The latter phenomenon is used by injecting gentamicin into the vitreous as a treatment in globes with absolute glaucoma and in which enucleation is contraindicated.

Surgical Treatment

Surgical treatment is necessary when the vitreous is displaced within the pupil during anterior segment surgeries and in the treatment of RDs. Additional details on vitreous surgery are provided later in this chapter.

Developmental Disorders

Developmental disorders form a group of relatively rare ophthalmic anomalies. Usually, these anomalies are part of syndromes associated with persisting intraocular vasculature or with other ocular developmental disorders, such as microphthalmia, Collie eye anomaly (CEA), and retinal dysplasia.

Persistent Hyaloid Artery

The anomaly PHA results from failure of part or all of the hyaloid artery to regress (Figure 13.1). The artery may have persisted as a string (in some cases containing blood) situated in the vitreous space, between the optic disc and the lens. In PHA, only a small, dense, white, connective tissue string usually remains adhered to the posterior lens capsule. The optic disc may have a conical shape (i.e., Bergmeister’s papilla), and during ocular movements, PHA structures lag slightly behind and thus may show a “waving” motion. PHA has been suggested to be hereditary in the Sussex Spaniel and the Dobermann.

PHA alone rarely requires surgical treatment. If the associated cataract formation leads to visual impairment, however, surgery may be indicated. In these cases, the risk of complications is slightly higher than that in cases of cataract alone, because in PHA‐related cataracts, central fenestration of the posterior lens capsule and anterior vitrectomy are indicated.

Other Anomalies

The vitreous may be involved in diseases of its bordering structures as well. In CEA, a partial failure of vitreal development, which is only recognizable with use of a slit‐lamp microscope, has been described. Vitreal syneresis, vascular anomalies, hemorrhages, and RD may also be found in CEA. These anomalies may include preretinal vascular loops penetrating into the vitreous, and such vessels may easily give rise to vitreal hemorrhage. In case of RD, the neuroretina is partially or totally detached into the vitreous.

In the focal and geographic forms of retinal dysplasia, the retina folds slightly into the vitreous. In severe forms of retinal dysplasia, as has been described for the Bedlington Terrier, Yorkshire Terrier, and Labrador Retriever (in combination with skeletal abnormalities), the retina is partly or totally detached and dislocated into the vitreal space.

Acquired Disorders

Vitreous Floaters

Vitreous floaters, muscae volitantes, or “flying flies” are larger flakes or streaks in the vitreous that may lag behind ocular movements. In the past, this was thought to cause the so‐called fly‐biting syndrome, but today, this behavior is suspected to result mainly from nonophthalmic causes, such as temporal or occipital lobe dysfunction. Vitreous floaters are uncommon and rarely require surgical treatment.

Asteroid Hyalosis

Asteroid hyalosis is characterized by many small and possibly slightly pigmented particles (i.e., “asteroid bodies” from 0.03 to 0.10 mm in diameter) in the vitreous of one or both eyes (Figure 13.4a and b). These particles move both during and following movements of the globe, but they also return to their initial position. They generally have no distinct influence on vision by their presence alone; however, asteroid hyalosis may be associated with posterior uveal changes or (progressive) retinal atrophy. Comparisons of vitreous humor containing asteroid bodies from affected dogs indicate that asteroid bodies contain calcium and phosphorus.

Synchysis Scintillans

Synchysis scintillans is characterized by numerous cholesterol particles in a more or less liquefied vitreous. Especially after eye movements, they can resemble a snow flurry behind the lens, and against bright light, they may cause dazzling. With ocular movement, these opacities move within the liquid vitreous; when the globe is till, they settle to the bottom of the vitreous space. The abnormality is rare and seldom causes recognizable problems in dogs.

Intravitreal Membranes

Intravitreal membranes are associated with past and/or current intravitreal hemorrhage. Additional common findings in that study included epiretinal membranes, retinal neovascularization, preiridal fibrovascular membranes, and glaucoma.

Vitreal Inflammations

Because the adult vitreous has no intrinsic vasculature nor nerve supply, the possibilities of reaction to noxae are limited. Hence, inflammation of the vitreous itself (i.e., hyalitis and vitritis) will almost always be secondary to inflammatory reactions of adjacent structures. Floaters of hemorrhagic or other exudate in the vitreous, especially if diffuse or bilateral, often result from exudative uveitis, chorioretinitis, retinitis, or optic neuritis.

Free blood in the vitreous is relatively uncommon (Figure 13.5a and b). Hemorrhage may result from congenital anomalies, such as the persistence of fetal vasculature (e.g., PHA and PHTVL/PHPV), CEA, trauma, infection, or systemic diseases (e.g., coagulopathies, vasculitis, systemic hypertension, and neoplasms). Blood in the vitreous has been described to have a destructive effect on the gel structure: vitreous adjacent to a hemorrhage is prone to liquefaction. The arrival of macrophages induces an inflammatory reaction, which results in the formation of vitreal fibrinous membranes and traction bands.

Depending on the geographic location of the patient, various infectious agents are known to induce vitreal exudates. Infections reported to cause vitreal exudates include blastomycosis, cryptococcosis, histoplasmosis, brucellosis, and other diseases. In these cases, therapy should be directed primarily at the underlying cause.

