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HEREDITARY EYE DISEASE AND THE
BVA/KC/ISDS EYE SCHEME
The main purpose of the British Veterinary Association/Kennel Club/International Sheep Dog Society Eye scheme is to ensure that there is no evidence of hereditary eye disease in dogs used for breeding. In order to achieve this aim it is important that not only all the dogs which are to be used for breeding are examined under this scheme, irrespective of whether there are known inherited eye problems within the breed, but that the scheme is kept under active review with regard to the inherited eye diseases and breeds which should be included. This review is currently considering the Bullmastiff. The conditions currently certified under the scheme are reviewed in this article. They comprise the congenital inherited conditions of
For some of the congenital inherited problems, litters of puppies are screened to establish the status of the whole litter. For dogs of any age, individual certificates are issued with respect to the known inherited eye diseases for the breed under examination.
goniodysgenesis/primary glaucoma
Glaucoma is the term used to describe the effects of intraocular fluid pressure. The clinical features shown are those which are the result of structural ocular damage and the consequent impairment or loss of sight. In particular, it is the optic neuropraxia which is the most significant feature in sight loss, rendering glaucoma an emergency situation if blindness is to be avoided. Once the process of optic nerve degeneration has begun, the most any effective therapy can achieve is retardation of the loss of sight.
Glaucoma is not a single disease entity, but rather a degenerative process which can result from a number of causes. As in man, two broad categories of glaucoma may be described in the dog - the primary and secondary glaucomas. Primary glaucoma denotes an inherent defect within the aqueous drainage pathway and in some breeds the defect is considered to be inherited; the modes of inheritance have not been determined, but clear breed and line dispositions indicate a genetically determined cause. The secondary glaucomas are associated with uveitis, primary lens luxation, trauma and neoplasia.
Although the aetiology is complex, all the canine primary glaucomas are due to impairment or cessation of aqueous outflow from the anterior chamber of the eye. Aqueous outflow is through the iridocorneal angle and in the dog the angle is extended posteriorly into the ciliary body as the ciliary cleft. It is within the ciliary cleft that the trabecular meshwork is found and the canine equivalent of the primate canal of Schlemm, the aqueous plexus, is situated in the scleral tissues which form the outer wall of the cleft. It is a defect of the iridocorneal angle and the structures associated with the ciliary cleft that is responsible for the rise in intraocular pressure in primary glaucoma.
Normal healthy eyes for comparison. (left) External eye. 9middle) Fundus - the tapetal fundus, non-tapetal fundus, optic disc (papilla) and retinal blood vessels are all apparent. This appearance is typical of dogs with a dark iris. (right) Fundus - lack of tapetum is a normal feature of the subalbinotic eye so that the choroidal vessels and white colour of the sclera are visible in addition to the retinal vessels of the optic disc. This type of appearance is typical of dogs with a pale iris (blue merle)
CLASSIFICATION - The classification of primary glaucoma is based upon the appearance of the iridocorneal angle as determined by gonioscopy. A suitable lens is placed on the anaesthetised cornea and the magnified view of the angle allows detailed examination of the entrance to the ciliary cleft. Currently, two types of primary glaucoma may be distinguished, angle-closure and open-angle glaucoma. This nomenclature has been borrowed from human medicine and, although acceptable, it does not describe the situation as completely as possible. When these terms are used to describe primary glaucoma in the dog, they denote the appearance of the entrance to the ciliary cleft. Thus, in the angle-closure glaucoma the cleft is closed and in open-angle glaucoma, the cleft is open.
ANGLE-CLOSURE GLAUCOMA - In the normal dog, the ciliary cleft entrance is between 1.5 & 2mm in width and is spanned by a number of iris root fibres, collectively known as the pectinate ligament. Dogs which develop primary angle-closure glaucoma demonstrate a congenital predisposition in that the entrance to the ciliary cleft is much narrower than normal and both eyes are affected. The pectinate ligament is dysplastic and may be seen as sheets of undifferentiated mesodermal tissue rather than the normal fibrous processes. A narrowed angle with pectinate ligament dysplasia is referred to as goniodysgenesis. In the UK, the breeds in which the angle closure glaucoma is considered to be inherited and which are certified under the Eye Scheme are the Basset Hound, English and American Cocker Spaniels, Welsh Springer Spaniel and Flat Coated Retriever and Siberian Husky. The possibility of primary disease is also being investigated in dogs a s diverse as the Dandie Dinmont and the Great Dane. The age of onset tends to vary with breed but, in most, the disease is one of middle age. Gonioscopy can be used as a method of screening out the predisposed animals in the affected lines within susceptible breeds before the disease makes its appearance. Routine gonioscopy can be completed by 5 -6 months of age in most breeds and the avoidance of breeding from dogs with goniodysgenesis has proved to be an effective method of disease control.
