Revised from 6th edition of Veterinary Ophthalmology, Chapter 20: The Canine Glaucomas, by Caryn E. Plummer, András M. Komáromy, and Kirk N. Gelatt The definition of glaucoma in the dog has evolved during the past seven decades, reflecting our better understanding of this disease group. William Magrane, who first investigated the canine glaucomas in some detail during the 1950s, wrote, “Glaucoma, whether it be in man or beast, is not in itself a disease entity. It, rather, consists of a ‘wastebasket’ group of diseases which have as their common feature an abnormal elevation of intraocular pressure (IOP). This group may be referred to as the glaucomas.” Peter Bedford in 1974 described glaucoma as “a disease process of complex etiology, in which elevation of the internal fluid pressure (IOP) of the eye results in destruction of ocular structures and function.” Recent definitions of the glaucomas in humans have described the glaucomas as “an ocular disorder characterized by the progressive loss of retinal ganglion cells (RGC) and their axons, accompanied by gradual loss of the visual field.” While this description is most appropriate for primary open‐angle glaucoma, it is not so accurate for the other 25 or so types of primary and secondary glaucomas. In veterinary ophthalmology, the 20 or so thus recognized different types of glaucomas in animals always include elevated internal fluid pressure (IOP), which have adverse visual effect on the retinal ganglion cells (RGCs), but very high IOP also affects all of the retinal layers. While primary open‐angle glaucoma has its primary characteristic of a slow increase in IOP and cupping of the optic nerve head (ONH), and initial damage to the peripheral RGCs, our more common clinical glaucoma in dogs (primary narrow/closed glaucoma) has as its dominant clinical sign an abrupt and very high elevation in IOP and damage to all of the retinal layers. As a result, the veterinary definition of glaucoma for animals is a little different, but the major focus is still the RGCs! The different type of IOP elevations (slow progressive IOP elevations over several years versus acute very high elevation in IOP over hours, days, or a few weeks) may influence the ocular tissues differently but eventually result in the loss of vision! Martin in 1977 reported the prevalence of the canine glaucomas as 0.5% using the Veterinary Medical Database, and the Canine Eye Registry Foundation lists a large number of predisposed breeds. Two studies in 2004 determined that the prevalence of the primary or breed‐related glaucomas and secondary glaucomas in dogs presented to the veterinary teaching hospitals in North America over about four decades has been gradually increasing. Prevalence range for the breed‐related or primary types increased from 0.29% (1964–1973), 0.46% (1974–1983), 0.76% (1984–1993) to 0.89% (1994–2002). Predisposed breeds varied by decade, but the American Cocker Spaniel, Basset Hound, Wire Fox Terrier, and Boston Terrier were constantly high from 1964 through 2002. Although 27 breeds were presented with glaucoma above the baseline of mixed‐breed dogs (0.71%), those breeds with the highest prevalence during 1994 through 2002 were American Cocker Spaniel (5.52%), Basset Hound (5.44%), Chow Chow (4.70%), Shar‐Pei (4.40%), Boston Terrier (2.88%), Wire Fox Terrier (2.28%), Norwegian Elkhound (1.98%), Siberian Husky (1.88%), Cairn Terrier (1.82%), and Miniature Poodle (1.68%). Gender effect varied among breeds by decade, and in some breeds females were more often affected (i.e., American Cocker Spaniel, Basset Hound, Cairn Terrier, English Cocker Spaniel, Jack Russell Terrier, Norwegian Elkhound, Samoyed, and Siberian Husky). Age of presentation with these glaucomas varied by breed but was generally between 4 and 10 years. Of the top 27 breeds identified, only about 8 breeds with possible inherited glaucoma have been investigated in any detail and reported in the literature. Studies of the canine glaucomas are very expensive and long duration; fortunately, with some breeds’ genetic mutations discovered, these tests can be applied rather inexpensively to other breeds. The prevalence of the secondary glaucomas in the dog in North America from 1964 to 2002 also varied by decade: 0.25% (1964–1973), 0.46% (1974–1983), 0.79% (1984–1993), and 0.80% (1994–2002). The secondary glaucomas investigated were not inclusive and focused on those associated with cataract formation, lens luxation, cataract surgery, uveitis of unknown cause, hyphema of unknown cause, and intraocular neoplasia. To ensure these patients had secondary glaucoma, the preexisting condition (e.g., cataract, lens luxation, etc.) was diagnosed prior to the onset of the ocular hypertension. The secondary glaucomas associated with cataract formation and lens‐induced uveitis represented 81% of the total secondary glaucomas. The prevalences of the secondary glaucomas from the other causes were less: lens luxation (12.0%), postcataract surgery (5.1%), uveitis of unknown cause (7.1%), hyphema of unknown cause (7.3%), and intraocular neoplasms (3.5%). Thus, the combined prevalence of the primary or breed‐related and the secondary glaucomas in the dog during the past decade was 1.7%, which is comparable to the estimated 1–2% worldwide prevalence of the glaucomas in humans. The largest series of the canine primary glaucomas reported is based on the US College of Veterinary Medicine Teaching Hospitals. Smaller but important epidemiology studies are available from university‐based patients. These reports, like those in human medicine describing patient populations in small cities, islands, or countries, provide important information on the prevalence of the specific types of glaucomas, breeds of dogs predisposed, possible geographic differences, and other factors. The Vienna study in 1982 published four reports on the glaucomas in the dog based on patients at the Vienna Small Animal Hospital during 1975–1980, which included a total of 167 dogs. Primary glaucoma affected 51 dogs (30.5% of the glaucoma dogs; 84 eyes). The breeds and number of 167 affected dogs included the Miniature Poodle – 99 (Pudel), Fox Terrier – 9, Welsh Terrier – 8, Japanese Terrier – 7, English Cocker Spaniel – 6, Bastard – 6, Dachshund – 5, American Cocker Spaniel – 2, Bernhardiner – 2, Deutsche Schäferhund – 2, Airedale Terrier – 2, Mittelschnauzer – 2, and other breeds – 17. The fourth publication of this series included 116 dogs with secondary glaucomas. Causes for the secondary glaucomas included, in part, cataract, trauma, uveitis, zonular defects and lens displacement, chorioretinitis, intraocular tumor, uveokeratitis, corneal perforation, progressive retinal atrophy, aphakia, Collie eye anomaly, and retrobulbar tumor. The Utrecht study