The prognosis of vitritis strongly depends on the underlying cause. Small amounts of blood or exudate may be resorbed, but larger amounts usually cause visual disturbances, even if the inflammatory reaction can be controlled. Vitreal membranes and traction bands may develop. In turn, vitreal displacement, prolapse, herniation, and traction caused by traction bands or membranes may cause secondary RDs even months after the primary disorder has resolved.

Cysts

Cysts, most likely originating from the pigmented epithelial layer of the iris or the ciliary body, may extend into the vitreous. These cysts are much less common than anterior chamber uveal cysts. Cysts may also be caused by parasites. Vitreal cysts have the appearance of spherical or oval, translucent bodies that may be stationary or move slowly in liquefied vitreous following movement of the globe. Depending on their size and location, they seldom interfere with vision.

Parasites

Migrating larvae of Dirofilaria immitis, Toxocara canis, the larvae of flies (i.e., ophthalmomyiasis interna), and Echinococcus sp. may penetrate the vitreous. Living or dead intraocular parasites may cause local irritation, uveitis, or cyst formation. Killing intraocular dirofilaria by medication is sometimes possible. However, the intraocular presence of a dead parasite generally induces severe immunogenic uveitis, with possible subsequent endophthalmitis. Therefore, if the parasite can be reached without an unacceptable risk, surgical removal is to be preferred.

Neoplastic Disease

Intraocular neoplasms generally arise from the uvea and may occupy part, or almost all, of the vitreous space. Neoplasms may be primary, metastatic, or systemic/multicentric. Depending on location and size, a vitreal tumor may cause more or less displacement of the vitreous and lens as well as posterior uveitis and RD. Primary neoplasms of the retina, choroid, and optic nerve are extremely rare in the dog, and neoplasms originating from the anterior uvea are relatively uncommon in this species. Uveal neoplasms mainly comprise malignant melanomas, but other neoplasms have been reported. The prognosis for an eye affected by a neoplasm extending into the vitreous depends on both the type of neoplasm and its extension, but such a neoplasm generally should be considered an indication for enucleation.

Lens Luxation

The lens may dislocate when its suspension system is compromised by dysplasia, degeneration, and/or rupture of the Zinn zonular fibers. The zonular fibers may have developed abnormally or have degenerated; in exceptional situations, they can rupture from external trauma. If several zonular fibers have ruptured, vitreous may leak into the anterior chamber along the lental equator and through the pupil. If the fibers have ruptured over a greater area, subluxation of the lens will occur. If the lens becomes completely unattached, it may remain more or less in its normal position, be displaced toward anterior or posterior, or topple. Because of its volume and the strong attachment of the posterior lens capsule to the vitreous, a dislocated lens will dislocate part of the vitreous as well. Subsequently, vitreous may prolapse or herniate in the pupil, thus impairing, or even blocking, drainage of aqueous between the posterior surface of the lens and the anterior surface of the iris (if the lens has become dislocated into the anterior chamber) or, at the level of the drainage angle, causing secondary glaucoma in all cases. The earliest recognizable sign of a lens luxation is the presence of slight vitreous protrusions, which are recognizable on slit‐lamp biomicroscopy as thin, white clouds along the pupil margin.

Behavioral Testing

Behavioral testing is relatively simple and can be quantified by difficulty of the maze, time to complete successfully the maze, amount of illumination, and other measurable factors. Careful questioning of the owner is usually an important source of information about a dog’s visual performance; however, this information may be incomplete or invalid. Furthermore, the ability of a visually impaired or blind dog to adapt to familiar surroundings by relying on other senses and a memorized image of the environment can mask the signs of impaired vision.

Vision may also be assessed from the dog’s response to falling objects (visual tracking) that do not create a noise or current of air (e.g., small cotton balls). The balls can be dropped both in front of the dog and to the sides to get an impression of central and peripheral vision. The results should be interpreted with some caution, however, because of patient indifference.

Testing Reflexes and Responses

The pupillary light reflex (PLR) requires a functional retina but also depends on postretinal transmission of signals. Loss of the PLRs is not a definite sign of retinal dysfunction or even of loss of vision. They can also be partially inhibited in an apprehensive patient because of an increased sympathetic tone. Furthermore, residual PLRs are often present in dogs even with advanced retinal degeneration, such as in progressive retinal atrophy (PRA), especially if the inner retina is preserved. The reason for this phenomenon is that the PLRs are driven by the photoreceptors at low light levels and have been shown in various species to be driven by the melanopsin‐containing ganglion cells at high light intensity stimulation. The presence of the PLRs is therefore not a guarantee of a healthy retina in dogs with opaque media (e.g., preoperatively in those with dense, extensive cataracts) that prevents ophthalmoscopic examination.

Ophthalmoscopy

Direct and indirect ophthalmoscopy are both used in veterinary ophthalmology to visualize the fundus. Three types of ophthalmoscopes are available: (i) the standard monocular direct ophthalmoscope; (ii) pan‐ophthalmoscope; and (iii) monocular and binocular indirect ophthalmoscopes. Each type of ophthalmoscope has advantages and limitations, and can complement each other.

