Glaucoma
Contents
The most useful clinical definition of glaucoma is an elevation of intraocular pressure (IOP) beyond that compatible with normal ocular function that is the result of the perturbation of normal aqueous circulation through or from the eye. Visual impairment results from the detrimental effects of the elevated intraocular pressure on the neurons of the retina, and the elevated IOP may be a source of pain and discomfort. The clinical signs and effects of the elevated IOP are species dependent. The myriad of pharmacologic and surgical therapeutic options available attest to their unpredictable efficacy, and most ophthalmologists will agree that glaucoma is the most challenging disease entity with which they must battle.
Physiology of the Aqueous Humor and the Intraocular Pressure
The IOP is dependent upon several dynamic factors: the rate of aqueous humor production by the ciliary body epithelium; the circulation of the aqueous humor from the posterior chamber through the pupil into the anterior chamber; the egress of the aqueous humor from the eye; the volume of the vitreous humor, as influenced by the state of vitreous hydration; and the elasticity of the cornea and sclera, or the ocular rigidity.
Aqueous dynamics
Aqueous is produced by a combination of both active and passive pressure driven and active processes by the ciliary body epithelium. The rate of production has been estimated at 1-2 microliters per minute in the dog, 14-20 in the cat. Rate of aqueous production probably decreases with age (thus IOP in an older animal is likely to be lower than in a younger animal), with intraocular inflammation, and with elevated IOP as the passive production of aqueous humor is affected in a compensatory mechanism, or pseudofacility (1, 2).
Circulation of aqueous humor through the pupil into the anterior chamber occurs due to the effects of gravity associated with head movement and thermal convection currents, the cornea being cooler than that of the interior of the eye. The aqueous returns to the peripheral venous circulation through the ciliary cleft and across the trabecular meshwork; while both passive pressure driven and energy dependent active transport are involved, the former predominates. This pathway is referred to as conventional outflow (3,4). Aqueous fluid can also leave the eye via the nonconventional or uveoscleral outflow route (5,6); this pressure independent mechanism involves the flow of aqueous fluid into the ciliary body in a posterior direction with movement into the uveal venous vasculature and exit via the vortex veins. The relative contribution of uveoscleral outflow is species dependent (about 3% of outflow in cats, 15% in dogs (7,8)). Both the conventional and uveoscleral outflow pathways are known to be impaired in canine primary glaucoma.
Intraocular Pressure
The balance between aqueous humor production, circulation, and outflow account for maintenance of the normal intraocular pressure. In addition, the aqueous humor plays a critical role in ocular homeostasis by providing nutrients for and carrying away metabolic wastes of the tissues of the anterior segment, notably the avascular lens and cornea.
Normal intraocular pressure is a somewhat elusive biologic variable dependent on many factors including individual (including age and sex), diurnal cycles, and systemic blood pressure. Most would agree that tonometric measurements above 25mm Hg are pathologic, and in the great majority of animals, "normal" will fall between 10 and 22mm Hg. Human glaucoma is a much different disease from that encountered in domestic species where significant attention has been focused on the sensitivity of individual optic nerves to glaucomatous damage, and normotensive glaucoma, where progressive optic atrophy is observed in the presence of IOP within normal ranges, is well documented. While differences in species and individual sensitivities to neuronal damage in glaucoma certainly is a factor in the patients that we deal with, normotensive glaucoma has not been unequivocally demonstrated in lower mammals. Ocular hypertension is the presence of normal ocular function in the presence of IOP at or slightly above normal limits and occurs in both humans and animals.
Any classification scheme assumes a simplistic approach to a complex disease process that we are only beginning to understand. Nonetheless they can be useful if one keeps in mind the artificial nature of such schemes.
Primary and secondary glaucoma
Based upon pathogenesis, glaucoma may be categorized as either primary or secondary. Primary glaucoma is genetically determined and occurs without antecedent or concurrent ocular disease and almost always bilateral, although not necessarily concurrently so. It is caused by anatomical and/or physiological alterations that occur in the ciliary cleft and/or trabecular meshwork.
Secondary glaucoma arises when precedent ocular disease results in obstruction of circulation or outflow of aqueous humor; this obstruction may occur at the cilio-vitreal or lens-pupil diaphragms or the outflow pathway.
The distinction between primary and secondary glaucoma is an important one clinically because it implies that in secondary glaucoma recognition and management of the primary disease condition may indeed ameliorate the elevated intraocular pressure, and, early on, this generally is true.
Congenital and acquired glaucoma
Less meaningfully, glaucoma can be classified as either congenital or acquired. Congenital glaucoma is extremely rare in domestic animals and is usually associated with anterior segment dysgenesis. While at first glance relatively straightforward, this classification becomes somewhat problematic when one considers that the human literature has expanded the terminology "congenital" to include both glaucomas that are present at birth as well as those that develop early in life. This interpretation would even add more confusion to veterinary glaucomatology, because the majority of primary glaucomas in dogs are associated with congenital abnormalities of the outflow pathways (goniodysgenesis), one might indeed consider them congenital. We will somewhat arbitrarily choose to limit the classification of congenital glaucoma in animals to those glaucomas that are present, or presumed to be present, at birth.
Classification based on duration and severity
Perhaps the most practical classification of glaucoma relates to its duration and severity. Whether primary or secondary, management of glaucoma is determined by the segregation of globes into those that are potentially visual from those that are likely irreversibly blind. Few would argue that the irreversible neuronal damage that occurs with elevated intraocular pressure is directly proportional to the extent of IOP elevation and its duration. However, little scientific data is available to specifically direct our efforts.
We classify glaucoma severity as mild in the 25-35 mm Hg range; moderate from 36-50 mm Hg; and severe greater than 50 mm Hg. Of course, one can only measure what the pressure is when the patient is there on your examining table, and one cannot know whether the pressure the day before was higher or lower than that which you have measured at one particular point in time.