in 1985 reported on the canine and feline glaucoma patients during a four‐year period at the University of Utrecht based on 421 patients (379 dogs and cats), which accounted for 8.6% of all of the small animal clinic patients. Primary glaucoma occurred most frequently in the American Cocker Spaniel, Bouvier, Basset Hound and Basset Artésien Norm, Beagle, Duitse Dog and Duitse Herder, English Cocker Spaniel, and Toy and Miniature Poodle breeds. The secondary glaucomas were grouped into those secondary to lens dislocations, iritis or uveitis, trauma, tumor, and post‐lens extraction. Of the secondary glaucomas, 182 had lens dislocations and were concentrated in the small terrier breeds. Another report was from the University of Zurich in 2011: 4 congenital, 123 primary, and 217 secondary cases of canine glaucoma were documented from a period of 1995 through 2009. Primary glaucoma occurred with an overall male to female ratio (M:F) of 1:1.41, and the age of onset ranged from 0.12 to 18.3 years (mean 7.3 ± 3.6 years). Breed predisposition occurred in the Siberian Husky, Magyar Vizsla, and Newfoundland. The secondary glaucomas affected dogs ranging in age from 88 days to 19 years (mean 7.7 ± 3.6 years), and accounted for 3.6% of all ophthalmology patients seen at the University of Zurich. Breed predisposition for the secondary glaucomas occurred in the Cairn Terrier (ocular melanosis), Jack Russell Terrier (lens displacement), and English Cocker Spaniel breeds. Most of those eyes with bilateral disease shared the same risk factor (anterior uveitis or lens luxation). Causes identified with the secondary glaucomas included anterior uveitis (23.0%), lens luxation (22.6%), intraocular surgery (13.4%), intraocular neoplasia (10.6%), unspecified trauma to the globe (8.3%), ocular melanosis (6.9%), hypermature cataract (6.9%), and hyphema (3.23%). Finally, a recent five‐year study from the University of California, Davis reported that the secondary glaucomas in the dog occurred in 156 of 2257 (6.9%) animals examined because of ophthalmic disease and affected both eyes in 33 (21.2%) of these dogs at first presentation. The most common causes of secondary glaucoma were nonsurgical anterior uveitis (44.9%), anterior uveitis associated with prior phacoemulsification (15.8%), and lens dislocation (15.2%). Certain breeds were predisposed to the secondary glaucoma and included Parson Russell Terriers, Toy and Miniature Poodles, Boston Terriers, American Cocker Spaniels, Rhodesian Ridgebacks, and the Australian Cattle Dogs. Based on the specific breed predilection of primary glaucomas, a genetic etiology is suspected to be responsible, and affected dogs should be excluded from breeding. Despite the high prevalence of primary glaucomas in dogs, genetic etiologies have been studied in only a relatively small number of breeds. Primary angle‐closure glaucoma (PACG) is the most common form of primary, breed‐related canine glaucomas, suggesting a genetic etiology. Many breeds have been studied, with the highest prevalences documented in the American Cocker Spaniel, Basset Hound, Chow Chow, Siberian Husky, Shiba Inu, Shih Tzu, Magyar Vizsla, and Newfoundland. Because a simple mode of Mendelian inheritance could not be identified in most canine breeds studied, PACG appears to be a complex trait with multiple suspected genetic and environmental risk factors contributing to the disease. The possible exceptions are Welsh Springer Spaniel with a proposed autosomal dominant trait, as well as Siberian Husky and Basset Hound with suggested autosomal recessive inheritance. PACG genetics has been investigated most extensively in the Basset Hound, thanks to the availability of a closed colony with informative pedigree. Genome‐wide association study has revealed three genetic loci as possible contributors to the PACG phenotype in this breed with the following three positional candidate genes: COL1A2, RAB22A, and NEB. All three have been shown to be expressed in the anterior segment of the eye where they may play a role in aqueous humor outflow. While COL1A2 (encoding the pro‐alpha 2 chain of type I collagen) is a promising PACG candidate gene due to the suspected involvement of collagen and other extracellular matrix components in the PACG pathogenesis, subsequent studies focused on NEB, which encodes for nebulin, a protein that is expressed in the ciliary muscle where it may regulate muscle contractility. It is possible that changes in nebulin and its function may alter muscle function and thereby contribute to PACG development. The disease‐associated NEB allele is commonly found in the Basset Hound population: 88% of PACG‐affected Basset Hounds are homozygous for the NEB risk allele; the remaining 12% are heterozygous. Among PACG‐unaffected Basset Hounds, 33% and 44% are homozygous and heterozygous for the NEB risk allele, respectively, while 22% are homozygous for the non‐risk allele. The identification of the NEB risk allele in the Basset Hound represents a significant progress toward the better understanding of canine PACG; however, it remains a complex disease since not all of the homo‐ and heterozygous animals develop glaucoma; additional genetic and environmental factors likely contribute. Progress in the understanding of canine PACG genetics has been made in other breeds as well, and investigations are ongoing. In Shiba Inus and Shih Tzus, SRBD1 was identified as a PACG risk gene. It encodes for S1 RNA‐binding domain and has been associated with human forms of primary glaucoma; however, its function remains unknown. In the Dandie Dinmont Terrier, a 9.5‐megabase region on canine chromosome 8 has been identified as susceptibility locus for canine PACG; no specific disease gene has been identified yet. Goniodysgenesis or pectinate ligament dysplasia (PLD), combined with the narrowing of the iridocorneal angle (ICA) and ciliary cleft, is a well‐recognized risk factor of PACG. The inheritance of PLD and the width of the ciliary cleft have been studied in a number of dog breeds, such as English Springer Spaniel, Flat‐Coated Retriever, Great Dane, and Samoyed. Quantitative polygenic traits are most likely, based on the observation that both the severity of PLD and narrowing of the ciliary cleft worsen with the degree of kinship in PACG‐affected animals. Breeding of only animals with normal ICAs led to a reduction in the presence and degree of ICA abnormalities in the English Springer Spaniel. The Bouvier des Flandres is the only breed to date where a recessive inheritance of PLD has been proposed. Because much remains unknown about the link between the presence of PLD and glaucoma development and the genetics of PLD, there is no consensus between veterinary ophthalmology organizations regarding the inclusion of gonioscopy