The ophthalmoscopic examination is performed in a darkened room using short‐acting mydriatics, such as 0.5–1.0% tropicamide (Mydriacyl; Alcon Laboratories, Ft Worth, TX, USA). Direct ophthalmoscopy, in general, provides the observer with a smaller field of view that is of greater magnification and detail than that with indirect ophthalmoscopy. The newer pan‐ophthalmoscope has lower magnification and a larger viewing field. Direct ophthalmoscopy is mainly used to examine the central parts of the fundus, especially the region of the optic nerve head (ONH), but it is considered inadequate to examine the peripheral fundus of domestic animals. Indirect ophthalmoscopy allows a more complete examination of the fundus in a shorter time. Moreover, it allows stereopsis, which is useful in appreciating the topographical features of the retinal surface such as when appraising RDs, colobomas, and papillary edema. Different indirect lenses can be selected to allow for a more highly magnified view when required. For additional details, see Chapter 4.

Scanning Laser Ophthalmoscopy

Scanning laser ophthalmoscopy (SLO) is a diagnostic imaging technique developed for very precise and detailed fundus visualization. Lasers of different wavelengths allow the examiner to obtain information about specific tissues and layers on the basis of their reflection and transmission characteristics. The SLO can also be utilized in an angiography mode in order to correlate functional with morphological aspects in disease processes affecting the retinal and/or the choroidal vasculature.

Optical Coherence Tomography

During the past decade, an imaging technique called optical coherence tomography (OCT) has been developed and used both in research and for clinical purposes to evaluate in vivo retinal structure. High‐resolution, cross‐sectional images of optical reflectivity are obtained. The technique is based on the principle of low‐coherence interferometry in which distance information concerning various ocular structures is extracted from time delays of reflected signals. This in vivo microscopy technique gives information about retinal organization and structural integrity. For example, photoreceptor layer thickness can be quantified using OCT. Instrumentation has also been developed that utilizes both OCT and SLO techniques simultaneously.

Adaptive Optics

Newer noninvasive imaging techniques are under development. Some use adaptive optics to adjust for the aberrations of the optical media allowing for highly magnified examination of the retina in vivo. Individual photoreceptors can be imaged using the adaptive optics techniques.

Ultrasonography

Ultrasonography is a valuable aid in detecting and monitoring pathological conditions in the canine posterior segment. In patients with opaque media (e.g., dense cataracts and intraocular hemorrhage), ultrasonography can be used to detect, for example, a detached retina or posterior segment neoplasm. Furthermore, ultrasonography can be used to study space‐occupying conditions that are difficult to examine because of their location (e.g., neoplasms in the choroid close to the ciliary body).

Angiography

Angiography is a helpful adjunct in the diagnosis of retinal diseases. It is mainly used to evaluate disease processes in which the vasculature of the eye is involved, such as vascular anomalies, posterior segment neoplasms, hypertension, RD, inflammatory processes, diabetic retinopathy, and degenerative processes. The procedure is performed in sedated, anesthetized, or conscious dogs, depending on the preference and need of the examiner. Fluorescein sodium solution (Fluoresceine 10%; Faure, France) is given as an intravenous bolus into the cephalic vein. Fundus photography is then performed using a fundus camera connected to a power‐back unit to allow for quick recycling of the black‐and‐white or color film, as well as using the newer digital cameras.

Electroretinography

When the retina is stimulated by light, a diffuse electrical response is generated by neuronal and nonneuronal cells that can be recorded as the electroretinogram (ERG). This response is a summation of electrical potentials that result from light‐induced changes in the movement of ions, mainly sodium and potassium, within the extracellular space. Thus, the ERG is an objective, functional test of the retina and is critically dependent on the function of the photoreceptors (i.e., the rods and cones). It has a characteristic waveform that varies depending on several factors, but mostly on the type of stimuli used. The intensity, duration, frequency, and wavelength of the light stimulus as well as the interval between stimuli, size of the retinal area illuminated, pupil size, and (very important) stage of retinal adaptation are variables that account for alterations in the ERG response. The ERG is recorded by using an active contact lens electrode, and a reference and a ground electrode, and the results are displayed on an oscilloscope, ink writer, or computer screen (Figure 13.7).

Pattern ERG

The pattern ERG (PERG) measures a retinal response to a phase‐reversing pattern stimulus that is focused onto the retina and maintains a constant overall mean luminance. The response is an electrical potential thought to derive from the retinal ganglion cells (RGCs) and the neighboring inner retinal structures. The main characteristics of a pattern stimulus include overall screen brightness (i.e., mean luminance), brightness contrast of neighboring bars or checks (i.e., percent contrast), rate of pattern reversal (i.e., temporal frequency), and bar or check size (i.e., spatial frequency). Moreover, for measurements to be reliable, the refractive error of the patient must be corrected during the testing so that the stimulus is focused on the retina. Other methods to estimate canine visual acuity include behavioral testing, assessment of the optokinetic response, and measurement of visually evoked cortical potentials (VEPs).

DNA‐Based Tests for Retinal Dystrophies

Appendix A lists the tests currently available. However, this is a rapidly progressing field and the reader is advised to review the current literature and websites of the laboratories offering genetic tests for the most up‐to‐date information.

Tapetal Fundus

The combination of the tapetum lucidum and an absence of pigment in the overlying retinal pigment epithelium (RPE) is the anatomical basis for the tapetal fundus. The tapetal fundus forms an almost triangular area, with a horizontal base, in the dorsal half of the fundus. The area is usually brightly and beautifully colored, and reflective. The size of the tapetal fundus varies extensively. Usually, it is large, and it may sometimes surround the ONH in gaze hounds (i.e., dogs that hunt by sight [e.g., Greyhounds]) and large breeds. It is often poorly developed, however, in toy breeds (e.g., Papillons). In the latter case, the tapetal fundus often only occupies a small area, usually temporal and dorsal to the ONH. The retinal blood vessels transverse the tapetal fundus, and the vessels are more easily viewed in the tapetal zone than in the nontapetal area when ophthalmoscopy is performed. The nontapetal fundus surrounds the entire tapetal area and is typically darkly pigmented.