The determination of duration is equally problematic; the signs of mild or moderate glaucoma in dogs and cats, and even severe glaucoma in the cat, may be subtle and unnoticed by a pet owner. Most of the time the clinician can only surmise the duration of the disease. We do know that in severe glaucoma neuronal damage begins almost immediately and after 48-72 hours usually has resulted in damage significant enough to leave an eye irreversibly blind. Nonetheless, by a combination of history and findings upon ophthalmic examination, the clinician must attempt to prognose and recommend management options not only for the affected eye but for the fellow eye as well.
Other classifications
Glaucoma can be classified by the anatomic alterations observed in the outflow pathways observed upon gonioscopy or histopathology. The information may provide impressions of predictability of response to medical therapy and risk of future glaucoma in fellow eyes and will be addressed in later sections.
Up to this point, we have alluded to our lack of understanding of the events that lead to primary glaucoma. We have addressed the challenge of prognosis. If this seems a bit disconcerting to the reader, prepare yourself, for rather than clearing, the waters become more murky indeed.
The Anatomy of the Outflow Pathway
An appreciation of the normal anatomy of the outflow pathway in the domestic animals is critical if one is to accurately interpret gonioscopic observations, accurately classify glaucoma, and understand the histopathology observed in glaucomatous globes. The anatomy of the outflow pathways of the domestic animals is similar among species but quite different from the human, where the trabecular meshwork is externalized into the scleral sulcus. These distinctions in anatomy and the historical tendency to borrow from the human nomenclature have led to semantical confusion and hindered our understanding of the pathogenesis of the disease in animals. We have attempted to develop and apply semantics that when applied to the animal eye are clarifying and elucidating.
Gonioscopic anatomy
The gonioscopic classification of glaucoma relates to the clinical observations made of the outflow pathway when examined by a corneal contact lens (9-11). These anatomical features are schematically depicted in Figure 1.
Figure 1 - Schematic drawing of the gonioscopic anatomy in the dog.
The iris root inserts on the inner corneoscleral tissue by a broad band of uveal tissue referred to as the pectinate ligament. The pectinate ligament is composed of somewhat variably shaped and sized pillars of uveal tissue. The aqueous humor flows through the spaces between the pillars to gain access to the recesses of ciliary cleft, a space formed by the separation of the ciliary body stroma into an inner and outer leaflet as it courses anteriorly. The outer ciliary body leaflet gives rise to the trabecular meshwork, which consists of multiple layers of collagen and elastic fibers lined by flattened endothelial cells that are actually of neural crest origin. The spaces between the trabecular fibers lead to the endothelial walls of deep scleral vascular channels, the trabecular veins, which in turn communicate with the scleral venous plexus which in turn drain to the episcleral veins.
By gonioscopy one can visualize the iridocorneal angle, that is the angle formed by the root of the iris and pectinate ligament and the inner corneal surface; the origin and insertions of the fibers of the pectinate ligament; the anterior recesses of the ciliary cleft; the outer leaflet of the ciliary body, which gonioscopically is referred to as the inner or deep pigmented zone; and the pigmentation that is normally and variably present at the corneoscleral junction, which is referred to as the outer or superficial pigmented zone. By gonioscopy (or, by histopathology if one is studying a slide of a glaucomatous eye), one can classify the iridocorneal angle as either being open, if the pectinate fibers are visible; narrowed, if the iris root is displaced anteriorly; or closed, if the pectinate fibers and inner pigmented zone are obscured by the iris directly apposed to the acute pigmented zone (Figure 2).
Figure 2 - Gonioscopy allows the examiner to judge whether the iridocorneal angle is open or not. When the iridocorneal angle is narrowed, the part of the pectinate ligament closest to its origin is obscured by the anteriorly bulging iris surface. The deep band of the pigment zone as well as the insertion of the pectinate fibers at the inside of the corneoscleral junction are visible (left). If the iridocorneal angle is closed, the iris is in contact with the inner surface of the cornea (right).
Figure 3 - The difference between normal width of the entrance to the ciliary cleft (left) and a narrowed entrance (right). Note that all structures are visible when the entrance is narrowed, but the height of the pectinate ligament is less than in the normal eye. However, gonioscopy do not permit extensive evaluation of the structures inside the ciliary cleft.
The ciliary cleft can be evaluated only if the iridocorneal angle is open or narrow; if the iridocorneal angle is closed, it is likely a valid assumption that the ciliary cleft is collapsed as well. The width and depth of the ciliary cleft are difficult to visualize by gonioscopy, but the anterior recesses can be appreciated (Figure 3). Due to the limitations of visualization in clinical cases, and tissue distortion during histopathologic processing, we categorize the ciliary cleft as either open or collapsed, appreciating that there are intermediate stages of narrowing. As clinical diagnostic techniques, such as high frequency ultrasound, become perfected, clinical evaluation of the features of the ciliary cleft may be more meaningfully interpreted.
Primary Glaucoma
Open-angle glaucoma without goniodysgenesis
The causes of the primary glaucomas are unknown and probably breed dependent. The inherited glaucoma described in the laboratory Beagle is characterized by an insidious increase in intraocular pressure early in life during which the only detectable abnormality is an increase of glycoaminoglycans within the trabecular meshwork (8, 12, 13). Later in the disease process, the ciliary cleft collapses. The clinical features One form of primary glaucoma in the Norwegian Elkhound are has similar clinical features as the open-angle glaucoma in the Beagle, that is a normal appearance of the iridocornal angle and the entrance to the ciliary cleft initially and a slow progressive increase in intraocular pressure over time (14); h. However, there is evidence that the Norwegian Elkhound also can develop glaucoma where goniodysgenesis may be a component of at least some cases of Elkhound glaucoma, suggesting that multiple forms of glaucoma or combinations of predisposing factors can be seen in the same breed. Occasionally, one will encounter other breeds of dogs that appear to have a chronic rather than acute elevation of IOP; however, this condition appears however to be a rare clinical entity in pets.