as part of routine genetic eye screening in order to provide breeding advice. Furthermore, without the additional assessment of the ciliary cleft width by high‐resolution ultrasonography (HRUS) or ultrasound biomicroscopy (UBM), gonioscopy alone may not provide a full picture about the status of the aqueous humor outflow pathways. While the American College of Veterinary Ophthalmologists (ACVO) has not issued recommendations against breeding of PLD‐affected dogs, the European College of Veterinary Ophthalmologists (ECVO) has adopted stricter rules with recommended gonioscopy for a number of breeds, including the American Cocker Spaniel, all types of Bassets, Bouvier des Flandres, English Springer Spaniel, Flat‐Coated Retriever, Siberian Husky, and Samoyed. While dogs with mild degree of PLD (fibrae latae affecting less than 25% of the pectinate ligament circumference) are considered unaffected, a diagnosis of laminae and occlusion will result in a recommendation against breeding. Thanks to the monogenic, autosomal recessive inheritance of all currently known forms of canine primary open‐angle glaucoma (POAG) and the availability of well‐established POAG Beagle colonies, great advances were made in recent years toward the better understanding of canine POAG genetics. All currently known canine POAG‐causing mutations have been identified in two genes encoding for secreted matrix metalloproteinases: ADAMTS10 and ADAMTS17. The first mutations were identified in the ADAMTS10 gene of affected Beagles (p.G661R missense mutation [glycine to arginine change at position 661]) and Norwegian Elkhounds (p.A387T missense mutation [alanine to threonine amino acid change at position 387]), a gene that is strongly expressed in the trabecular meshwork (TM). These findings were followed by the discovery of ADAMTS17 mutations in POAG‐affected Petit Basset Griffon Vendéen (PBGV) dogs (inversion in intron 12), Basset Hounds (19‐bp deletion in exon 2), Basset Fauve de Bretagne dogs (p.G519S missense mutation [glycine to serine change at position 519]), and Chinese Shar‐Peis (6‐bp deletion in exon 22). Routine genetic testing for some of these mutations is available. The p.G661R ADAMTS10 missense mutation responsible for Beagle POAG was excluded as a cause of primary glaucoma in the American Cocker Spaniel, Australian Cattle Dog, Chihuahua, Jack Russell Terrier, Jindo, Siberian Husky, Shiba Inu, Shih Tzu, and Yorkshire Terrier. It is likely that modifier genes are involved in determining whether an ADAMTS10‐ or ADAMTS17‐mutant dog presents to the veterinary ophthalmologist because of primary lens luxation (PLL) or primary glaucoma. In our clinical experience, even ADAMTS10‐mutant Beagles can present with limited PLL, even though this has not been observed over four decades in the POAG Beagles housed at the University of Florida. Based on these recent genetic discoveries, we think it is important for the clinician to consider a POAG component in “classic” PLL breeds, such as terriers, because of their genetic defect in ADAMTS17 (splice donor site mutation: ADAMTS17c.1473+1 G>A). These canine patients may present with elevated IOP without lens displacement into the anterior chamber or pupillary block but instead with lens subluxation or posterior lens luxation. Furthermore, glaucoma often persists following surgical lens removal. In other words, glaucoma associated with PLL may not be entirely secondary to anterior lens dislocation and vitreous prolapse as generally perceived; instead, there may be a POAG component. Like canine POAG, PLL also appears to be an autosomal recessive trait in most affected breeds; hence, most heterozygous dogs that carry an ADAMTS17 mutation remain clinically unaffected. Interestingly, an estimated nearly 5% of heterozygous Miniature Bull Terriers, and a few heterozygous dogs of other breeds, such as the Parson Russell Terrier, Chinese Crested Dog, and Tenterfield Terrier, may develop PLL. This phenomenon could be attributed to haploinsufficiency, a dominant negative effect of the mutant ADAMTS17 protein, or additional, still unknown mutations in ADAMTS17 or elsewhere in the genome. The Animal Health Trust recommends that carriers of ADAMTS17 mutations be regularly screened for signs of PLL. Diurnal IOP and/or tonography studies in these dogs with DNA mutations may help separate those dogs with PLLs (and secondary glaucoma) from those dogs with a combination of PLL and primary glaucoma that may exhibit at different times. Because of their important function in microfibril formation, mutations in ADAMTS10 and ADAMTS17 result in not only an ocular phenotype with ectopia lentis/PLL and glaucoma in affected human Weill Marchesani syndrome (WMS) patients, but also short body stature, fingers, and toes. In contrast, the canine disease phenotype appears to be limited to ocular symptoms. However, there have been speculations that PLL‐affected, ADAMTS17‐mutant dogs may be slightly smaller than unaffected littermates and that selection toward smaller body size may have contributed to the higher frequencies of the disease allele in affected breeds. The division of canine primary glaucoma into POAG and PLL–primary closed‐angle glaucoma (PCAG) types is still unresolved. Some breeds may share both types of glaucoma. Unfortunately, there are no detailed clinical descriptions for most of them, only reports of the genetic defect in ADAMTS17. In other words, glaucoma associated with PLL may not be entirely secondary to anterior lens dislocation and vitreous prolapse as currently perceived; instead, there may be a POAG component. Tonography has suggested that some Wirehaired Fox Terriers presented with anterior lens luxations and glaucoma in one eye and normal IOP in the fellow eye with no evidence of lens luxations, have decreased aqueous outflow in the normotensive eye. The relationship between lens luxations and glaucoma is at best unsettled and requires investigations. ADAMTS17 mutations have been discovered in POAG‐affected Basset Hounds (19‐bp deletion in exon 2), Basset Fauve de Bretagne dogs (p.G519S missense mutation [glycine to serine change at position 519]), and Chinese Shar‐Peis (6‐bp deletion in exon 22). It is important for the clinician to consider a POAG component in “classic” PLL breeds, such as terriers, because of their genetic defect in ADAMTS17 (splice donor site mutation: ADAMTS17c.1473+1 G>A). These canine patients may present with elevated IOP without lens displacement into the anterior chamber or pupillary block but instead with lens subluxation or posterior lens luxation. Furthermore, glaucoma often persists following surgical lens removal. In other words, glaucoma associated with PLL may not be entirely secondary to anterior lens dislocation and vitreous prolapse as