In dogs with a merle coat color (e.g., blue merle Collies, Shetland Sheepdogs, Australian Shepherds, and related breeds), the tapetal fundus may be absent. Occasionally, the tapetal fundus may also be missing in other dogs, and in this case, the entire fundus resembles the nontapetal zone (i.e., dark, dull, and nonreflective). The palette of the tapetal fundus includes hues of yellow, orange, green, and blue. Often, more than one color is present.

Among breeds in which pale blue or heterochromic irides may appear (e.g., merle‐coated Collies, Shetland Sheepdogs, and related breeds, harlequin‐coated Great Danes, and Cardigan Welsh Corgis, which also carry merle genes, and some arctic breeds such as Siberian Huskies), a subalbinotic fundus may be found. The appearance of the fundus ranges from a small segment of albinism or subalbinism situated randomly in the tapetal or nontapetal fundus to almost complete absence of pigmentation in the fundus. The tapetal fundus has a light or dark blue color in young pups up to the age of five to seven weeks. After this age, the adult coloration starts to develop.

Nontapetal Fundus

The nontapetal fundus comprises the largest area of the ocular fundus in the dog. The junction between the tapetal and nontapetal fundi exhibits a continuous variation, from a distinct line of demarcation to a gradual transition with scattered foci of tapetal cells, which become more and more sparse with increasing distance from the center of the tapetal fundus. The nontapetal fundus has a nonreflective, usually dark or grayish brown to black color. In the dog (regardless of the breed) with a brown, chocolate, or liver coat color associated with a paler brown iris, the nontapetal fundus is less heavily pigmented and will appear paler brown or reddish brown. Sometimes, the choroidal vessels will cause a striped or tigroid appearance when viewed through the ophthalmoscope.

In the dog with a subalbinotic fundus, parts of the nontapetal fundus will be unpigmented, thus showing the choroidal vessels overlying the white sclera. Absence of pigment in the entire nontapetal region is common (e.g., in blue merle Collies).

Ophthalmoscopy

It is normally impossible to examine the ocular fundus in pups younger than two weeks, because the eyelids remain closed and the ocular media, especially the cornea, are not sufficiently clear. When the eyelids open and ophthalmoscopic examination can be performed, there is no discernible difference between the tapetal and nontapetal fundi. At this stage of development, the entire ocular fundus has a dull, dark gray color, and the ONH is small and flat due to immature myelination. The retinal blood vessels, however, are easily identifiable and appear relatively large in size.

The developing tapetal fundus appears paler, and the nontapetal region relatively darker, after three to four weeks of age. The tapetal fundus then takes on a lilac to blue coloration, which becomes more intense with increasing age. After approximately seven to eight weeks, the tapetal fundus becomes more granular in appearance. The bluish, immature tapetal fundus then becomes more brightly colored over time, until a tapetal fundus of adult structure and coloration is developed at approximately three to four months of age.

Functional and Morphological Development of the Retina

Retinal differentiation and maturation (mainly of the photoreceptors) in dogs is complete by seven to eight weeks of age. At the end of this period, the retina, as monitored by ERG and both light and electron microscopy, is adult‐like.

Collie Eye Anomaly

CEA is a congenital ocular syndrome involving defects of the posterior vascular and fibrous tunics of the eye. CEA affects primarily the Collie types of dogs but also some other breeds: Rough and Smooth Collie, Shetland Sheepdog, Australian Shepherd, Border Collie, Nova Scotia Duck Tolling Retriever, Longhaired Whippet, Boykin Spaniel, and the Lancaster Heeler. The pathogenesis of the defect is considered to be an abnormal mesodermal differentiation, which results in defects, mainly of the sclera, choroid, optic disc, retina, and retinal vasculature. The severity of the disease varies from no apparent visual deficit to total blindness. CEA is bilateral and has no sex predisposition. There is no difference in frequency related to coat color, type of coat, or presence of the merling gene. The cardinal sign is a geographically defined region of choroidal hypoplasia lateral to the optic disc, which may or may not be accompanied by obvious retinal or scleral defects or by colobomas. Other anomalies are RD and intraocular hemorrhage.

The hereditary trait for the disorder was established and a simple autosomal recessive inheritance postulated by Yakely and colleagues through a test breeding scheme. This mode of inheritance was further supported by the results of pedigree analysis and test matings conducted by Bedford in 1982. The genetic studies have established the primary CEA phenotype, choroidal hypoplasia, to segregate as an autosomal recessive trait with nearly 100% penetrance. Some heterozygotes for the mutant allele showed mild choroidal hypoplasia. The CEA locus was mapped to a 3.9‐cM region of canine chromosome 37. An intronic deletion in the NEHJ1 gene was identified. The prevalence of CEA has been high in Rough and Smooth Collies and Shetland Sheepdogs throughout the world. In 1969, the incidence of CEA in the Collie was between 75% and 97% in the United States. Because of selected breeding, this prevalence decreased within several years to 59%. The incidence of CEA in Border Collies is low, and only sporadic cases are diagnosed, while in the Lancashire Heeler, a somewhat high incidence was reported: 13.7%.