Glaucoma associated with goniodysgenesis and collapse of the ciliary cleft
The most commonly encountered subtype of primary glaucoma in the dog in clinical ophthalmology associated with goniodysgenesis,-a congenital dysplasia of the pectinate ligament, the trabecular meshwork, and/or the ciliary cleft (15-20). Those alterations that are located anteriorly involving the pectinate ligament or the anterior recesses of the ciliary cleft can be appreciated and classified by gonioscopy and can serve as a marker for the risk of development of glaucoma in the future (Figure 4). While there is contemporary controversy as to whether the intraocular pressure in these animals may be somewhat elevated, or experience greater diurnal fluctuations than those seen in dogs without goniodysgenesis, the majority of these cases present as acute episodes of glaucoma later in life, generally between 3 and 6 years of age. The intraocular pressure is within the normal ranges one day, and in the 50s or 60s the next.
Figure 4 - Goniodysgensis or dysplasia of the pectinate ligament. The normal appearance of the pectinate fibers is seen in the drawing to the left. In the middle and left hand drawings the fibres form more solid sheets of tissue partially blocking the entrance to the ciliary cleft. The trabecular meshwork behind the dysplastic fibers may also be abnormal. However, this is not possible to evaluate by gonioscopy.
One of the authors (RLP) has documented an American cocker spaniel presented for acute glaucoma in one eye that was treated surgically; prior to the procedure, the normotensive fellow eye was evaluated by gonioscopy, where there was mild to moderate pectinate ligament dysplasia, and tonography, which demonstrated outflow within normal limits. The patient recovered from surgery and during the period of convalescence while in the hospital developed acute glaucoma in the fellow eye that just a few days before had had normal intraocular pressure, normal coefficient of outflow, and less than striking goniodysgenesis.
This acute elevation of IOP is associated with a collapse of ciliary cleft. The iridocorneal angle remains open, at least in the early stages of the disease, and these cases of primary glaucoma in dogs are most appropriately classified as open angle, collapsed cleft glaucoma (19).
The events that lead to the collapse of the ciliary cleft are not understood. Histopathologic study of dogs with primary glaucoma has confirmed the open iridocorneal angle, the collapse of ciliary cleft, and most interestingly, the abnormal production of basement membrane material, with similarities to Descemet's membrane, by the trabecular meshwork. We believe that the production of this excess basement membrane material by the trabecular cells is a marker of trabecular meshwork dysplasia and plays a role in the pathogenesis of the disease process. This process has been, we believe, inappropriately compared to and labeled "acute angle closure," as documented in humans, which is essentially a pupillary block glaucoma.
Glaucoma associated with relative pupillary block
Primary glaucoma associated with decreased depth of the anterior chamber, anterior displacement of the iris with resultant shelling of the anterior chamber, and narrowing of the opening to the ciliary cleft, large and anteriorly positioned lenses, and finally appositional closure of the iridocorneal angle followed by collapse of the ciliary cleft has been described in related Samoyed dogs (21-24). These morphologic features are consistent with a pathogenesis involving increased resistance of flow of aqueous through the pupil, we believe that the pathogenesis and the commonly encountered acute primary glaucoma in dogs infrequently involved pupillary block. Evidence that supports this hypothesis is of the failure of either pupillary dilation or constriction, nor iridotomy or iridectomy, relieve the elevated IOP. However, we have documented increases in IOP in "normal" fellow eyes within less than an hour after they were treated prophylactically with miotics (pilocarpine and/or latanoprost). We have also seen "normal" American Cocker Spaniels that experienced increases in IOP to greater than 40 mm Hg following dilation with tropicamide. These observations suggest that in soe instances that the anatomical relationship between the iris and lens, and/or the iris and the iris root and ciliary cleft, may indeed be a factor in increased resistance to aqueous circulation. However, these observations are not repeatable across large numbers of patients and it appears much more commonly that closure of the ciliary cleft is the primary event in primary glaucoma, rather than changes involving the iridocorneal angle.
Secondary Glaucoma
Secondary glaucomas occur because a precedent ocular disease results in obstruction of aqueous circulation or outflow. This obstruction can occur at the cilio-vitreal-lenticular interface, as exemplified by narrow angle glaucoma in cats; at the pupil, as occurs in lens luxations or anterior uveitis with extensive posterior synechiae; by closure of the iridocorneal angle with peripheral anterior synechiae, usually a sequele of preiridal fibrovascular membranes (25); or infiltration and obstruction of the ciliary cleft, as exemplified in cats with chronic lymphoplasmacytic uveitis, where inflammatory cells nodules obstruct the cleft, or in melanocytosis or neoplasia, where neoplastic cells fill the ciliary cleft and obliterate the trabecular meshwork and outflow pathways with obstruction of the egress of aqueous.
Regardless of cause, obstruction of aqueous circulation or flow results in an elevation of intraocular pressure that has deleterious effects on the ocular tissues. These can be related to one of four mechanisms:
These alterations can be related to clinical signs and are summarized in Table 2.
Sensitivity to and manifestations of the ocular tissues to these mechanisms are species dependent. Of key importance are the events that effect the retina and optic nerve. As mentioned above, multiple mechanisms are likely at play, including tissue hypoxia, compression of ganglion cell axons, and neuroexcitoxin release.
In human eyes, glaucoma tends to be a process confined to the inner retina, and even in chronic and severe cases histopathology will reveal minimal alterations in the inner and outer nuclear layers. The dog retina appears to be exquisitely sensitive to elevations in intraocular pressure, and related to both severity and duration, cell death and subsequent atrophy may be seen in all the layers of the neurosensory retina. An interesting feature, first noted by Smith, Peiffer and Wilcock, is that of tapetal sparing-that is, the superior retina, roughly corresponding to that overlying the tapetal cells, is less sensitive to glaucomatous degenerative changes than the retina elsewhere. One may speculate a variety of vascular or non-vascular reasons why tapetal sparing occurs, but none have been substantiated scientifically.