generally perceived; instead, there may be a POAG component. Canine glaucomas may be classified on the basis of (i) the possible cause (primary, secondary, or congenital), (ii) the gonioscopic appearance of the filtration angle (i.e., open, narrow, or closed iridocorneal angle and open, narrow, or collapsed ciliary cleft), and (iii) the duration or stage of the disease (Box 10.1). Because no single classification scheme is totally satisfactory, combinations of all three schemes typically are used. There have been recent suggestions that the classification schemes of animal glaucomas have limited usefulness because of microanatomical differences in the outflow pathways between primates and the dog; however, alternate schemes have not emerged nor been recommended. In the dog, the majority of the filtration angle (e.g., the corneoscleral meshwork and all of the uveal trabecular meshwork) is located in the ciliary cleft, which can only be imaged by ≥20 MHz ophthalmic ultrasonography. Primary glaucomas, which are thought inherited, may result from abnormal biochemical metabolism of the trabecular cells of the outflow system or the physical effects of pupillary blockage and changes in the iridocorneal angle and sclerociliary cleft. PLD or the consolidation of adjacent pectinate ligaments into broad sheets (initially termed mesodermal dysgenesis) is common in the dog, and often described in many primary narrow‐ or closed‐angle glaucomas. In our classification scheme, the persistent mesodermal bands and PLD‐associated glaucomas in selected breeds have been classified with the primary glaucomas because the clinical signs of these glaucomas occur later in life. These anomalies appear to predispose to elevated IOP, but their direct role is not known. As the basic pathogenesis for all breed‐related glaucomas becomes documented, however, these glaucomas could be reclassified into more specific types (Table 10.1). In the secondary glaucomas, the increase in IOP is associated with some known antecedent or concurrent ocular disease that physically obstructs the aqueous outflow pathways. They tend to be unilateral conditions and are not inherited. Some of the conditions that may initiate these forms of glaucoma, however, may be genetically determined in certain breeds, such as those with cataracts and lens luxation (i.e., dislocation). The secondary glaucomas are divided according to cause as well as by an open, narrow, or closed anterior chamber angle and ciliary cleft at gonioscopy. In the dog, the primary and breed‐related glaucomas as well as the secondary glaucomas constitute the largest clinical groups. Table 10.1 Types of glaucomas reported. a Pectinate ligament dysplasia. In the congenital glaucomas, the increased IOP is associated with often multiple anterior segment anomalies, and the elevation in IOP develops soon after birth. Congenital glaucomas with overt anterior segment anomalies during the first few months of life are rare. Classification of the canine glaucomas by duration (i.e., acute, subacute, and chronic) is useful clinically. Such classification may be misleading, however, regarding the amount of damage present and the pet owners’ critical observations. Corneal edema, conjunctivitis, and a dilated pupil may be the first clinical signs of glaucoma noticed by a pet owner or veterinarian. Because an IOP in excess of 40 mmHg is necessary for corneal endothelial dysfunction to develop, these eyes may not truly be at an early or acute stage of the actual disease at presentation. Glaucoma in one eye, with only slight elevation in IOP, is often not noticed by the owner; hence, most dogs are not presented to a veterinarian until extensive damage or even blindness is present in the first eye with the primary glaucomas. In fact, in both the dog and humans, presentation of the initial eye with PACG is associated with 25–50% blindness before examination by a medical professional. In addition to the duration of the IOP elevation, glaucoma is also influenced by the amount of IOP elevation. An IOP of 35 mmHg is not as damaging as an IOP of 70 mmHg! The three basic procedures for the diagnosis and clinical management of glaucomatous patients are tonometry, gonioscopy, and ophthalmoscopy. Recently introduced high‐resolution imaging procedures, such as 20, 35, 50, or 60 MHz ultrasonography and anterior segment optical coherence tomography, can noninvasively observe the dog’s trabecular meshwork and sclerociliary cleft and are beginning to be used for clinical patients. Reliable tonometry is essential for optimal clinical management of canine glaucomas. Of the three types of tonometry (i.e., indentation [Schiotz], applanation, and rebound tonometers), only the latter two types are recommended in veterinary ophthalmology. Current tonometers for animals are based on the Mackay–Marg applanation principle, the rebound magnetic effect, or the exchange of gas (now air) with the pneumatonograph. In the rebound tonometers, a magnetic field is induced that propels a small magnetized probe (plastic tip is 1.4 mm) against the cornea. The probe “rebounds” at different velocities and levels of IOP from the cornea causing voltage changes within the tonometer’s collar, which are converted into electrical signals that have been calibrated to different levels of IOP in selected species. Currently models used include the TonoPen® XL, TonoPen Vet™, and TonoPen Avia Vet (Reichert, Buffalo, NY); AccuPen Vet (Automated Ophthalmics, Columbia, MD); TonoVet® Rebound Tonometer (Icare Labs, St Petersburg, FL; Vedco, St Joseph, MO; and TioLat, Helsinki, Finland); and the pneumatonograph model 30 (Reichert, Buffalo, NY). In general, tonometric measurements with the older TonoPen models underestimate IOP levels starting at about 30 mmHg and above, and are progressively less accurate as IOP increases (e.g., 60 mmHg). However, the new TonoPen Avia Vet (Reichert, Buffalo, NY) has been updated and reported by the manufacturer as more accurate at the higher levels of IOP than its previous models. Clinical and experimental impressions suggest that the TonoVet measurements are slightly lower than those from the TonoPen XL results within the normal range of IOP (10–25 mmHg), but perhaps more accurate when IOP exceeds 40 mmHg. With use of only topical anesthesia and the dog loosely restrained in a sitting or standing position, applanation tonometry can be performed with the instrument held horizontal or vertical, and the tonometer tip perpendicular to the central cornea. Several reproducible readings with consistent IOP measurements should be obtained. With TonoVet rebound tonometry no topical anesthesia is necessary, but the instrument must be held horizontally. Normal IOP for the dog has been estimated at 16.7 ± 4.0 mmHg (TonoPen XL) and 