Documenta Ophthalmologica 104: 5–16, 2002. © 2002 Kluwer Academic Publishers. Printed in the Netherlands.
Clinical electrophysiology in veterinary ophthalmology – the past, present and future RON OFRI Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
Abstract. The aim of this review is to introduce the reader to the world of clinical veterinary electroretinography. An important indication for ERG recordings in the dog is the early diagnosis of progressive retinal atrophy, an inherited form of photoreceptor degeneration, analogous to retinitis pigmentosa in humans. In most of the 20 canine breeds in which the disease has been studied electrophysiologically, changes in the ERG appear long before the appearance of clinical signs. This early diagnosis is a vital tool in efforts to eradicate the disease through preventive breeding. Pre-operative screening of canine cataract patients is another common indication for electroretinography in the dog. The ERG is also used to diagnose inherited and nutritional photoreceptor degenerations in the cat, and retinal disorders in a number of other animal species. The abundance of animal species (and breeds) seen by the veterinary ophthalmologist lends additional importance to the problem of a harmonized ERG recording protocol. The European College of Veterinary Ophthalmologists has set up a special committee to formulate guidelines for such a protocol. International meetings and wetlabs are also being organized as part of an effort to improve the quality of electrophysiological diagnosis that veterinary ophthalmologists provide their patients. Key words: animal models, cat, dog, electroretinogram, progressive retinal atrophy, retinal dysplasia Abbreviations: CSNB – Congenital Stationary Night Blindness; ECVO – European College of Veterinary Ophthalmologists; ESVO – European Society of Veterinary Ophthalmology; PRA – Progressive Retinal Atrophy
Electroretinograms (ERGs) have been recorded in animals since the 19th century, starting with the early works of Holmgren who recorded the response of excised frog eyes to light and later recordings by Dewar [1–3]. Since then ERGs, and other evoked responses of the visual system, have been recorded in numerous species of animals. These recordings have served to expand our knowledge and understanding of the anatomy and physiology of the visual system, to study pathological and disease processes in the eye, and to improve the diagnostic and therapeutic capabilities of ophthalmologists. However, it is no secret that a significant proportion of the ERG recordings conducted in animals are aimed at improving the care that is provided to human patients. Animals play a very important, indeed vital, role in ophthalmic research, but in most cases they are not the intended beneficiaries of such research.
6 An exception to this trend may be found in the field of veterinary ophthalmology. There are several hundred such specialists throughout the world, working in veterinary schools and in private referral centers. These provide professional care to a great number of species, from ‘ordinary’ pets such as the dog and cat, to horses, ruminants, birds, exotic pets and zoo animals. As in humans, these patients may suffer from a wide range of problems, including inflammations and infections of the outer and inner coats of the eye, traumas, tumors, and inherited diseases ranging from eyelid malformations to retinal dysplasia. Cataracts are routinely extracted in dogs (and replaced, in many patients, by 41D intraocular lenses), glaucoma patients undergo laser or valve implant surgery, and retinopexy is performed to reattach detached retinas. The expansion in diagnostic, medical and surgical services that are now offered to the veterinary ophthalmologist’s patient is also reflected in the field of electrophysiology. Though pattern ERGs, focal ERGs, visual evoked potentials and other specialized tests are not routinely performed in animal patients, there is hardly a veterinary ophthalmology practice that does not have equipment to record a flash ERG. Modern-day clinical electrophysiology in animals most probably began in Britain in the 1950s. Herbert B. Parry, a veterinarian working at the Animal Health Trust in Newmarket, reported in 1949 on progressive retinal atrophy (PRA) in the Irish setter breed [4]. Suspecting that this was primarily a photoreceptor disease, Parry hypothesized that the degeneration could be studied electroretinographically. He went on to evaluate the ERG of the normal dog, studying, for the first time, the effects of dark adaptation, luminance and stimulus wavelength on the canine ERG [5]. These baseline values then served Parry in his research of retinal degenerations in the dog [6–7]. As part of his investigation of PRA, Parry was the first veterinarian to test-breed affected dogs and study the development of the ERG in young puppies afflicted with PRA [6]. Thus, he was able to demonstrate a diminished b-wave in dogs 22 days old, and correlate the reduction in amplitude with rod degeneration [6]. Ten years later, veterinary visual electrophysiology made its first appearance in North America and in a different species, when Lionel F Rubin used the flash ERG to study photoreceptor atrophy in three blind cats [8]. Though the cause of the retinal degeneration in these three cats was not determined, inherited degeneration, avitaminosis A and poisoning were offered as possible etiologies [8]. It is of historical interest to note how little information is provided about the ERG recording, considering its novelty in veterinary medicine in general and in cats in particular. In his paper, Dr. Rubin mentions that cats were anesthetized and their pupils were dilated, but he does not provide any additional information about the procedure. No mention whatso-
7 ever is made of the equipment, or the stimulating and acquisition parameters [8]. Reviewers were indeed more lenient in the early 1960s! Lionel Rubin did not restrict his electroretinographic recordings to cases of outer retinal atrophy. Working with dogs presented to the Ophthalmology Service of the School of Veterinary Medicine at the University of Pennsylvania, he performed ERG recordings to differentiate between cortical and retinal causes of blindness, to evaluate glaucoma patients and to diagnose canine retinal dysplasia [9]. Dr. Rubin was also the first veterinarian to report on what is currently the most common use of the flash ERG in veterinary medicine: Screening cataract patients, most commonly dogs, prior to surgery [9]. It should be borne in mind that unlike the human patient who can notice the first signs of visual disturbance caused by the initial appearance of cataract, the canine patient is frequently brought into the clinic at a very advanced stage of the disease, when the owner notices ‘a funny color in the eye’. At this stage of the disease, fundus details are usually obscured, thus preventing a thorough retinal examination. The problem of late presentation of the canine cataract patient is compounded by the high prevalence of inherited retinal degeneration in this species. PRA is an encompassing name for a group of inherited photoreceptor degenerative and/or dysplastic diseases [10]. Canine PRA is the phenotypical equivalent of human retinitis pigmentosa (RP) [11], and serves as a spontaneous animal model for this disease [12]. Affected dogs usually possess history, clinical signs, electroretinographic abnormalities and histopathological findings characteristic of progressive rod degeneration and reduced scotopic function [13]. The disease progresses (as implied by its name), to cone degeneration and generalized retinal atrophy. Since Parry’s historic studies in the Irish setter [4–7], the disease has been shown to be hereditary in approximately 20 dog breeds [10, 14]. Unfortunately, these include some of the most popular breeds in the world, including poodles [15], English and American cocker spaniels [16] and Labrador retrievers [17]. The situation is further complicated by the fact that many affected breeds are the same breeds that suffer from inherited cataracts [18–19]. While the debate about the cause-andeffect relationship between these two diseases in some patients continues, the close association between these problems makes an electroretinographic assessment of the canine patient a prerequisite for successful cataract surgery. Since the fundus of cataractous dogs can not be thoroughly examined for the clinical signs associated with PRA, canine cataract surgery is rarely performed without a preliminary electrophysiological assessment of outer retinal function.