The cat retina, on the other hand, appears to be remarkably resistant to glaucomatous degeneration. Cat eyes can retain some functional vision long after elevations of similar magnitude and duration would have blinded most dog eyes, and this is borne out by the remarkable integrity of the retina, including persistence of some ganglion cells, in eyes removed from cats with chronic and severe disease.
The canine retina can occasionally show a remarkable tolerance when the ciliary cleft is collapsed and the IOP over 40-50 mm Hg.
Acute Glaucoma
The clinical presentation of glaucoma is influenced by the severity and duration of the elevation of intraocular pressure and the species involved.
In acute severe glaucoma, as commonly seen in a dog with collapse of the ciliary cleft, there may be a mild seromucoid discharge. The eye may be painful as manifested by blepharospasm and altered behavior. The episcleral and conjunctival vessels will be injected and the conjunctiva mildly edematous. The cornea will be diffusely and generally mildly to moderately edematous; the pupil will be moderate or widely dilated and fixed; if the outflow pathway can be visualized by gonioscopy, the cleft will be collapsed but the iridocorneal angle usually open. Vascular hypoxia can result in compromise of the blood aqueous barrier with resultant leakage of plasma proteins into the extraocular fluid compartments to present as a pseudouveitis. Ophthalmoscopy will demonstrate an optic nerve that can vary from appearing somewhat pale, to mild hyperemia and edema. Focal peripapillary hemorrhages of the inner retina are not uncommon. The retinal vessels, especially the venules, may appear somewhat attenuated, and while there may be mild retinal edema the background fundus is generally not notably abnormal. These eyes, as one might expect, have significant visual impairment.
Chronic glaucoma
Which chronicity, enlargement of the globe becomes apparent as the cornea and sclera stretch in response to the elevated intraocular pressure. This enlargement can occur quite rapidly and be quite dramatic in animals less than a year of age, where the cornea and sclera are less rigid than in the adult. With time, the pain that accompanies the acute disease subsides to a more tolerable level of discomfort. As the globe enlarges, linear arbiform fractures of Descemet's membrane may occur and are manifested clinically as gray deep corneal opacities, or striae.
Globe enlargement can lead to inadequacy of the eyelids and tear film to adequately protect the cornea, with resultant exposure keratopathy that may be characterized by a broad spectrum of clinical presentation from vascularization and scarring to ulceration to pigmentation and epidermadalization.
Uveal atrophy occurs and the iris becomes permanently dilated. Long-term damage to the ciliary epithelium in combination with other chronic changes will severely impair normal aqueous production-gradually reducing the IOP in advanced stages of glaucoma. Therefore the IOP in chronic, enlarged globes may be within "normal" limits.
The lens, dependent upon aqueous circulation for its metabolic needs, becomes cataractous; as the globe enlarges, the zonules may stretch and rupture with resultant subluxation or luxation; in the latter case the lens usually remains posterior, and rests on the floor of a liquefied vitreous cavity.
Thinning of the sclera can lead to staphyloma, most prominent between the limbus and the equator, which allow visualization of the pigmented underlying ciliary body and choroid.
In the dog, the progressive nature of the retinal degeneration can be variable and ophthalmoscopically range from near normal to geographic areas of retinal thinning characterized by tapetal hyper-reflectivity, mild vascular attenuation, and pigmentary changes in the non-tapetum. Histologically, the outer retinal layers degenerate, following the initial involvement of the inner retina; this change is more pronounced in the dog than in the cat. The appearance of the optic nerve is also variable, ranging from progressive atrophy without cupping to atrophy with prominent cupping; papillary and peripapillary hyperpigmentation, frequently in a circumferential pattern, is common.
Feline glaucoma
As alluded to, cat eyes tend to be more resistant to elevations of IOP and as such the clinical signs tend to be more subtle than in the dog. Surprisingly high elevations of IOP can be accompanied only by episcleral injection, variably accompanied by mild corneal edema and pupillary abnormalities.
With chronicity, globe enlargement does occur in the cat; progressive optic atrophy with or without cupping and hyperpigmentation occur as well, although the optic disc of the cat, being normally small, unmyelinated, and occasionally pigmented, makes critical evaluation of glaucoma-related optic atrophy somewhat problematic. The retinal degeneration is likely to remain ophthalmoscopically subtle, being limited to the ganglion cell layer, even into advanced disease, with persistence of even some ganglion cells late in the course of the disease.
The somewhat unique nature of the cat eye in relationship to glaucoma give rise to two clinical axioms:
While glaucoma can be suspected based upon breed, history, and clinical signs, quantitation of intraocular pressure by tonometer is required to definitely diagnose glaucoma.
Tonometry
The Schiotz indentation tonometer remains a tribute to Scandinavian ingenuity and remains a reasonable option to practitioners that do not have access to the more sophisticated technology of applanation. The tonometer estimates the intraocular pressure by measuring the amount of indentation of the cornea that occurs in response to a given force, or weight, and is based upon the principle that the greater that pressure within the eye, the lesser the indentation. The technique of obtaining reliable and reproducible IOP measurements while not as facile as that of applanation tonometry is readily mastered with a bit of practice; following topical anesthesia and the patient in a sitting position, the nose is elevated and the instrument applied perpendicular to the center of the cornea. The lids are retracted digitally without compressing the globe, and gentle restraint, if required by an assistant, is achieved without compression of the jugular veins which may result in artificial elevation of IOP. Three readings are taking; all should be within 1 or 2 scale readings, and averaged. Species specific conversion tables are available (26), but for clinical usage the human scale that accompanies the instrument provides an adequate approximation. In general, with a 5.5 gram weight, scale readings of 5 or above are considered within a normal range; from 3-5, moderate to mild elevation of intraocular pressure; from 1-3, moderate elevation; and 0 marked elevation. Additional weight can and should be added to the instrument to obtain greater sensitivity in semi-quantitation of higher IOP, with expansion of the scale in the higher pressure ranges.
Schiotz tonometry is influenced by a number of variables, including corneal curvature and resiliency and a clean instrument with a freely mobile plunger. Making tonometry a routine part of your physical examination will develop your technique and confidence to where you can obtain dependable data under more dire circumstances.