15.7 ± 4.2 mmHg (Mackay–Marg®), and in a larger group at 18.7 ± 5.5 mmHg (TonoPen XL) and 18.4 ± 4.7 mmHg (Mackay–Marg), and 12.9 ± 2.7 mmHg (TonoPen XL) and 10.8 ± 3.1 mmHg (TonoVet). Body position as well as manual restraint can also affect tonometric measurements. Tonometry in the outpatient clinic provides only an “instant snapshot,” or a single point in time, while multiple measurements of IOP over a 24‐h period can be more informative, because IOP is a biological variable. Acclimation to the clinical environment and multiple IOP measurements over 24 h can provide a more accurate estimation of the actual IOP. Diurnal variations in IOP have also been documented in the dog, with higher levels in the early morning and the lowest readings in the early evening, and may be the most informative clinically. In the normal dog, these diurnal variations span approximately 2–4 mmHg within an eye, and between fellow eyes. The peak levels of IOP are potentially the most damaging! Tonometry is a critical procedure in both the diagnosis and clinical management of canine glaucomas. As presented later, both “safe” and “target” IOP levels can be addressed only if applanation tonometry is routinely performed on the glaucomatous patient at every visit. Gonioscopy is the diagnostic examination of the iridocorneal angle and opening of the ciliary cleft (i.e., the filtration angle), usually performed by the veterinary ophthalmologist. The uveal trabeculae are located immediately posterior to the pectinate ligaments and are visualized directly during gonioscopy. Only the opening of the ciliary cleft, however, can be visualized at gonioscopy, though the entire cleft can be imaged at HRUS. Gonioscopy has been documented and performed in the dog since the 1930s. Because the primary glaucomas represent progressive diseases of the aqueous humor outflow pathways (both open‐ and narrow–closed‐angle types), serial gonioscopy in glaucoma patients is most informative. Gonioscopy permits classification of glaucoma on the basis of the iridocorneal angle and anterior sclerociliary cleft morphology (i.e., open, narrow, and closed filtration angles and sclerociliary clefts) (see Chapter 4) by the veterinary ophthalmologist. Both direct and indirect gonioscopic lenses are used, with the former type of lenses most popular and less expensive. Gonioscopic findings in both primary open‐ and narrow‐angle/angle‐closure glaucomas are dynamic, changing as the glaucoma and globe enlargement progress. Regardless of the basis for these changes, the continual narrowing and eventual closure of these outflow pathways indicates that progressively more aggressive medical and surgical therapy will be required as the glaucoma progresses. Gonioscopic findings must be compared with tonometric results and clinical findings because gonioscopic results do not directly correlate to level of IOP or aqueous humor outflow. Gonioscopy observations should include the following: width of iridocorneal angle; depth of the sclerociliary opening and cleft; length and diameter of pectinate ligaments; any abnormalities – most often PLD; size of dysplastic areas; and number of flow holes by quadrant or degrees (Figure 10.1). The information gleaned from gonioscopic examination may be useful for giving breeding advice for breeds predisposed to PLD and glaucoma. Recommendations to examine the ICA by gonioscopy as part of the genetic eye screening and in giving breeding advice for dogs with PLD differ between the ACVO and the ECVO. The ECVO has stricter guidelines regarding the need for gonioscopy and the exclusion of PLD‐affected animals from breeding. Gonioscopy is advised by the ECVO in the following breeds: American Cocker Spaniel, all types of Bassets, Bouvier des Flandres, Chow Chow, Border Collie, Dandy Dinmont Terrier, Rough‐Haired Dutch Shepherd, English Springer Spaniel, Entlebucher Mountain Dog, Flat‐Coated Retriever, Siberian Husky, Leonberger, Magyar Vizsla, Samoyed, and Tatra. PLD is classified by the ECVO, based on severity, as free, fibrae latae (abnormally broad and thickened pectinate ligament fibers), laminae (solid plates or sheets of pectinate ligament tissue), and occlusion (persistence of an embryonic sheet of ICA tissue and the absence of intraligamentary spaces, except for flow holes). Fibrae latae, laminae, and occlusion are associated with a narrow ICA. With fibrae latae affecting 50% or less of the pectinate ligament circumference, the animal can still be considered unaffected; however, a diagnosis of laminae in more than 50% of circumference is considered severely affected. In addition to PLD, the ECVO recommendations also include ICA width: open, narrow, or closed. Performing a gonioscopy as part of the genetic eye screening remains optional according to the ACVO, despite the recent issue of a special form by the ACVO Genetics Committee and the Orthopedic Foundation for Animals for information gathering and tracking information related to PLD. There are currently no ACVO guidelines against the breeding of PLD‐affected dogs. The less restrictive ACVO recommendations were justified by the poor predictive value of gonioscopy findings for PCAG development in individual dogs and their offspring. Furthermore, without the additional assessment of the ciliary cleft width by HRUS or UBM, the examination of the ICA by gonioscopy alone may not provide a complete picture of the status of the aqueous humor outflow pathways. Figure 10.1 Grading by gonioscopy and a schematic of the iridocorneal angle and opening of the sclerociliary cleft: (from left to right) closed; very narrow; narrow; open (or normal); and more open than normal. As the ocular fundus is directly influenced by elevated IOP, clinical management of the canine glaucomatous patient requires a combination of direct and indirect ophthalmoscopy (Figure 10.2). The direct ophthalmoscope and the small‐pupil indirect ophthalmoscope permit careful examination of the ONH and retina. The direct method has the higher magnification than the indirect method (17.2× lateral and 405× axial versus 1.7× lateral and 4× axial, respectively), which favors detailed ONH inspections. The red‐free filter of the direct ophthalmoscope, which results in a green light source, permits examination of the retinal nerve fiber layer for nerve fiber bundle defects as well as examination of the neuroretinal rim. The panoptic ophthalmoscope provides a little less magnification but a larger view of the ocular fundus. Glaucomas with abrupt bouts of marked elevations in IOP tend to produce progressive optic nerve degeneration and often “watershed” areas of retinal degeneration (wedge‐shaped areas of retinal degeneration adjacent to the optic disc secondary to short ciliary artery ischemia), while slow and gradual