Clinical Findings

Clinical findings in CEA include a high degree of pleomorphism. In a single litter, there is often great variation in the severity of the changes and there may be variation between the eyes of an affected individual. Choroidal hypoplasia is considered the diagnostic lesion for CEA and is always bilateral, though the extent of the lesion may vary between eyes (Figures 13.10 and 13.11). The four main defects included in the CEA syndrome are listed in Table 13.1. Other changes also included in this syndrome by some authors are excessive tortuosity of the retinal vasculature and retinal folds in young pups. The CEA syndrome is most accurately diagnosed in pups at six to seven weeks of age. These same dogs should be examined annually (to confirm the puppy exam results) as well as before their first breeding.

Merle Ocular Dysgenesis

The Australian Shepherd dog is affected by multiple ocular anomalies. Affected dogs may show microphthalmia to varying extent and varying size of the globes. The defect is associated with microcornea of an irregular shape and, infrequently, with mineralization of the anterior corneal stroma. Affected dogs also exhibit heterochromia irides with dyscoria and corectopia with an oval pupil in which the long axis is vertical. The hypoplastic irides permit transillumination and respond poorly to mydriatics. False polycoria occurs in 5–10% of affected dogs. Often, the defect extends into the iridocorneal angle and posteriorly into the ciliary body. Cataracts occur in 60% of affected dogs with microphthalmia and colobomas. In 54% of affected Australian Shepherds, large equatorial staphylomas occur. The staphylomas are either a single depression or several small excavations grouped together. The choroidal vasculature is greatly reduced or absent in the staphylomas, and the sclera is irregular and thin. Large staphylomas may extend from the ora serrata to the optic disc. Retinal vasculature in the staphylomas may be markedly reduced or even absent. In 50% of cases, complete RD occurs, and approximately 30% of the detachments have intraocular hemorrhage. Microphthalmia with colobomas in Australian Shepherds is inherited as an autosomal recessive trait with incomplete penetrance. Affected dogs are homozygous merles and have excessively white hair coats. A similar syndrome has been observed but not studied in merle Collies, Shetland Sheepdogs, Harlequin Great Danes, and other merle breeds. In general, affected puppies result when both parents are merles (sometimes not very noticeable).

Retinal Dysplasia

Retinal dysplasia has been defined as an anomalous differentiation of the retina accompanied by a proliferation of one or more of its constituent elements. It is characterized histopathologically by linear folding of the sensory retina and formation of rosettes composed of variable numbers of neuronal retinal layers around a central lumen. The defect is associated with several spontaneously occurring and experimentally induced disorders of the developing eye in both humans and animals. Dysplastic retinal lesions may be associated with systemic abnormalities, or they can be a primary ocular defect, either as a single defect or together with other lesions such as microphthalmos or colobomatous defects. Known causes of retinal dysplasia include viral infections, vitamin A deficiency, X‐ray irradiation, certain drugs, and intrauterine trauma. Many forms in dogs have a hereditary basis.

Spontaneous Retinal Dysplasia

The pathogenesis for spontaneous retinal dysplasia may vary, depending on the retinal tissues affected. Often the different forms of retinal dysplasia occur in specific breeds (Tables 13.2 and 13.3).

Clinical Signs

Clinically, the lesions of retinal dysplasia are unilateral or bilateral and may be grossly divided into three different types or forms (see Table 13.3). Clinically, most lesions in retinal dysplasia do not appear to change with time. The least severe type (i.e., focal or multifocal retinal dysplasia) usually remains unaltered (Figure 13.12). In a few cases, however, the lesions become less obvious, and some folds may disappear. At the same time, the area around others, especially if the lesions are numerous, may become more demarcated, with hyperpigmented spots and streaks as well as hyperreflective areas in the vicinity of the dysplastic lesions. In the geographic type, the lesions never disappear but instead become focally more demarcated with time. The most severe form, with complete RD, remains unaltered in most cases, but complications including vitreal hemorrhage, cataracts, and secondary glaucoma may arise (Figure 13.13a–c).

Type	Ophthalmoscopic findings
Focal or multifocal	Retinal folds and rosettes are seen as areas of reduced tapetal reflectivity, appearing as gray or green dots or linear, “V,” or “Y” streaks
	Occur anywhere in the tapetal region, but most often centrally and usually above the optic disc
	May appear elevated, distorting the course of the overlying vessels
	Retinal folds in the nontapetal fundus appear as gray or white linear or irregular streaks
Geographic	Appear as an irregular or horseshoe‐shaped area, most often in the central tapetal fundus
	May include focal retinal thinning and elevation
	Usually, hyperreflective area with variable pigmentation
Complete with detachment	Usually, a completely detached neural retina floating in the vitreous, attached around the ONH