8 The high prevalence of PRA in certain dog breeds (in miniature poodles, for example, it can be as high as 7%) [10], is the basis for another important indication for ERG testing of canine patients: early diagnosis. As in the case of cataracts, early diagnosis of PRA is hampered by the fact that the veterinary ophthalmologist can not communicate directly with the patient. Rather, the practitioner has to rely on the owner’s sensitive perception for early presentation. Since many dogs live in familiar surroundings, such as apartments or fenced yards, they may appear to navigate quite well in their environment even though their photoreceptor function may already be severely impaired. Therefore, in many cases the patient is presented only in very advanced stages of the disease. Unless the dog is brought in for periodic ophthalmic examination, early diagnosis of PRA is rare and is usually the result of a change in the dog’s surroundings, such as moving to a new house or going on a trip. Since there is no cure for PRA, and no treatment to stop its progression, one might argue that the stage of the disease at which the patient is presented is of little relevance. However, this argument ignores one preventive option available to veterinary ophthalmologists that is generally unavailable to their M.D. colleagues-preventive breeding. Diagnosing the disease before the dog reaches sexual maturity would enable breeders to restrict the breeding of affected dogs, thus removing them from the gene pool. In several breeds affected with inherited PRA, such early diagnosis is made possible by electroretinography. In the poodle, for example, behavioral visual deficits and ophthalmoscopic lesions associated with PRA typically appear at 3–5 years of age [15]. However, impaired rod function, expressed as increased scotopic bwave implicit times and abnormal dark-adaptation curves, can be documented electroretinographically at age 8–9 months [15]. A more extreme example can be found in the miniature schnauzer. In this breed, clinical signs of PRA typically appear at age 2–5 years, while abnormal ERGs (decreased amplitudes of dark-adapted b-waves and rod flicker responses) can be recorded as early as 8 weeks of age [20]. Therefore, an exhaustive test of retinal function in young schnauzer or poodle puppies can prevent the birth of scores of affected and carrier dogs. In the Irish setter, absence of rod response, reduced and delayed cone responses, and abnormal flicker response can be detected at age 24 days [21], and in the collie an electroretinographic diagnosis can be made at age 16 days [22]. Studies into changes in ERG function of PRA-affected dogs have also been conducted in the longhaired dachshund [23], papillon [24], Tibetan terrier [25], samoyed [26] and the Labrador retriever [17, 27]. In the Norwegian elkhound, the ERG proved particularly useful in distinguishing between two forms of photoreceptor abnormalities. Rod dysplasia (rd) is characterized, electroretinographically, by absence of rod responses at a very early age,
9 followed by progressive reduction in cone responses which are abolished by 3 years of age [28]. In early retinal degeneration (erd), the b-wave fails to develop, and the ERG is dominated by an a-wave, which also diminishes with age [29]. These abnormalities reflect developmental abnormalities in the Norwegian elkhound’s photoreceptor inner and outer segments, as well as the rod and cone synaptic terminals [29]. The fact that numerous forms of PRA have been identified, distinguished by the breed prevalence, age of disease onset and the rate of its progression, points to another similarity between canine PRA and human RP. These differences are likely due to the fact that different enzymatic defects are transmitted by different gene mutations in the various breeds. In the Irish setter, a mutation in the gene for the β subunit of cyclic GMP phospohodiesterase has been shown to cause elevation in cyclic GMP levels associated with rod-cone dysplasia 1 (rcd 1) [30], while the α subunit of the enzyme is defective in the cardigan Welsh corgi [31]. Different (non-allelic) gene loci have been shown to be responsible for distinct forms of PRA in the collie (affected by rcd 2), the Norwegian elkhound (affected by rd and erd), and the various breeds (poodle, American and English cocker spaniels and Labrador retrievers) affected by progressive rod-cone degeneration (prcd) [16, 32]. Thanks to extensive genetic research conducted at the Baker Institute for Animal Health in Cornell University, DNA-based tests for some of these forms of PRA are now available commercially. As more genetic tests become available, a day may come when electrophysiological diagnosis of PRA will be obsolete! A different inherited retinal disease has been identified in the briard dog. This breed is affected by a disorder which has been variously named congenital stationary night blindness (CSNB) [33], CSNB with partial day blindness [34], or slowly progressive rod-cone dystrophy associated with retinal pigment epithelium (RPE) inclusions [35]. Genetic studies confirm that these names describe an identical disease [36], characterized by lipid accumulation in the RPE, degenerative changes in rods and varying degrees of cone atrophy [37]. Electroretinography in the briard shows severe rod dysfunction, manifested as drastically reduced a- and b-waves in dark adapted animals, and cone function impairment, manifested as reduced responses to 30 Hz white light flicker [34, 38]. There are several other indications for electroretinography in the dog. Sudden acquired retinal degeneration (SARD) is a disease in which the patient is presented with acute blindness, normal-looking fundi and dilated, unresponsive pupils. Autoimmune, dietary, toxic and endocrinological causes have been suggested, but the exact etiology remains unknown [39]. The disease is characterized by ‘silent retinas’, as no ERG responses can be elicited from affected eyes [39]. This feature helps the practitioner distinguish