elevations of moderate IOP tend to produce a gradual optic disc cupping, gradual loss of myelin, and smaller and pigmented optic discs. Figure 10.2 ONHs in three Beagles. (a) Normal optic disc. (b) Optic disc in early hypertension with electrophysiological evidence of glaucoma. (c) Optic disc in a moderate stage of POAG with enlargement of the optic cup. Classification of the canine glaucomas based on histopathological examinations of end‐stage and advanced glaucomas is of limited value and may indicate erroneous assumptions as to the genesis of elevated IOP. With these newer noninvasive imaging clinical procedures, examination of the anterior chamber and outflow pathways can approximate routine histology resolutions and can be performed in the early stages of the diseases (and before enucleation is usually possible) by the veterinary ophthalmologist. Both HRUS (20 MHz) and UBM (50–60 MHz) have been reported in dogs, with the latter method requiring sedation or general anesthesia. Both methods require a latex rubber sleeve or eye cup as an interface between the ultrasound probe and the eye. Both methods can image the iridocorneal angle, pectinate ligaments, and sclerociliary cleft (Figure 10.3). As with any new diagnostic, it may be a few years before these imaging procedures become commonplace in the clinical management of the canine glaucomas. Figure 10.3 (a) HRUS or UBM of the iridocorneal angle and ciliary cleft in a normal dog, and (b) an American Cocker Spaniel with iridocorneal angle closure and collapse of the ciliary cleft. (Courtesy of Ursula Dietrich, North Downs Specialist Referrals, Bletchingley, Surrey, UK.) C, cornea; S, sclera; I, iris; PL, pectinate ligament; CC, ciliary cleft; and A, iridocorneal angle. Tonography is tonometry expanded over 2–4 min, and it permits quantification of the IOP‐sensitive component of the aqueous humor trabecular meshwork outflow, and has had limited use in the investigations of the canine glaucomas. Tonography is the clinical procedure that documents the pressure‐sensitive (trabecular meshwork) aqueous humor outflow. It has not been used clinically in the canine glaucomas, except in POAG in the Beagle. Combined with fluorophotometry, tonography can reveal, in relative terms, both the conventional (i.e., pressure‐sensitive corneoscleral–trabecular outflow) and unconventional (i.e., pressure‐insensitive uveoscleral outflow) components of the glaucomas. In three separate pneumatonographic studies, the mean ± SD for conventional outflow for the normal dog was 0.30 ± 0.15, 0.28 ± 0.09, and 0.35 ± 0.129 μl/min/mmHg. A‐scan ultrasonography is important to measure the anteroposterior globe, depth of the anterior chamber, lens thickness, and anteroposterior dimension of the vitreous body. Results of ultrasonic studies of primary glaucoma in Samoyeds suggest a narrow‐ or closed‐angle glaucoma pathogenesis with a narrowed anterior chamber and increased thickness of the axial lens and vitreous body. These same findings have been reported in human PACG in people. Electrophysiology studies have received limited attention in the canine glaucomas; however, there are reports on normal dog eyes with abruptly increased IOP. Pattern electroretinography, multifocal electroretinography, and flash electroretinography with different colors of light stimuli, particularly blue, may be useful. Provocative tests are used traditionally to evaluate an eye and its predisposition to both open‐ and narrow‐angle glaucomas in humans. They can provide insight into the possible mechanism(s) about the increase in IOP. Provocative tests may not be indicated for the individual patient, but they may be employed by veterinary ophthalmologists and vision scientists investigating the pathogenesis of glaucoma or screening IOP‐reducing drugs. The common tests for the POAGs include the water provocative and steroid provocative tests. The provocative tests for the closed‐angle glaucomas include the mydriatic drug test and the darkroom test. Table 10.2 Clinical effects of elevated IOP. All glaucomas are diseases of constant and progressive change, with decreases in aqueous humor outflow throughout the disease. In contrast to most ophthalmic diseases, elevated IOP affects all of the ocular tissues as the disease progresses (Table 10.2). Observations on the pathology of glaucoma globes from clinical patients must be carefully interpreted because these globes are usually from advanced stages of the disease, have irreversible blindness, and may have received treatment with medications and/or surgeries for varying lengths of time. The determination of the underlying cause for the elevation in IOP is often a challenge, and may or may not always be possible. Possible mechanisms for the development of the secondary glaucomas included open iridocorneal angle with ciliary cleft closure; open iridocorneal angle obstructed by preiridal fibrovascular membranes (rubeosis iridis), endothelialization and descemetization, lens epithelialization, inflammatory cells, or red blood cells; open angle with pupillary obstruction; closed angle caused by anterior synechia; closed angle secondary to lens luxation and pupillary block; and obliteration of the outflow structures secondary to neoplasia or necrotizing inflammation. The intraocular tissues in chronic glaucomas and those with high IOP often also exhibit inflammation probably secondary to direct tissue damage as well as ischemia. Clinical signs of the glaucomas depend on the stage of disease and, to some extent, on the type of glaucoma (Table 10.3). Clinical signs are also directly related to the level and duration of the elevation in IOP. As the primary glaucomas are usually progressive diseases, the clinical signs of the disease also change, and are used to ascertain the relative stage of the glaucoma. The stage of glaucoma may be asymmetric in the fellow eyes of the same dog, with one eye at advanced stages of disease and the other apparently normal or at very early stages. In the earliest phase of the primary open‐angle and narrow‐angle glaucomas in the dog, the disease is usually insidious, and the eyes are usually asymptomatic. Cross‐ or mixed‐breed dogs can also develop primary glaucoma with an overall frequency in North America of about 1%. Table 10.3 Clinical signs of the primary glaucomas in the dog. Early signs range from none, slight mydriasis, mild but transient corneal edema, variable episcleral congestion, normal ONH appearance, to IOPs of approximately 25–30 mmHg. Unless periodic and even diurnal applanation tonometry and careful ophthalmoscopy are performed, these early glaucomatous eyes are not usually presented to the veterinarian for ophthalmic examinations until the disease advances to more overt clinical signs. The clinical signs of