Applanation tonometry is based on the principle that the force necessary to flatten a given area of cornea is proportional to the pressure within the eye (27); while most would agree that it is easier to perform than Schiotz indentation, as head and eye position are not a factor, it still is somewhat demanding in terms of technique and care must be taken not to exert pressure on the globe while retracting the lids, and the angle and force of contact with the cornea are critical aspects of technique which, as with Schiotz tonometry, are readily mastered with a bit of practice. But, technology has its price.
We would definitely like to recommend routine use of tonometry by small animal practitioners as part of their physical and ophthalmic examination, with a caveat regarding the nature of glaucoma in animal species, especially the dog. There is no prognostic value in a single tonometric measurement taken at a given point in time in a particular animal. The vast majority of canine cases that one encounters will have pressures within the normal range one day, with marked elevations the next. The value of looking at IOP fluctuations over time, either in a diurnal or longer fashion, may or may not prove to be predictors of animals that are likely to develop glaucoma in the future.
Gonioscopy
Similar limitations should be recognized in regard to gonioscopy; a variety of gonio lenses are available and preference is at the discretion of the examiner. One of the authors (RLP) prefers an indirect 3 mirror lens because of the quality of the optics and the ability to readily examine the 360 degrees of the outflow pathway simply by rotating the lens, rather than subjecting oneself to a variety of contortions in order to obtain less than optimal visualization of all quadrants. The second author (BE), more nimble, prefers the Lo-Vac Barkan lens which is very easy to handle and provides a direct, magnified view of the periphery of the anterior chamber.
The gonioscopic anatomy has been described earlier; as mentioned, we classify gonioscopic appearance as either being normal; the presence of pectinate ligament dysplasia as characterized by imperforate ligament (Figure 5) and/or anterior insertion of pectinate fibers; the width of the ciliary cleft; and the nature of the iridocorneal angle (open or closed).
Figure 5 - Dysplasia of the pectinate ligament in a dog seen through the goniolens. On the left side of the photo, the pectinate ligament is dysplastic and only a small, circular flow hole can be seen. To the right of the whitish flash artefact, the appearance of the pectinate ligament is more normal. The height of the pectinate ligament is smaller than normal, indicating that the width of the entrance to the ciliary cleft is more narrow than normal too. It is essential to view the pectinate ligament around the entire circumference in order to detect focal abnormalities.
Gonioscopy may be useful in the detection of proliferation lesions such as primary or metastatic neoplasia within the outflow pathway. While there is a likely association between the presence and severity of goniodysgenesis and the possibility of future glaucoma in normal animals, or normal fellow eyes, this association is somewhat ambiguous. Eyes with remarkable goniodysgenesis and only one or two small flowholes can remain normotensive life-long. Conversely, glaucoma can develop in eyes with minimal pectinate ligament dysplasia. This is likely because the events that lead to glaucoma are taking place in the trabecular meshwork at a level we are unable to evaluate with gonioscopy. We regard pectinate ligament dysplasia as a marker of goniodysgenesis that in a particular dog may be associated with the trabecular meshwork changes as a distinct and separate aspect of goniodysgenesis.
Ophthalmoscopy
Athough the diagnosis of glaucoma can not be based solely on the ophthalmoscopic findings, ophthalmoscopy can provide additional clues to the diagnosis and prognosis. Indirect ophthalmoscopy gives a good, low-power overview of the retinal vessels and tapetal reflection. To be able to really appreciate the changes in the optic nerve head, a direct ophthalmoscope is needed to give sufficient magnification (Figure 6).
Figure 6 - Ophthalmoscopic evaluation of the optic nerve head provides valuable information. A normal optic nerve head with a physiologic cup in its center is diplayed to the left. The drawing in the middle shows a glaucomatous optic nerve head where the cup is enlarged; excaved. In advanced glaucoma the entire optic nerve head can be pushed backwards (right). The cupped nerve head and the vessels are also atrophic and the tapetal reflection is increased, indicating a thinning of the overlaying retinal layers.
Because of the risks associated with pharmacological dilation of the pupil in some glaucomatous dogs, ophthalmoscopy should be performed without instillation of mydriatic eye drops. This rarely presents a problem to the examiner, because the pupil is frequently dilated in these patients due to iridal ischemia or impaired retinal and optic nerve function.
Additional examination techniques
Other more sophisticated diagnostics that may some day assist in patient management continue to be explored as research tools; the use of high frequency ultrasound to elucidate the morphology of the outflow pathway may prove more sensitive than gonioscopy.
Quantitation of aqueous circulation and outflow utilizing techniques such as tonography and fluorphotometry might facilitate prognostication for normal eyes.
Sophisticated electrophysiology that isolates ganglion cell function may someday allow determination of visual potential, and tools for the study of optic nerve morphology and posterior segment correlation are emerging.
But, realistically, diagnostic aspects of glaucoma have changed little since the senior author (RLP) approached his cases with Schiotz tonometer in one hand, Franklin gonio lens in the other; only the bounce in the step has changed.
Orbital disease
A recurring challenging differential involves the distinction between exophthalmos secondary to a space occupying orbital lesion, either neoplastic or inflammatory, from the globe enlargement that occurs with chronic glaucoma. The latter will be distinguished by other signs of intraocular disease; unless the optic nerve is involved, eyes with orbital disease generally have normal pupils and are visual. While the intraocular pressure may be slightly elevated from compression of the globe with a space occupying orbital lesion, elevation of pressure is generally disproportionate to the degree of exophthalmos (although occasionally one will encounter chronically enlarged glaucomatous eyes with normal or subnormal intraocular pressure). Caliper measurement of horizontal corneal diameter in comparison to the fellow eye (if normal) or with no normal values (15-16 mm in an adult canine) can help distinguish enlargement from exophthalmos. Ultrasound can be utilized to document size and position of the globe and the presence or absence of orbital disease.