OPEN-ANGLE GLAUCOMA - Here, glaucoma is a chronic disease as a result of a low grade rise in intraocular pressure. The iridocorneal angle remains open until the final stages of the disease and it has been suggested that the impairment of the aqueous outflow is due to a defect within the trabecular meshwork and/or the inner scleral tissues. The disease is silent in onset and, whereas defective vision heralds its appearance in man, it is globe enlargement or partial blindness which first draws attention to the canine patient. The most notable breeds which suffer from this form are the Miniature Poodle and the Elkhound. This variant of the disease is not currently certifiable.
Goniodysgenesis predisposes dogs to a painful and sight threatening disease. As treatment of glaucoma is often unsatisfactory for a number of reasons - not least the impossibility of reversing damage which has already occurred - examination of susceptible breeds under the Eye Scheme is essential in order to prevent breeding from affected dogs.
The pupillary membrane consists of mesenchymal tissue and associated mesodermal vascular arcades ( irido-pupillary vessels ) which completely occlude the pupil in utero; the vessels anastomose with the network of blood vessels known as the tunica vasculosa lentis anterioris which surrounds the lens. During the last three weeks of fetal development this tissue undergoes spontaneous degeneration and, in most puppies, atrophy is complete six weeks after birth. Persistence of the pupillary membrane is a common phenomenon in many breeds of dog, but only in the Basenji has the defect been demonstrated to be an inherited one; the Basenji is, therefore, the only breed currently certified for persistent pupillary membrane under the Eye Scheme. However, it is under investigation in the Bullmastiff, Miniature Wire Haired Dachshund, Lancashire Heeler, Petit Basset Griffon Vendeen, Rottweiler, Siberian Husky, Cocker Spaniel and west Highland White.
The extent and severity of pupillary membrane persistence varies. Mild involvement is typified by pigmented strands of mesodermal tissue arising from the iris collarette ( center of iris ) which bridge the anterior surface of the iris, or cross the pupillary aperture forming iris to iris attachments. These remnants occur as a single strand or as a cobweb-like mesh of several strands linked centrally. Occasionally, strands of tissue can be seen attached at one end only. Extensive forms of pupillary membrane persistence involve mesodermal remnants which attach to the corneal endothelial surface, anterior lens capsule, or both. Focal corneal opacities result from pigment deposition and endothelial fibroplasia, but the lesion or lesions , are generally small and non-progressive. Corneal opacities may appear extensive when the eyes open in puppies, but become less dense and do not enlarge as the cornea grows. a more severe form is seen occasionally in which the whole cornea has a bluish-white opacity due to endothelial disruption by extensive pupillary membrane remnants; this form is encountered rarely in the Basenji. Opacities of the anterior lens capsule are similar to the common type of corneal opacity in that they are small, focal, single or multiple and non-progressive and, as such, are unlikely to cause any visual impairment.
Persistent pupillary membrane is a condition which is unlikely to be associated with an obvious visual defect and for which treatment is unnecessary in the majority of cases. Its significance largely rests with the genetic implications. Although the incidence in the Basenji is high, about 50%, the severe forms are uncommon and the mode of inheritance is unclear. The condition does not follow a simple pattern of inheritance and it is sometimes difficult to distinguish a slightly affected dog from the normal dog.
persistent hyperplastic primary vitreous
The embryonic lens is supplied with nutrient by the hyaloid artery ( which grows forward from the optic stalk to reach the posterior lens surface at about day 25 of gestation ) and the tunica vasculosa lentis ( which is formed by day 30 of gestation ). Regression of the vascular supply starts at about day 45 of gestation and is complete some two to four weeks after birth. Persistence of these vessels and proliferation of associated mesodermal elements of the tunica vasculosa lentis posterioris produce the main lesion of fibrovascular plaque formation on the posterior lens capsule. This plaque appears as a dense yellow/white opacity with multiple pigment foci attached to the posterior lens capsule. Blood vessels maybe visible within the plaque and at its periphery. Other features of persistent hyperplastic primary vitreous include persistent capsulopupillary vessels ( iridohyaloid vessels ), coloboma of the lens, posterior lenticonus, intralenticular and retrolental hemorrhage, secondary cataract, persistence of the hyaloid artery and Bergmeisters papilla, ( remnant of the glial sheath around hyaloid vessels on the optic disc )and retinal dysplasia.