10 between SARD and optic neuritis, which may have a similar clinical presentation but in which the ERG is usually recordable. Electroretinography has also been conducted in dogs with neuronal ceroid lipofuscinosis [40–42]. The cat is another species frequently seen in veterinary ophthalmology clinics, and a number of feline retinal diseases may also be diagnosed electroretinographically. Feline central retinal degeneration is a unique disease, caused by feline dependence on dietary intake of taurine [43]. Nutritional deficiency of this amino acid leads to progressive photoreceptor degeneration (as well as cardiomyopathy). As in the case of canine PRA, electroretinography can be used to diagnose the disease in suspected cats long before the appearance of funduscopic changes. Decreased photopic a- and b-wave amplitudes and increased latencies can be observed after 10 weeks of taurine deficiency [44], months before the appearance of clinical signs [45–46]. The magnitude of both the wave delay [45] and the amplitude reduction [44] were closely correlated with retinal taurine levels, proving the essential role of this amino acid in the cat. Furthermore, cone ERG abnormalities have been demonstrated even when the funduscopic lesion was very localized and non-progressive, reflecting the widespread cone damage that was present in taurine-deficient cats [47]. This emphasizes the importance of the full flash ERG in detecting widespread photoreceptor damage, even when an ophthalmoscopic examination reveals only focal abnormalities. Electroretinography also provides early diagnosis in two inherited retinal disorders in the Abyssinian cat. Inherited rod-cone dysplasia is an autosomal dominant disorder that is observed in young kittens. The ERG is barely recordable in affected 17 day old animals, though ophthalmic lesions appear only 6 weeks later [48]. The disease is characterized by dysplastic development of rod and cone inner and outer segments [48–49]. Older Abyssinians may be presented with progressive rod-cone degeneration. The first ophthalmoscopic signs usually appear at age 1.5–2 years, and advanced lesions are seen by 4 years of age [50]. The amplitudes of the a- and b-waves are depressed in the early stages of the disease; more pronounced changes in these response components, as well as in the c-wave and in the standing potential, are observed as the disease progresses [50–51]. As noted earlier, the dog and cat are but two of the many species seen, and diagnosed electrophysiologically, by the veterinary ophthalmologist. Appaloosa horses may be afflicted with CSNB, with resulting ERG changes [52]. The electroretinogram has also been used to study pigs with arsanilic acidinduced blindness [53], sheep infected with listeriosis [54] and blind cattle [55]. Obviously, the great number of breeds and species examined in veterinary ophthalmology clinics lends added importance to the problem of ERG
11 protocol standardization. The recording protocol in a given species must be adapted to the current knowledge and understanding of this species’ ocular anatomy. For example, differences in pupil size between herbivores and carnivores will have a profound effect on retinal illuminance. The existence of the tapetum, a reflective layer located in the choroid of many domestic animal species, results in increased retinal illumination that must be taken into consideration during scotopic stimulation; in the cat, its presence increases retinal illuminance by 130 times [56]. Some species, such as the garter snake [57] possess a pure-cone retina, while many of the nocturnal species have a rod-dominant retina lacking a fovea or area centralis, thus affecting the need for a test of rod or cone function. All animals must be anesthetized for a thorough ERG examination, and the effect of anesthetics on the recorded signal must also be remembered. In the dog, halothane anesthesia retards dark adaptation, reduces scotopic threshold response and b-wave amplitudes, but increases the amplitudes of the oscillatory potentials [58]. Furthermore, species may differ in their reaction to anesthetic agents, resulting in varying effects on the retinal signal. For example, morphine may be used as a sedative in dogs, but in cats and horses it causes excitement [59], leading to potentially conflicting effects on the ERG. The problem of species variation affects not only the stimulating protocol, but also the interpretation of the recorded signal. For example, in dogs anesthetized with isoflurane and