Episcleritis and conjunctivitis
The episcleral injection that accompanies glaucoma might be mimicked by other extra or intraocular inflammatory disease but tonometry and intraocular examination will readily allow differentiation. Episcleritis may be accompanied by a mild anterior uveitis, but intraocular examination is usually otherwise unremarkable.
Conjunctivitis also causes a red eye. However, there is no engorgement of the deep vessels on the sclera and also several other hallmarks of an elevated IOP are missing in patients with an inflammation restricted to the conjunctiva.
Anterior uveitis
With anterior uveitis, the pupil is usually miotic and the IOP lower than normal; the diagnosis of secondary glaucoma resulting from uveitis can generally be made by the presence of elevated intraocular pressure associated with other signs indicative of chronic inflammation including peripheral anterior synechia, iris bombay, rubeosis irides, or keratic precipitates.
Corneal diseases
Endothelial dystrophy may be accompanied by episcleral injection and corneal edema, but pressure and pupillary light reflexes will be normal.
Other conditions
The staphyloma that occur with chronic glaucoma might be confused with intrascleral extension of an intraocular melanoma, and the distinction becomes even more problematic if the melanoma has resulted in secondary glaucoma. Ultrasound can be extremely helpful in these eyes, especially if changes in the anterior segment preclude detailed intraocular examination.
Other conditions that result in loss of vision, optic atrophy, and are pupillary dilation (such as optic neuritis) will be characterized by normal IOP, characteristic findings upon ophthalmic examination, and absence of the other signs that characterize chronic glaucoma.
The challenge of glaucoma
Glaucoma is at best a challenging disease to manage. Life long application of expensive drugs may be required. Surgical options with depressing predictability will likely be a necessity not once but perhaps multiple times. Normal fellow eyes are at risk for an equally tragic course. And in spite of heroic efforts by the ophthalmologist and significant physical, emotional, and financial input by the pet owner, there remains the strong likelihood that the pet may be left blind, regardless.
Like it or not, in spite of the progress that has been made, this is what we deal with. There is no cookbook approach and each case is an experiment with the clinician responding to the response of the patient to each intervention. Because of this, we believe that client education is the foundation of glaucoma management, and the decisions made by a client fully informed from the start made in conjunction with the ophthalmologist are essential for an optimal outcome for the patient.
Glaucomatous eyes can be segregated into two groups for management purposes; those that are potentially visual (acute or mild glaucoma in dogs, most glaucoma in cats) and those that are irreversibly blind. In dogs with acute severe glaucoma, the prognosis for vision is poor with pressures greater than 50mm Hg after 48 hours. The presence of vision on functional testing, a consensual pupillary light reflex, and/or minimal funduscopic changes are factors that indicate the potential for preservation of some vision; there is empirical evidence that in acutely blind animals, some reversibility of the blindness is possible if IOP can be controlled (Figure 7). The presence of chronic glaucoma as indicated by history and clinical signs bode poorly for vision; in adult dogs obvious enlargement of the globe is ominous in this regard. In young dogs, however, enlargement may not be incompatible with visual potential.
Figure 7 - Advanced funduscopic changes indicate that there is a minimal chance that the patient will regain vision. In this canine patient with chronic glaucoma, the optic nerve head is cupped and atrophic, the number and appearance of the retinal vessels highly abnormal and the light reflection from the tapetal fundus increased.
The objective of treatment in eyes with visual potential is both the prompt and prolonged maintenance of intraocular pressure and IOP level where progressive deterioration of retinal neurons will not occur; while this is an elusive variable to pin down, we suggest that 20mm Hg is the maximal target value one should shoot for but recognizing that for optimal control lower is generally better.
Comments on acute treatment
Immediate reduction of intraocular pressure may involve medical or surgical interventions. Hyperosmotic agents administered either intravenously or orally will dehydrate the vitreous, decreasing ocular volume and lowering intraocular pressure; Mannitol administered at 1-2g/kg I.V. over a 30 minute period, or oral glycerin administered at 1-2ml/kg orally will generally lower intraocular pressure within 60 minutes and may be repeated once within a 6 hour period if required.
Carbonic anhydrase inhibitors decrease aqueous production and can be administered intravenously, orally, and/or topically (Table 3). Topical autonomic agents (Table 4) may be used alone or in combination with other agents; prostaglandin agents (Table 5) work by increasing uveoscleral flow and can result in a dramatic increase in intraocular pressure in acute canine glaucoma.
Once IOP is within an acceptable range, plans for long term management may be addressed. Again, they fall into medical and surgical options; in our experience, the most consistent long term results are the result of combined surgical and medical management.
Medical therapy is expensive, dependent upon client compliance with both administration and regular follow-up examinations, and less likely to be effective for long term control of the glaucoma. Much of the limitation of medical therapy is related to the unpredictability of response of individual cases and a lack of knowledge regarding drug efficacy both alone and in combination. Much of the data in the literature requires inter-species correlation of scientific data, extrapolation from models that have few similarities to the clinical disease, or rely upon data on effects of drugs on IOP in normal, rather than diseased, animal eyes. We do not know what drugs or combination of drugs will work best, or indeed will work at all, in any particular case of glaucoma.
The initial intervention
However, clinical experience has provided us with impressions that serve as guidelines. Based upon these guidelines, these are the recommendations that we would make in the management of potentially visual eyes with acute glaucoma: administer Mannitol I.V. and apply 1 drop of dorzolamide and latanoprost to the affected eye. Monitor IOP at 30 minute intervals; if IOP is not less than 20mm Hg in 60-90 minutes, aqueous decompression is performed.
We have found aqueous decompression to be a safe and reliable way to rapidly decrease intraocular pressure and will use it where medical therapy is not resulted in an IOP of less than 20 mm Hg within 1-2 hours. Under topical or light general anesthesia, a 30 gage needle on the hub of a tuberculin syringe with plunger removed is inserted through the limbus anterior and parallel to the plane of the iris just to the point when aqueous can be observed to rise in the syringe; over a period of 30-60 seconds intraocular pressure will equilibrate with that of the atmosphere, aqueous drainage will cease, and the needle is withdrawn. Effect is transient (up to 12-24 hours); there is a suggestion that many of the pharmacological agents will work with greater efficacy in an eye that is normal or hypotensive. Intraocular hemorrhage, lens trauma, and reperfusion injury are potential complications that need to be weighed against the disadvantage of the deleterious effects of persistent elevated IOP.