Breed (mode of inheritance)	Type of RD	Other abnormalities
Akita	Complete	Microphthalmia, cataract, posterior lenticonus
American Cocker Spaniel (AR)	Multifocal	None
	Multifocal	Microphthalmia, cataracts, persistent pupillary membranes
Australian Shepherd	Complete	Iridal heterochromia, cataracts, staphylomas, RDs
(AR, incomplete penetrance)
(any breed with homozygous merling)
Beagle	Multifocal	Microphthalmia
Bedlington Terrier (AR)	Complete	Microphthalmia, cataracts, RDs
Cavalier King Charles Spaniel	Geographic	Microphthalmia, cataracts, posterior lenticonus
Chow Chow	Complete	Severe ocular defects
Doberman Pinscher (AR)	Complete	Microphthalmia, anterior segment dysplasia, aphakia, hyperplastic primary vitreous
English Springer Spaniel (AR)	Geographic	Microphthalmia, cataracts, RDs
Golden Retriever	Geographic	None
Labrador Retriever	Multifocal	None
	Geographic	None
(AR)	Complete	Microphthalmia, cataracts, intraocular hemorrhage
(AD)	Complete	Cataracts; retarded growth of the radius, ulna, and tibia; separated hypoplastic anconeal and coronoid processes; hip dysplasia; delayed development of the epiphysis
Rottweiler	Multifocal	None
Sealyham Terrier (AR)	Complete	Microphthalmia, cataracts, RDs
Samoyed	Complete	Microphthalmia, cataracts, hyaloid artery persistence, and skeletal defects as in the Labrador Retriever
Yorkshire Terrier	Multifocal	None

AD, autosomal dominant trait with variable penetrance; AR, autosomal recessive trait.

Since retinal dysplasia is a defect of retinal differentiation, lesions are mainly congenital in nature. Therefore, early screening of dogs at six to eight weeks has been encouraged for breeds in which the defect is prevalent. A second examination was recommended to be performed between six months and one year of age in breeds affected with the geographic form of retinal dysplasia.

Breed Incidence and Inheritance

Spontaneous retinal dysplasia occurs in several breeds, and hereditary factors have been shown or suspected to be the cause in many breeds (see Table 15.3). It is not uncommon to find retinal dysplasia in conjunction with other severe ocular defects, as described in the Doberman Pinscher, Akita, Chow Chow, and Australian Shepherd dog. In some breeds, such as in the Samoyed and the Labrador Retriever, retinal dysplasia occurs in combination with other nonocular defects (termed canine oculoskeletal dysplasia).

Induced Retinal Dysplasia

Infection with canine adenovirus has been shown to cause retinal dysplasia. Another infectious agent causing retinal dysplasia is canine herpesvirus. Experimental studies have demonstrated that severe ocular inflammation with subsequent retinal dysplasia and associated ocular anomalies can be induced in neonatal pups. The immature mammalian retina is also susceptible to radiation, which has been demonstrated in the dog. Irradiated newborn puppies exhibited retinal rosette formation. The rosettes were either few or numerous, and they involved both tapetal and nontapetal fundi. Morphological studies showed lesions indicative of aberrant development after radiation‐induced damage.

Canine Multifocal Retinopathy

A unique inherited multifocal serious and bullous retinopathy was first described in the Great Pyrenees breed. Similar changes were then observed in the Coton de Tulear, English and French Mastiff and Bullmastiff dog breeds, and the Lapponian Herder. Pedigree analysis and prospective matings in the Great Pyrenees dog indicate an autosomal recessive inheritance for the disorder. Ophthalmoscopic lesions have been described as multifocal, gray to tan fundic patches that vary in size from barely visible to some lesions that are larger than the optic disc. Lesions start to develop at approximately 11 weeks of age; usually they are sparse, but they develop bilaterally in the peripheral tapetal fundus, around the optic discs, and occasionally under the major veins inferior to the optic disc (Figure 13.15). The peripapillary lesions, observed as serous RDs, develop within a few hours but remain the same size for years, while the peripheral lesions develop gradually over years and appear to increase slowly in size and number until the age of 20 weeks.

The lesions do not appear to be congenital but are detected suddenly in young puppies. The retinal degeneration and RPE changes are focal and related only to the serous retinal and RPE detachments. An investigation of potential candidate genes revealed that affected dogs had a mutation in the canine BEST1 gene (cBEST1). In humans, mutations of this gene cause vitelliform macular dystrophy type 2, or Best macular dystrophy. The cBEST1 gene is predominantly expressed in RPE/choroid and encodes bestrophin, a 580‐amino acid protein of 66 kDa. Two disease‐specific mutations were identified in the cBEST1 gene of affected dogs, cmr1 mutation in mastiff‐related and the Great Pyrenees dog breeds, and cmr2 in the Coton de Tulear dog breed. Recently, a third form of cmr disease was identified in the Lapponian Herder breed, although this also resulted from a mutation in cBEST1. It manifested as a somewhat later onset of the multifocal lesions, at approximately one year of age.

Classification of Canine Hereditary Retinal Degenerations

Canine retinal degenerations primarily affect the photoreceptors, RPE, or both. The first well‐documented report of an inherited retinal degeneration in a Gordon Setter from Sweden was in 1910. To these conditions, the general term PRA has been applied. Since then, clinicians have divided PRA into two types depending on the ophthalmoscopic appearance of the fundus lesions: generalized PRA and central PRA (CPRA). In generalized PRA, there is generalized hyperreflectivity of the retina at the end stage of the disease, indicating a generalized atrophy of the neural retinal structures and clinical blindness. In CPRA, there are multifocal accumulations of pigment within the retina, and encircling these changes are areas of hyperreflectivity at the end stage. The latter disorder is the result of a primary defect in the RPE and does not always lead to blindness. Thus, the two disease entities represent completely different disorders. During the last few decades, PRA has been subdivided further into more specific diseases at the cellular level and also at the molecular level, and gene symbols are used to differentiate these disorders (see Appendix A). The term CPRA has been replaced by the term retinal pigment epithelial dystrophy (RPED), which more specifically relates to the disease entity.