Currently the Doberman and Staffordshire Bull Terrier are certified under the Eye Scheme. The mode of inheritance is complex, but the genetic data available suggest an autosomal dominant gene with variable or incomplete penetrance.
Severe lesions cause marked visual loss or blindness. Milder cases of retrolental plaque formation spare the lens periphery and allow adequate vision. Although these milder lesions tend not to cause progressive cataract formation in the Staffordshire, cataracts in affected Dobermans often progress to severe impairment or blindness. The Staffordshire also suffers less from the posterior lens capsule deformities, but has more widespread folds or retinal rosettes then the Doberman. The condition is not common in either breed within the UK, but represents a serious congenitally inherited problem requiring constant vigilance. Surgical treatment of those cases with visual problems is fraught with difficulty and there is a high risk of post-operative complications.
The term retinal dysplasia embraces a number of congenital conditions resulting from disorderly proliferation and atypical differentiation of the retina during embryonic life. In addition to genetically determined hereditary retinal dysplasia, a wide variety of extraneous insults (e.g. infectious agents such a canine herpesvirus) to the developing retina may cause acquired , non-inherited retinal dysplasia. Defective retinal development results in extremely varied clinical and microscopical appearances so that, for example, folds, ridges, rosettes, geographic abnormalities and localized detachments are all possible in multifocal retinal dysplasia whereas total retinal dysplasia is most commonly associated with non-attachment of the retina.
MULTIFOCAL RETINAL DYSPLASIA - Linear folding of the sensory retina and the formation of rosettes composed of variable numbers of neuronal cells are the hostological characteristics of MFR. Typically the lesions range from vermiform grey streaks to multiple focal sites of tapetal hyperrreflectivity hitch may or may not be associated with hypertrophy
The incidence of Collie eye anomaly in the UK is high in the Rough Collie, Smooth Collie and Shetland Sheepdog, with the Border Collie much less affected. The condition has a worldwide distribution and ocular lesions of identical ophthalmoscopic appearance have been described in a number of other non-collie breeds, such as the Australian Sheepdog. The classical lesion is of choroidal hypoplasia in the lateral or dorsolateral region of the fundus near the optic disc. In some animals the hypoplasia may be more extensive and it is not uncommon for the two eyes to be dissimilar. The lesion is apparent as a “pale patch” and is due to a localized lack of some, or all, retinal and choroidal pigment and tapetum. The choroidal vessels in the affected region are also abnormal, usually in size, number and disposition. In merle dogs, with little fundic pigment and no tapetum, choroidal hypoplasia will be less obvious and the appearance of the choroidal vessels then becomes the important diagnostic feature. In addition to choroidal hypoplasia there may be papillary and peripapillary colobomas, and the colobomatous defects can sometimes be the only abnormality in susceptible breeds. Retinal detachment and intraocular haemorrhage are fortunately rare; thus the majority of dogs with collie eye anomaly show no apparent visual defect.
Tortuosity of the retinal vessels and retinal folds, the latter usually in the form of vermiform streaks, are not now regarded as part of the syndrome, but may relate to the smallness of the eye. There has been no detailed investigation of eye size in relation to collie eye anomaly.
Most studies indicate that collie eye anomaly is caused by a simple autosomal recessive gene with pleitropic effects. (Pleitropy is where specific genes influence more than one character). The situation with regard to colobomatous defects and collie eye anomaly remains unclear and, in a proportion of the “at risk” breeds, these are the only ocular abnormalities detectable with an ophthalmoscope. It has been suggested that adult dogs in this category may be “go normals”. The inappropriate term “go normal” has been applied to cases where post natal development (pigmentation and tapetal development) obscures the choroidal hypoplasia which is the key diagnostic feature, so that adult dogs have a fundus of normal appearance. The phenomenon is common enough to call into question the relevance of examining dogs as adults rather than as puppies. Data on collie eye anomaly in the rough collie in Norway, for example, has indicated that the diagnosis of the condition in a group of dogs of more than three months of age was almost half that for a group of puppies of seven weeks to three months of age. Furthermore, when puppies which had been diagnosed as having collie eye anomaly with mild choroidal hypoplasia at between seven weeks and three months of age were re-examined at about one year of age, 68 per cent has a fundus of normal appearance.