Surgical intervention is encouraged and if elected is performed within 12-24 hours, continuing BID topical administration of the dorzolomide and latanoprost and monitoring IOP regularly within the interval. If attempts at medical management are elected, initial treatment includes BID dorzolamide and latanoprost with daily IOP checks until the clinician is confident that the IOP is reasonably well controlled. If the IOP cannot be adequately controlled with the 2 topical hypotensive agents, additional hypotensive agents may be added, one at a time, and oral carbonic anhydrase inhibitors may be initiated as well. In general, however, the expense of the more contemporary topical hypotensive agents makes surgical options attractive both from a perspective of economy as well as efficacy.
Surgical treatment options
Surgical options for the management of acute glaucoma and potentially visual eyes fall into 2 main groups of procedures; those that are cyclodestructive, that is partially ablate the ciliary body epitheliaur with resultant reduction in aqueous humor production (28-30), or enhance aqueous flow from the eye by the creation of transscleral pathways (31-37). In addition, the management of secondary glaucoma may involve surgical approaches to management of the primary disease; anteriorly luxated lenses require intracapsular lens extraction and usually radical anterior vitrectomy. Cilio-vitreal-lenticular block glaucoma in cats may require a similar procedure.
Cycloablative procedures
Surgical cycloablative procedures involve the application of either heat or cold with resultant partial destruction of ciliary body and a subsequent reduction in aqueous production and thus intraocular pressure. Transscleral cyclocryotherapy involves the application of a 2-2.5mm cryoprobe 3.5mm posterior to the limbus; 2 freeze-thaw cycles of 1-2 minutes duration are applied at each site to reduce the ciliary epithelial temperature to minus 15 degrees C. 6-8 sites are treated circumferentially, avoiding the long posterior ciliary vessels at 3:00 and 9:00. The size of the cryoprobe, the number of sites frozen, the duration of freezing, and the number of freeze-thaw cycles are all variables that the surgeon can manipulate, as well as choice of cryogen which will obviously affect these parameters.
The technique may cause postoperative chemosis for 24-72 hours and has other potential side effects including uveitis, a transient elevation of intraocular pressure over the first 24-48 hours, exudative retinal detachment, and phthisis bulbi if freezing is excessive. Our protocol involves pre and postoperative use of anti-inflammatories, aqueous decompression at the time of surgery, and postoperative pharmacologics as required.
In the experience of the authors, long-term control of IOP is achieved in approximately 30% of operated patients. As the ciliary body epithelium may regenerate, with resultant insidious elevation of IOP, these patients must be followed closely long-term and hypotensive medications tittered to effect. Advantages of cyclocryoablation include its simplicity and non-invasive nature; ease of repetition if required; and relative cost of instrumentation.
Laser cyclophotocoagulation uses a hand-held, neodymium: yttrium, aluminum, garnet (YAG) laser; 7-8 joules of energy are delivered transsclerally at a point 5mm posterior to the limbus, with a total of 230-250 joules delivered over 25-30 sites. A diode laser can be used to apply a total of 70-80 joules of energy over 25-35 sites. Success rates have been touted to be higher than those achieved with cyclocryoablation, and inflammation somewhat less; as with freezing, postoperative elevations of IOP may be seen. Other reported complications include uveitis, hyphema, mild corneal edema, and cataract formation.
Prophylactic cycloablation of normal fellow eyes has been advocated; however, no data are available as to risk-benefit ratios to sway arguments one way or the other.
Filtering procedures
Filtering procedures allow for external drainage of aqueous via a surgically created scleral defect or via synthetic drainage devices placed into the anterior chamber. These techniques provide immediate lowering of IOP, but results over time are somewhat discouraging, especially when compared to the success rates of filtering procedures in humans. Filtering sites become occluded by uveal tissue, vitreous tissue, fibrin, and eventually fibrosis. Goniotubes may become occluded by uveal tissue, fibrin, or cellular membranes; extrascleral reservoir sites become encapsulated by fibrous tissue that prevents the escape of sequestered aqueous into the orbital spaces and blood vessels. The number of variations on this theme in regard to both filters and gonio devices attest to their inadequacy, and a success rate of 50% is quite optimistic.
Of the filtering procedures, posterior sclerotomy, cyclodialysis, and transscleral iridencleisis is still utilized by one of the authors (RLP), with some success. Gonioimplantation is somewhat technically demanding, notably in regard to scleral hemorrhage during flap preparation and precise positioning of the goniotube. Postoperative complications include implant instability with tube retraction; conjunctival erosion overlying the reservoir; fibrosis around the reservoir with or without formation of the cystic bleb; and tubal occlusion.
There is some clinical evidence that superior results are obtained by combining a cycloablative and filtering procedure, rather than depending on either one individually; the disadvantage is that the inflammation that occurs as a consequence of either laser or cryocycloablation may complicate filtering procedures. The use of postoperative EPA and aggressive anti-inflammatory therapy may minimize this possibility.
Cosmetic Procedures for Irreversibly Blind Chronically Glaucomatous Globes
It is generally accepted that eyes with elevated intraocular pressure result in some level of discomfort that may be manifested in behavioral changes, even in the absence of signs of the vert ocular pain, such as blepharospasm, and treatment of these eyes to ensure an optimal quality of life is indicated. Sources of discomfort include elevated intraocular pressure and exposure keratitis. Occasionally, a chronically glaucomatous eye will return to normal tension and require no treatment. The limited efficacy of hypotensive agents in such eyes with chronic IOP elevation, their expense, especially when administered on a long term basis, and their potential side effects limit their usefulness in achieving cosmesis. A variety of surgical approaches are applicable.