The PRA diseases are subdivided grossly into developmental and degenerative diseases. The developmental class represents a large aggregate of genetically distinct disorders expressed cytologically during the postnatal period, when the visual cells are beginning to differentiate, i.e., dysplasia of the rod or cone photoreceptors (or both), and each has its own unique disease course and phenotype as assessed by functional and morphological criteria. Typical for the photoreceptor dysplasias is that before the retina is adult‐like (approximately eight weeks of age in the dog), they show rather severe structural alterations of the rod or cone photoreceptor cells, and the rate of progression and loss of photoreceptors in the disease process is most often rapid.

In contrast, the degenerative diseases represent defects in which photoreceptor cells degenerate after having differentiated mainly in a normal way. In the latter group, disease occurs more slowly and is modified by temporal and topographical factors. One form of primary photoreceptor degeneration (progressive rod–cone degeneration, prcd) is known to be allelic in many breeds of dog, and the underlying gene mutation has been identified. Within the photoreceptor dysplasia and degeneration groups, the diseases are subdivided still further according to the type of cell primarily affected (e.g., rod–cone dysplasia of Irish Setters and cone degeneration of Alaskan Malamutes).

Progressive Rod–Cone Degeneration

The “classical type of PRA” that is termed progressive rod–cone degeneration (prcd) has an autosomal recessive inheritance. The defect has been known for some time to be an allelic condition in many dog breeds with late‐onset type of PRA (www.optigen.com). A mutation in a previously unidentified gene, PRCD, has been identified and expression studies showed that this gene is predominant expressed in the retina, with equal expression in the RPE, photoreceptor, and ganglion cell layers (Table 13.6). Interestingly, a human retinitis pigmentosa patient was identified with an identical mutation in the human PRCD gene.

prcd in the Miniature and Toy Poodle

In the Toy and Miniature Poodles, structural and functional abnormalities in prcd do not become evident until after the visual cells have developed normally. The frequency of prcd in Poodles has been high over the years. Night blindness is the first behavioral sign, being observed in affected dogs usually at three to five years of age, but there is considerable variation in onset. Night blindness is followed by reduced vision in daylight and, finally, by complete blindness, which occurs at a variable age, usually between five and seven years. Development of a secondary cataract may exacerbate vision loss and therefore influence the age at which the condition first becomes apparent to the owner. Ophthalmoscopic fundus changes are usually advanced by the time owners have noticed vision problems (see Figures 13.16 and 13.19, and Table 13.6).

Early Retinopathy

These breeds include Bernese Mountain dog; an early‐onset retinal degeneration has been described. The disease can be detected by ophthalmoscopy and behavioral studies at approximately one year of age.

Cone Degeneration

A recessively inherited disease has been described in Alaskan Malamutes that specifically affects the cones and causes congenital day blindness (originally described as hemeralopia). Clinically, behavioral signs in affected dogs are usually apparent at 8–10 weeks of age. The affected dog shows severe loss of vision in daylight and in high levels of artificial illumination, but it becomes less insecure when taken into dim lighting conditions. Recovery of vision takes several minutes, though loss of vision on returning to bright light is immediate. No funduscopic changes are observed at any stage of disease, and the PLRs are normal in both dim and bright light. The ERG of an affected dog reveals normal rod function but an absence of cone responses. In the day blind dog, the cone contribution to the ERG, including the response to rapidly flickering lights, is lost. Flicker fusion studies are particularly valuable in diagnosing day blindness: the cone branch of the bipartite flicker fusion response curve (20–70 Hz) is usually absent, whereas the rod branch (less than 20 Hz) resembles a normal response.

Cone dystrophy has also been reported in the German Short‐Haired Pointer. Breeding studies showed that the disease in the German Short‐Haired Pointer is allelic with the Alaskan Malamute cone degeneration. A point mutation in CNGB3 was identified in German Short‐Haired Pointers. Gene therapy using an adeno‐associated viral vector to introduce a normal copy of the CNGB3 gene to affected Alaskan Malamutes and German Short‐Haired Pointers restored cone function.

The clinical condition has also been described in the Miniature Poodle and three single cases: in a Rhodesian Ridgeback cross, an Australian Cattle Dog, and a Chihuahua.

Photoreceptor Dysplasia

A condition was described in Belgian Shepherds as a form of photoreceptor dysplasia in which complete blindness was observed at eight weeks in the absence of ophthalmoscopic changes. By 11 weeks, a multifocal pattern of retinal folding or thickening was seen. The foci degenerated, and subsequently, there were hyperreflective lesions with a marked central pigmentation. The ERG was nonrecordable from at least four weeks of age.

Hereditary Retinal Dystrophy/Lipid Retinopathy/RPE65 Null Mutation/Canine Leber’s Congenital Amaurosis

In the Briard dog, an interesting retinal dystrophy (with many names) has been described. The hereditary, clinical, and morphological characteristics of the disease were elucidated in groups of inbred and outcrossed dogs in Sweden. Initially, the disease was described as congenital stationary night blindness, since it affected Briards from birth; affected dogs had nonrecordable rod ERGs, and no funduscopic changes were observed until the dogs were two to three years old. Further clinical and morphological studies showed that there was a progressive component in the disorder. The neural retina and the RPE were both affected by a retinal degenerative disease with unusually slow progression.