dark adapted for 60 min, the mean a- and b-wave amplitudes of the maximal response are 99.3 and 316.7 µV, respectively [60]. In cats studied under similar conditions, the respective maximal values are approximately 50% higher [61]. Thus, a signal interpreted as normal in the dog would obviously be judged as being depressed in the cat. As a result of all of these problems, there is a need to establish individual testing protocols for each species that is evaluated electroretinographically. Normal baseline values, recorded in age-matched animals of the same breed under the same anesthetic protocol, must also be established for each species. Unfortunately, such protocols have yet to be formulated in veterinary medicine. This unfortunate situation has led some experts to express their concern that veterinary ophthalmologists are misusing an excellent diagnostic tool [62]. With this problem in mind, the European College of Veterinary Ophthalmology (ECVO), a body that governs the specialty in Europe, has decided to establish a special committee that will formulate recommendations for harmonized ERG protocols in veterinary ophthalmology. The committee is chaired by Prof. Kristina Narfström (College of Veterinary Medicine, University of Missouri-Colombia, USA). The committee secretary is Dr. Ron Ofri (Hebrew University of Jerusalem, Israel). Additional members include
12 Drs. Bjorn Ekesten (Swedish University of Agricultural Sciences, Sweden), Christine L. Percicot (Novartis Ophthalmics AG, Switzerland), Serge G. Rosolen (Clinique Vétérinaire Voltaire, France) and Bernhard M. Spiess (University of Zurich, Switzerland). The committee met several times during the past year, and has completed its most urgent task – drawing up guidelines for a standard flash ERG recording protocol in dogs. These guidelines have been published in this journal [63], and the committee is turning its attention to other projects including formulation of recommended protocols in additional species, anesthetic recommendations, etc. Formulating guidelines for recording protocols in a variety of species is an important undertaking, but obviously it is only one of several problems that the committee must address. Recommendations for canine ERG protocols have been published in the past [60, 64], but their impact has been limited by the fact that they did not reach a wide audience. Therefore, the ECVO ERG committee has made continuous education in veterinary visual electrophysiology, and training of ECVO members, one of its highest priorities. Towards this end, the committee organized the first European Meeting on Veterinary Visual Electrophysiology. Despite the geographic restrictions implied by the name, organizers believe it to be the first meeting of its kind held anywhere in the world. The meeting was held in May 2000 in Vienna, Austria, in advance of the annual meeting of the ECVO and the European Society of Veterinary Ophthalmologists (ESVO), and was attended by approximately 50 veterinary ophthalmologists from Europe and north America. It included lectures by two guest speakers (Drs. Mathias Seeliger of the University Eye Hospital, Tübingen, Germany, and Vittorio Porciatti of the Institute of Neurophysiology, Pisa, Italy) who introduced the audience to recent developments in visual electrophysiology [65–66], and talks by seven ESVO & ECVO members who presented research and clinical findings in the field [67–73]. Kristina Narfström presented the recommended guidelines for recordings in dogs, and chaired a group discussion of these recommendations [74]. Following the success of the meeting in Vienna, it was decided to hold a second meeting devoted to veterinary visual electrophysiology. This meeting was once again held in advance of the annual ECVO & ESVO meeting that took place in Stockholm, Sweden, in August 2001. It included guest lectures by Kristina Narfström, Geoffrey Arden (City University, London, Great Britain), and Mathias Seeliger, as well as an afternoon of practical ERG wetlabs. Veterinary visual electrophysiology was also the topic of a special session, organized by Serge Rosolen, at the 2001 ISCEV meeting in Quebec. Similar sessions and wetlabs are planned in conjunction with future meetings of the American College of Veterinary Ophthalmology; interested north American ISCEV members may contact me for additional details.
13 In conclusion, 2002 promises to be a memorable year in veterinary visual electrophysiology. It commences with the publication of this special issue of Documenta Ophthalmologica, and continues with two planned international meetings, and the formulation of guidelines for ERG recordings in additional species. It is hoped that these efforts will eventually enable us to provide better care to our animal patients. Acknowledgements I would like to thank Profs. Gustavo Aguirre (Cornell University, New York) and Kristina Narfström (Swedish University of Agricultural Sciences, Sweden) for their helpful insight, comments and advice. References 1. 2. 3.
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Addresss for correspondence: R. Ofri, Koret School of Veterinary Medicine, Hebrew University of Jerusalem, PO Box 12, Rehovot 76100, Israel Phone: +972-3-9688554; Fax: +972-3-9604079; E-mail:
[email protected]