Enucleation
Enucleation has the advantages of predictability; a single surgical procedure and outcome is virtually assured, and the use of a PMMA orbital spherical prosthesis will optimize postoperative appearance. Enucleated globes should always be examined histopathologically and may provide valuable information into the cause of the glaucoma, if previously undetermined, such as an occult intraocular neoplasm, and provide implications for prognosis of the fellow eye if goniodysgenesis is prominent.
Globe sparing procedures
There are pet owners with aversion to enucleation and desire a globe sparing procedure. Laser or cryo/cycloablation are about as predictable in chronically glaucomatous blind eyes as they are in those that are potentially visual; application of energy is somewhat problematic as the anatomy of the anterior segment changes as globes enlarge, and in general the landmark for transscleral energy application moves more posterior to the limbus. This is especially true in the cat.
Evisceration
Evisceration with insertion of a silicon intraocular prosthesis is perhaps the most predictable globe sparing procedure for the dog. The globe is entered through either a limbal incision, or through a circumferential incision posterior to the limbus, the intraocular contents removed, and a 16 mm black PMMA sphere inserted. Hemorrhage can be brisk and a suction apparatus facilitates the process; care must be taken to remove all of the intraocular tissue and not to damage the corneal endothelium. Like enucleated globes, eviscerated content should always be submitted for histopathologic evaluation. While these eyes can be readily distinguished from normal, they usually provide a very reasonable cosmetic result.
Pharmacologic ablation of aqueous humor production
Pharmacologic ablation of the ciliary body with the intravitreal injection of gentamicin or cidofovir provides a reasonably predictable way to lower IOP. These drugs lower IOP by their toxic effects on the ciliary body epithelium; they are likewise retina toxic, and thus their use should be reserved for eyes that are unequivocally irreversibly blind. Cosmetic results are somewhat unpredictable; both injections are accompanied by a transient inflammatory response that is in general more severe with gentamicin. Dense white cataracts are a frequent sequelae and some eyes may become phthisical, which is more desirable in terms of comfort than an eye with elevated IOP but which may fall short in terms of appearance and being totally maintenance free. These procedures have the advantages that they can be performed in most dogs with just topical anesthesia and are more economical than ocular surgery and are reasonable options if risk of anesthesia is high or financial constraints significant.
Gentamicin has the advantage of being readily available and the disadvantage that it requires a larger volume of injection, as well as the greater inflammatory response as detailed above. Following topical anesthesia (local anesthesia can be used to augment the topical by injecting a small amount of Litocane subconjunctivally), a 21-gage butterfly is directed into the globe through the sclera approximately 6 mm posterior to the limbus at 12:00 and towards the optic nerve, to avoid the lens. In the majority of chronically glaucomatous eyes, the vitreous will be liquefied and it will be possible to aspirate up to 0.5 mls; gentle manipulation of the tip of the needle may reveal pockets of liquefied vitreous if aspiration is difficult. If one is unable to aspirate vitreous, aqueosentesis is performed. Intravitreal injection of 10-25 mg of gentamicin and 0.5-1 mg of dexamethasone is performed-in a maximal total volume of 0.5 ml is performed. The butterfly is withdrawn with pressure applied at the needle site to minimize escape of injected medication. Cidofovir is an antiviral agent that is more difficult to acquire, and more expensive than gentamicin but has the advantage that very small volumes are required for effect and thus vitreous aspiration is not necessary. Post injection inflammation is less intense and cataracts and phthisis are less common than that seen with gentamicin. Again, the ocular surfaces are flushed with betadine solution; aqueous decompression is performed using a tubercular syringe with the hub removed and a 27-gage needle. The needle is inserted at the 12:00 limbus of the topically anesthetized eye just anterior and parallel to the plane of the iris; as the anterior chamber is entered, the aqueous is allowed to rise and the syringe to equilibrate to atmospheric pressure and withdraw. 375 to 500 microliters of cidofovir (0.1 to 0.2 mls) are injected into the vitreous in a fashion identically used to insert the 21-gage butterfly needle for gentamicin injection.
Both techniques are followed by the subconjunctival injection of 1 mg of triamacinalone and topical anti-inflammatories and systemic non-steroidals prescribed as required to control the postoperative inflammation, which generally resolves over a 3 to 4 week period. Hypotensive effects are evaluated 1-week post injection and in general tend to be permanent once achieved; if elevated intraocular pressure remains, injection can be repeated.
These techniques should not be utilized if there is a strong suspicion of intraocular neoplasia as demonstrated by clinical examination and ultrasonography, or in the case of glaucoma arundi termin etiology that histopathologic examination of tissues may be of benefit in managing either the patient or the fellow eye. In our histopathology archives (RLP), we have documented cases of primary ocular sarcomas occurring in cats following the insertion of intraocular prostheses and pharmacologic ablation of the ciliary body, and while the incidents and specifics of the association has not been defined, the aggressive nature of this neoplasm would seem to contraindicate the application of these techniques to the feline, where enucleation is recommended for all irreversibly blind globes.
The clinician can regard the management of glaucoma in dogs and cats as either an exercise in futility or a demanding challenge. Many eyes are lost, but some are saved with the dedicated efforts of clinician and owner. Surgical and pharmacologic interventions represent symptomatic treatment, and while the near future may provide small advances based on refinement of surgical techniques and the development of new pharmaceuticals, especially in regard to neuroprotection, advances are likely to continue to be limited until our understanding of the pathogenesis of primary glaucoma in animal species becomes more clearly ellucidated, and good hard scientific data is accumulated in regards to efficacy of treatment modalities in veterinary patients.
This section GLAUCOMA was authored by Robert L. Peiffer, Jr., Dept. of Ophthalmology, University of North Carolina, Chapel Hill, NC. and Björn Ekesten, Dept. of Ophthalmology, University of Minnesota, Minneapolis, MN. January 2002.
All figures and pictures in this section are of the copyright of Björn Ekesten.