Clinically affected dogs were congenitally night blind, whereas daylight vision could vary from near normal to more or less severely impaired. A rapid, horizontal nystagmus was seen in most (but not all) affected pups, and it was obvious in some of the animals that they were congenitally day and night blind. The resting pupillary diameter was approximately twice as wide both in bright and in dim lighting conditions among affected dogs compared with the diameter in normal dogs.

Ophthalmoscopically, the fundus appearance in dogs up to approximately three years of age was normal. With progression, a subtle alteration in tapetal sheen was seen in affected dogs, and in certain individuals, whitish gray spots were observed in the central and midperipheral nontapetal fundus, spreading peripherally with increasing age.

Through candidate gene analysis, the defect in Briards in Sweden was discovered to be a 4‐bp deletion in the RPE65 gene. This gene defect resulted in a frameshift and a premature stop codon, which truncated the protein and resulted in no RPE65 formation in the RPE. Clinical signs of the defect in affected Briard dogs had close similarities to the human counterpart, Leber’s congenital amaurosis type II. In 2001, treating three dogs affected with the retinal dystrophy with a corrective gene construct, subretinal injections were performed using a recombinant adeno‐associated virus (AAV) carrying normal dog RPE65. Vision was improved in eyes treated subretinally as demonstrated by ERG recordings, and transmission of the retinal activity was shown by pupillometry.

Pigmentary Chorioretinopathy

A novel disease has recently been described to cause retinal impairment and blindness in the Chinese Crested Dog (CCD). The disease is bilaterally symmetrical and has been observed in CCDs from northern Europe and the United States. Affected animals have been negative for the prcd mutation, which previously has been described (www.optigen.com; www.embarkvet.com) to be prevalent in the breed. Ophthalmoscopically, in three‐ to four‐year‐old affected dogs, darkly pigmented lesions, with a light center (doughnut‐like lesions) are seen in the peripheral fundus, most easily observed in the tapetal fundus, but prevalent also in the nontapetal area.

Neuronal Ceroid Lipofuscinosis

The neuronal ceroid lipofuscinoses (NCL) are a group of recessively inherited progressive neurodegenerative diseases that are characterized by brain and retinal atrophy and associated with selective necrosis of neurons. The term ceroid lipofuscinosis is derived from the histochemical and fluorescent properties of accumulated pigment, which resembles those of the lipopigments ceroid and lipofuscin common to these diseases. They are also linked to brain atrophy, a defect not found to the same degree in other lysosomal storage diseases. These diseases affect both humans and several other animal species, such as bovine, ovine, caprine, feline, and canine. A spectrum of biochemical defects has been implicated in these disorders. Most forms reflect an accumulation of subunit c of mitochondrial ATP synthase, while in other forms there is sphingolipid activator protein storage in granular osmiophilic deposits, mainly in neuronal cells. The central nervous system (CNS) appears to be the main focus of the pathogenetic defect. NCLs have been described in several dog breeds, including the English Setter, Dalmatian, Border Collie, Tibetan Terrier, American Bulldog, Miniature Schnauzer, Polish Owczarek Nizinny, Longhaired Dachshund, and others (for reviews on the disease in various breeds, see www.caninegeneticdiseases.net). A common clinical manifestation in both humans and dogs is blindness, which occurs with a broad spectrum of neurological abnormalities caused by the accumulation of autofluorescent lipopigments in neurons and in some other cells.

The mutation for NCL in the English Setter dog was elucidated: a mutation in the CLN8 gene was found to be responsible for the disorder. A group of American Bulldogs were revealed to have NCL and a defect in the gene for cathepsin D (CTSD) was elucidated; in the Border Collie dogs, there is a mutation in the CLN5 gene (see Appendix A). Recently, mutations in the CLN2 gene in the Longhaired Dachshund and a mutation in CLN6 in the Australian Shepherd have been identified as causes of NCL. A young Miniature Dachshund with neurological signs in keeping with NCL was found to have a mutation in the PPT1 gene.

Mucopolysaccharide Storage Diseases

In both humans and animals, mucopolysaccharide storage diseases are caused by the inherited deficiency of lysosomal enzymes, and they represent generalized, multisystemic abnormalities, of which ocular lesions are but one component (see Appendix E). The lysosomal enzymes participate in degradation of glycosaminoglycans. Morphological studies have shown accumulation of intracellular inclusions in secondary lysosomes in the enzyme‐deficient RPE.

Chorioretinitis

Chorioretinitis may have various causes, including several infectious diseases, neoplasia, foreign bodies, and trauma (Box 13.2 and Table 13.7). Infectious agents may be restricted to the eye, but signs in the ocular fundus may also be part of, or secondary to, a systemic infection. In many instances, the exact cause of the inflammatory process cannot be identified. The appearance of the lesions in the fundus may give some guidance as to the etiology, but this is seldom specific. Sampling from the choroid and retina presents certain difficulties and can be associated with undesired complications. Vitreous paracentesis to obtain material for cytology and culture can be informative, but is usually reserved for patients presenting with severe posterior segment inflammatory disease.