Significance
Despite a variety of fundamental issues combining to make this a frustrating problem for breeders and veterinary ophthalmologists alike, it is worth emphasizing that collie eye anomaly is a congenital condition which can be diagnosed as soon as eye examination is possible (i.e. at five to six weeks of age), and that it is diagnosed with greatest accuracy in such young dogs. There is little doubt that in those breeds examined under the Eye Scheme (border collie, rough collie, smooth collie and Shetland sheepdog), litter screening, combined with detailed pedigree analysis and the judicious use of test mating are the best means, albeit imperfect, at attempting to establish clear lines at present. That said, the high incidence of collie eye anomaly in the UK in all but the border collie has produced a situation which will be difficult to change until modern techniques enable the genetic defect to be identified. The possibility of using DNA-based techniques to establish genetic status would obviously be the most desirable future development
The canine lens is an asymmetrical, transparent, biconvex sphere, with the more convex aspect posterior. The adult lens consists of a central nucleus surrounded by cortical lens fibers and the nucleus itself is divisible into various regions according to age: the oldest, central portion of the lens is the embryonic nucleus; surrounding that is the embryonic nucleus; surrounding that is the fetal nucleus; and the outermost portion is the adult nucleus. The whole lens is contained within an acellular capsule (the anterior capsule is thicker than the posterior capsule). A single layer of epithelial cells lies immediately beneath the anterior capsule and it is these cells which form the germinal cell layer that produces new lens fibres throughout life. The epithelial cells migrate peripherally and elongate at the equator (circumference) of the lens. Each fibre extends anteriorly and posteriorly to meet fibres to the front and rear to form the suture lines. The suture line form an upright “Y” anteriorly and an inverted “Y” posteriorly.
Cataract is defined as any opacity of the lens or its capsule. There are many reasons for cataract formation – they may be congenital, due to in utero insult; traumatic, as a result of blunt or penetrating injury to the eye; metabolic, as a consequence of, for example, diabetes mellitus; toxic, caused by some drugs; nutritional, produced by inappropriate diets; or a complication of other primary ocular diseases such as uveitis and neoplasia.
A number of cataracts have been demonstrated to be inherited and it is these with which the Eye Scheme is concerned. Fortunately, the age of onset, appearance and evolution of the cataracts which are certified under the scheme are usually quite specific within the affected breeds (see table on the right), enabling inherited cataracts to be distinguished from cataracts to be distinguished from cataracts from other causes. At present, congenital cataract in the miniature schnauzer is the only congenital inherited cataract included in the scheme, the remainder are non-congenital types.
In addition to those cataracts currently included in the scheme, there are a number of other cataracts in a variety of breeds which are the subject of further investigation to see if there is sufficient evidence of inheritance for future incorporation within the scheme (see table above).
Significance.
Quite apart from the undesirable perpetuation of abnormality within breeding lines, a proportion of inherited cataracts progress to produce visual impairment and blindness. The only treatment for cataract is by surgical removal and, although modern techniques give good results, the procedure is expensive.
Primary Lens Luxation is a condition in which an inherent defect in the zonule leads to partial or complete dislocation of the lens at approximately four to five years of age; clinical signs are not usually observed before three years of age or later than seven years of age. It is a common cause of secondary glaucoma and, as such, an important disease to recognize because of the potential for pain and visual loss. Primary lens luxation is recognized as a familial problem in certain of the terrier breeds (miniature bull terrier, smooth fox terrier, wire fox terrier, Parson Jack Russell Terrier and Sealyham Terrier), the Tibetan terrier (which is not a true terrier breed) and Border Collie. Although literature is incomplete, the evidence would appear to support a recessive mode of inheritance in most breeds exhibiting primary lens luxation.
The condition is essentially bilateral, but almost invariably presents a uniocular condition as one eye may be affected weeks or months in advance of the other. Observant owners may notice a change in the appearance of the affected eye which correlates with the lens moving out of its normal position. When the lens moves anteriorly, secondary glaucoma develops rapidly and pain, blepharospasm, photophobia and lacrimation, an increase in intraocular pressure, together with a widely dilated non-responsive pupil, visual loss and episcleral and conjuctival congestion, are most obvious clinical features. With posterior lens luxation, secondary glaucoma is less likely, although most lenses will move forward at some stage. Careful observation will reveal the displaced lens (usually the lens equator is highlighted by the penlight used for examination). In addition, the iris trembles slightly with head and eye movement (iridodonesis) because it has lost the support of the lens.
Significance
Primary lens luxation is an inherited problem which can cause persistent pain and blindness without prompt surgical intervention to remove the lens (the only recommended treatment for lens luxation associated with secondary glaucoma). Affected dogs should not be bred from and the “at risk” breeds that are to be used for breeding should be examined under the Eye Scheme.
generalised progressive retinal atrophy
Generalized progressive retinal atrophy is an inherited disease which affects many breeds of dog. Those breeds which are currently certified under the Eye Scheme, together with the approximate age at which an ophthalmoscopic diagnosis can be made, are listed in the table. There are two main types of generalized progressive retinal atrophy – rod/cone dysplasia and rod/cone degeneration. The clinical and ophthalmoscopic signs for the two types are similar. In a breed such as the Irish Setter, with rod/cone dysplasia, the photoreceptors are abnormally formed and begin to degenerate before they are mature. The disease, therefore, affects these dogs at a relatively young age. A DNA-based test for the gene mutation is available and enables accurate identification of clear, carrier and affected animals, but the Irish setter is the only breed for which the test is currently available. The age of onset is later in, for example the rod/cone degeneration of the miniature and toy poodle, as the photoreceptors degenerate after reaching maturity.