moderate glaucoma include more prominent amounts of mydriasis (especially in a darkened room), episcleral congestion, variable degrees of corneal edema and striae, slight buphthalmia, early lens subluxation, variable retinal and optic disc changes, and IOPs of 30–40 mmHg. When primary glaucoma is advanced, clinical signs may include intermittent visual impairment to total blindness, persistent mydriasis, corneal edema with corneal striae, peripheral anterior synechiae and angle closure with peripheral corneal edema, buphthalmia, lens displacement from the patella fossa, cortical cataract formation, vitreous degeneration and syneresis, extensive retinal and optic disc degeneration, and IOPs of more than 40–50 mmHg. Occasionally, with IOPs in excess of 50 or 60 mmHg, mild papilledema may be detected through a less than transparent ocular media. Presumably, the optic nerve fibers within the prelaminar ONH and peripapillary retina are enlarged because of impaired axoplasmic transport at the prelamina cribrosa. With very high elevations in IOP, wedge‐shaped areas of chorioretinal degeneration based at the edge of the ONH may result, apparently from ischemia secondary to infarction of individual short ciliary arteries. ONH cupping is usually slight and most obvious with advanced atrophy. Loss of myelin within the ONH in glaucoma results in smaller and round optic discs. The signs of the secondary glaucomas are like those of the primary glaucomas, but the cause for the rise in IOP, such as an anterior uveitis, an intraocular mass, or a lens luxation, is evident. By gonioscopy, the iridocorneal angle and cleft may be open, narrow, or closed dependent on the inciting cause. The congenital glaucomas affect young puppies, usually within the first one to six months of life and, compared to the primary and secondary glaucomas, are quite rare. Often, the first clinical sign in these animals is rapid onset of buphthalmia, inability to completely close the palpebral fissure, and the development of exposure corneal disease. The primary glaucomas in the dog are divided into open‐angle and the narrow‐ or closed‐angle glaucomas, and are often breed‐specific (Table 10.4). In the veterinary medical literature, the association of abnormalities of the pectinate ligaments (goniodysgenesis or more precisely PLD) and the angle‐closure glaucomas in these dogs appears to be more than just coincidence. In clinical studies of American and English Cocker Spaniels as well as of the Basset Hound, narrow iridocorneal angles and sclerociliary clefts were common findings, and in the latter breed, dysplasia of the pectinate ligaments was noted. In the United States, primary glaucoma in the American Cocker Spaniel appears as a narrow‐angle or angle‐closure type, without significant amounts of PLD. In the Samoyed breed in Sweden, narrow iridocorneal angle width has been recently related to the development of glaucoma. Dysplasia of the pectinate ligaments (i.e., solid sheets of pectinate ligaments, initially termed mesodermal remnants) appears to be common in some breeds, but has not been directly related to an increased resistance to the outflow of aqueous humor. It would appear glaucoma may develop in only the most severity affected forms of PLD (well in excess of 180° of the iridocorneal angle involved). It is important to differentiate the iridocorneal anomalies (e.g., persistent mesodermal bands and PLD) from any inflammatory‐associated changes (peripheral anterior synechiae). In some breeds, i.e., Basset Hound, the extent of the PLD may progress over time and thereby predispose these dogs to glaucoma at later ages. Table 10.4 Breeds with primary glaucomas. In the years 1994–2002, 22 different breeds had 1% or higher prevalence of the glaucomas. The highest prevalence of glaucomas in the time period 1994–2002 by breed included American Cocker Spaniel (5.52%), Basset Hound (5.44%), Chow Chow (4.70%), Boston Terrier (2.88%), Wire Fox Terrier (2.28%), Norwegian Elkhound (1.98%), Siberian Husky (1.88%), Cairn Terrier (1.82%), and Miniature Poodle (1.68%). Breeds recently introduced to North America showing higher prevalences of the glaucomas included the Akita, Australian Cattle Dog, and Shar‐Pei. Those breeds consistently among the most frequent throughout the entire 38 years included American Cocker Spaniel, Basset Hound, Boston Terrier, Miniature Poodle, Wire Fox Terrier, and Siberian Husky. Breeds among the top 20 glaucoma breeds for three of the four periods of study (28–30 years) included Standard Poodle, Pekingese, Norwegian Elkhound, English Cocker Spaniel, Australian Cattle Dog, and Chow Chow. The prevalence of the glaucomas among other breeds or cross‐bred breeds also increased from 0.27% (1964–1973), 0.34% (1974–1983), 0.67% (1984–1993) to 0.71% (1994–2002). The effect of gender appears important in humans with narrow‐angle‐closure primary glaucoma with the female affected much more frequently, especially in the Asian race. Does the risk factor of gender also occur in the dog? Yes! Differences in the ratios of males to females for the glaucomas by gender appear in the American Cocker Spaniel, Basset Hound, Cairn Terrier, Chow Chow, English Cocker Spaniel, Samoyed, and perhaps the Siberian Husky. In the American Cocker Spaniel, the females were affected more often than the males (percentage male–female, 1:1.93). In the 1974–1983 interval, the percentage ratios of females to males were higher in the American Cocker Spaniel (male–female, 1:1.49), Basset Hound (1:1.65), English Cocker Spaniel (1:7.44), and Welsh Terrier (1:2.51). Age also appears to be an important risk factor and affects the time for presentation of most of the glaucomas in the purebred dog. In the majority of breeds, the glaucomas are presented most often in dogs at an average age of about six years, except in the Siberian Husky, Samoyed, and Welsh Springer Spaniel, which are usually younger. The other breeds range from 7 to 10 years of age, when first presenting with glaucoma (usually unilateral). Inherited open‐ and narrow‐angle primary glaucomas occur bilaterally in purebred dogs. Although the primary glaucomas have been reported in at least 45 breeds in the United States (see Table 10.4), very few breeds have been investigated to date. There is very limited information on the mode(s) of inheritance for the canine primary glaucomas. POAG in the Beagle is inherited as an autosomal recessive trait, and has been associated with the ADAMTS10 mutation. Genetic investigations of glaucoma in the American Cocker Spaniel and Basset Hound have heretofore failed to establish the inheritance of this condition in these breeds. Primary glaucomas in the Welsh Springer Spaniel and Great Dane appear to be inherited as a dominant trait, with variable expression.
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The Canine Glaucomas
Epidemiology of Primary and Secondary Glaucomas in the Dog
University of California Study
Genetics
Genetics of Pectinate Ligament Dysplasia and Ciliary Cleft Opening in the Dog
Genetics of Canine Primary Open‐Angle Glaucoma and Primary Lens Luxation
POAG and PLL in Other Canine Breeds
Classification of the Glaucomas
Cause(s) of the Glaucomas
Open angle
Closed angle
Beagle
Akitaa
Great Danea
American Cocker Spaniel
Keeshond
Basset Hounda
Norwegian Elkhound
English Cocker Spaniela
Poodle (Miniature/Toy)
English Springer Spaniela
Samoyed
Flat‐Coated Retrievera
Siberian Huskya
Golden Retriever
Poodles (Miniature/Toy)
Samoyed
Shiba Inua
Shar‐Peia
Welsh Springer Spaniel
Onset and Duration
Diagnostics
Applanation Tonometry
Gonioscopy
Ophthalmoscopy
High‐Resolution Ultrasonography and Ultrasound Biomicroscopy
Other Diagnostics
Provocative Tests
Ocular tissue
Changes in the glaucomas
Globe size
Enlargement from stretching of cornea and sclera; termed hydrophthalmos, buphthalmia, megaloglobus, and macrophthalmia. Occurs rapidly in puppies (often reversible)
Cornea
Becomes thicker because of stromal edema. Eventually corneal endothelial cell death occurs. Focal, linear breaks in Descemet’s membrane (i.e., Haab’s striae). Exposure keratitis later with buphthalmia
Sclera and lamina cribrosa
Sclera is stretched and becomes thinner. Areas of sclera through which the nerves and blood vessels penetrate may form large staphylomas. Scleral lamina cribrosa is distorted and compressed posteriorly
Iris
Mydriasis in most types of glaucoma. With time, the iridal stroma becomes thin, and the sphincter muscle becomes atrophied
Ciliary body
Gradual degeneration with atrophy of the pars plicata and individual ciliary processes. Both direct cellular damage and ischemia
Anterior chamber angle
Open‐ and narrow‐ or closed‐angle glaucoma. Secondary changes in the iridocorneal angle and ciliary cleft of the dog from buphthalmia invariably involve progressive narrowing, and eventual closure, of the iridocorneal angle and collapse of the ciliary cleft
Choroid and tapetum cellulosum
Depends on rapidity of onset, duration, and level of the IOP elevation. Areas of chorioretinal ischemia and degeneration in the ischemic zones with markedly increased IOP. Tapetal changes include degeneration and thinning
Lens
Cataract formation and changes in the lens position within the patella fossa (from primary zonular disease or secondary to globe enlargement)
Vitreous
Liquefaction and formation of vitreal cortical strands
Retina and ONH
Progressive degeneration with continued high IOP. Large‐diameter optic nerve axons appear particularly sensitive. The inner retinal layers, especially the RGC and nerve fiber layers, as well as the ONH appear to be very sensitive to IOP, and degenerate rapidly. With high IOP (≥50 mmHg), outer retinal damage (photoreceptors)
Clinical and Pathological Effects of Elevated IOP
Pathology of Canine Glaucoma in Clinical Patients
Clinical Signs
Stage of glaucoma
Clinical signs
Early
May be asymptomatic; slight mydriasis; mild but transient corneal edema; variable episcleral congestion; normal ONH appearance; IOPs of approximately 20–30 mmHg; visual. Often not detected by owner
Mild/moderate
Variable mydriasis, episcleral congestion, variable degrees of corneal edema/striae, slight buphthalmia, early lens subluxation, variable retinal and optic disc changes, and IOPs of 30–40 mmHg; vision to visual impairment. Usually detected by owner
Advanced
Persistent mydriasis, corneal edema with corneal striae, peripheral anterior synechiae and angle closure, buphthalmia, lens displacement from the patella fossa, cortical cataract formation, vitreous degeneration and syneresis, extensive retinal and optic disc degeneration, and IOPs of more than 40–50 mmHg; intermittent visual impairment to total blindness. Usually detected by owner
Primary and Breed‐Predisposed Canine Glaucomas
Pectinate Ligament Dysplasia
Akita
Italian Greyhound
Alaskan Malamute
Lakeland Terrier
Basset Hound
Maltese
Beagle
Miniature Pinscher
Border Collie
Miniature Schnauzer
Boston Terrier
Norfolk Terrier
Bouvier des Flandres
Norwegian Elkhound
Brittany Spaniel
Norwich Terrier
Cairn Terrier
Poodle Toy/Miniature
Cardigan Welsh Corgi
Samoyed
Chihuahua
Scottish Terrier
American Cocker Spaniel
Sealyham Terrier
Dachshund
Shih Tzu
Dalmatian
Shiba Inu
Dandie Dinmont Terrier
Siberian Husky
English Cocker Spaniel
Skye Terrier
English Springer Spaniel
Smooth Fox Terrier
German Shepherd
Tibetan Terrier
Giant Schnauzer
Welsh Springer Spaniel
Greyhound
Welsh Terrier
Irish Setter
West Highland White Terrier
Wire Fox Terrier
Breed Predisposition
Effect of Gender
Effect of Age
Inheritance of the Canine Glaucomas
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