Owners usually notice a loss of night vision, especially when the dog is in unfamiliar surroundings. The condition progresses to produce a loss of vision under all lighting conditions and there is a poor pupillary light reflex with dilated pupils. In time, secondary cataract formation is common. Ophthalmoscopic examination indicates a generalised, bilaterally symmetrical increase in tapetal reflectivity (a consequence of retinal atrophy). There is attenuation (narrowing) of the retinal vessels, especially the small peripapillary arterioles, which may become barely visible (“ghost vessels”) or disappear completely. In dogs with a poorly developed tapetum or an atapetal fundus, the attenuation of the retinal vessels may be the only obvious ophthalmoscopic sign of early generalised progressive retinal atrophy, necessitating careful observation. Later in the course of the disease the optic disc becomes paler due to atrophy of its capillaries and nerve fibers. The non-tapetal fundus also shows extensive areas of depigmentation as the condition progresses. The cataracts, which form late on in the condition, may manifest as opacities in the posterior cortext or as radial opacities, before progressing to total cataract.
Significance
There is no cure and the condition is one which progresses to total blindness. In all the breeds that have been investigated in sufficient detail the mode of inheritance appears to be a simple autosomal recessive.
central progressive retinal atrophy
Central progressive retinal atrophy is a disease of the retinal pigment epithelium cells, for which a better descriptive title is retinal pigment epithelial dystrophy. The breeds at present certified under the Eye Scheme are the border collie, smooth collie, golden retriever, Labrador retriever, Shetland sheepdog, cocker spaniel, English springer spaniel and Welsh Cardigan spaniel. Ophthalmoscopic signs may be detected on occasion in dogs of just over twelve months of age, but it is more usual to make diagnosis from about 18 months of age onwards. Electoretinography is not of value in early diagnosis.
The disease is caused by the inability of the retinal pigment epithelial cells to degrade spent photoreceptor metabolites, with the resultant accumulation of lipopigment within the retinal pigment epithelium. There are focal concentrations of lipopigment-laden cells which migrate into the true retinal layers. Degeneration of the photoreceptors (rods and cones) is secondary to the lipopigment accumulation and retinal pigment epithelial cell malfunction.
In dogs of working breeds, he owner may notice an inability to work in bright light, while vision in dim light may be adequate until the disease is advanced. In pet dogs, suspect vision may not be noticed as early. Affected dogs may exhibit a central visual defect, but the pupillary light response is often reasonable and complete blindness is unusual.
Ophthalmoscopic examination of early cases indicates light brown foci in the tapetal fundus. These become more numerous and eventually coalesce into larger areas of lipopigment with hyperreflective areas between. In advanced cases the pigment becomes less obvious as hyper reflectivity increases. The retinal blood vessels may become attenuated late in the disease, but the appearance of the non-tapetal fundus and optic disc alters little. Both eyes are affected.
Significance
Unlike general progressive retinal atrophy, central progressive retinal atrophy rarely causes blindness and secondary cataract formation is also unusual. However, when the disease develops in a working dog, the effects are predictably serious. The inheritance of the disease appears complex, and environmental factors (for example poor diet) may influence the phenotypic expression. Until more information is available it is prudent to advise against breeding from affected dogs and their relatives. Significantly, the incidence of central progressive retinal atrophy in ISDS registered dogs tested under the Eye Scheme has fallen from 14 per cent to less than 0.25 per cent over a period of 20 years.
Summary
The BVA/KC/ISDS Eye Scheme offers a means of identifying the presence or absence of inherited eye disease in a variety of dog. There is no doubt that conscientious breeders wish to use sound stock with known freedom from inherited eye disease. All those involved in small animal practice can help to achieve this ideal by:
§ Checking puppies’ eyes when they come for their first vaccination;
§ Informing per owners about the Eye Scheme; and
§ Ensuring that breeders recognize the need for eye examination in any dog which is to be used for breeding.
Up to date information on the Eye Scheme, which includes the conditions certified in individual breeds and under investigation in a variety of breeds, is published annually in The Veterinary Record.
