Selected lens diseases and cataract treatment (Proceedings)

Lens diseases can affect vision and if not treated properly can be devastating to the eye, often leading to blindness. Unfortunately, treating lens diseases often requires specialized surgical skills and equipment. Understanding the pathogenesis and pathophysiology of selected lens diseases will assist veterinarians in ensuring long-term vision and preventing other problems that result from certain lens diseases.

Embryology

The lens is formed early in embryogenesis. Inductive signals from the anterior neural plate give an area of surface ectoderm a "lens forming bias." Surface ectoderm is induced to differentiate over the optic vesicle starting at day 17 in the dog to form a lens placode. The lens placode then thickens and invaginates to form the lens vesicle, which separates from the ectoderm at day 25.

The early retina induces lens fibers to develop, and by day 29, the embryonic nucleus is formed. At day 40, secondary lens fibers form lens epithelial cells at the equator that remain mitotically active throughout life and produce the lens cortex. These secondary lens fibers are deposited outside the pre-existing fibers like an onion; these fibers course anterior to posterior and meet to form Y-sutures.

The embryonic lens receives its vascular supply from the tunica vasculosa lentis, which is made up of the hyaloid artery, posteriorly, and by the pupillary membrane, anteriorly. This vascular network starts to regress at day 45 in the dog, and regression is complete by two weeks postnatal.

Anatomy and physiology

The lens is biconvex, with anterior and posterior poles and a peripheral equator. The lens' main function is to focus light on the retina. For proper function, the lens must be transparent, in the proper position, and able to change shape to achieve accommodation. Lens transparency is due to the precise orientation of lens fibers, lack of pigment and blood vessels. The lens relies on aqueous humor for its nutritional and metabolic needs. The lens is suspended by zonular ligaments that arise from the pars plana portion of the ciliary body and course anteriorly to attach to the ciliary processes. The zonules extend to the lens capsule and attach via a network of bundles and fibrils that ramify over the lens capsule, ~2mm anterior and posterior to the equator. Posteriorly, the lens is held in place by the anterior vitreous or patella fossa and is supported anteriorly by the iris. Ciliary body contraction relaxes the zonules and changes the lens shape, allowing for accommodation.

The lens epithelium secrets a tough elastic capsule that surrounds the lens. The thickness of this protective capsule varies, being 50-70µm anteriorly, 8-12µm at the equator, and only 2-4µm posteriorly. This capsule restricts entry of particles into the lens based on size, charge, and lipid solubility.

Active Na+ pumps in the lens epithelium cell membranes maintain the level of hydration in the lens, which is relatively dehydrated, being about 2/3 water and 1/3 protein. The protein content of the lens is higher than that of any other bodily organ, and most protein synthesis occurs with the formation of new lens fiber cells. About 85% of the lens proteins are soluble proteins that make up the bulk of the lens fibers. Most of these soluble proteins are in the cortex, while most of the insoluble proteins are in the compact nucleus. With age, the level of insoluble to soluble proteins increases. Lens proteins are organ specific but not species specific, meaning that the body sees them as foreign antigens. The normal capsule and lens fiber membranes do not allow passage of protein into the aqueous.

Diseases of the lens

The most common congenital defects of the lens are related to vascular anomalies, specifically pertaining to the tunica vasculosa lentis, and manifest either as persistent pupillary membranes or persistent hyperplastic primary vitreous/persistent hyperplastic tunica vasculosa lentis. Persistent pupillary membranes are a far more common anomaly than the latter and occur when the anterior portion of the tunica vasculosa lentis fails to regress. The tunica vasculosa lentis forms pupillary membranes and, as mentioned previously, takes up to 14 days post-nataly to regress. These pupillary membranes typically originate from the iris collaret and can extend iris to iris, iris to cornea, or iris to lens, where they can create an anterior cortical cataract.

Persistent hyperplastic primary vitreous (PHPV) is a consequence of residual structures in the posterior tunica vasculosa lentis, most often due to failure of the hyolid artery to regress. PHPV can cause posterior cortical cataracts or, in severe cases, posterior lenticonus. It has been well described in Doberman Pinschers and has six grades of severity.

The most common manifestation of lens pathology is cataract formation. Loss of lens transparency is usually associated with derangement in the protein order or lens structure, which causes increased light scatter and is characterized by protein aggregation, changes in tissue hydration, phase separation of molecular components, breakdown of cell membranes, and changes in lens cytoskeletal structure. Most if not all of these changes occur during aging and cataract formation.

The earliest histologic feature of cortical protein degeneration is lens fiber swelling, leading to the formation of bladder cells and Morgagnian globules. Bladder cells are swollen, nucleated lens epithelial cells, and Morgagnian globules are spherical clumps of degenerating lens protein. Histopathologic changes of the lens capsule associated with cataracts include capsular thinning, wrinkling, plaque formation, and rupture. With an intumescent cataract you will see anterior and posterior capsular thinning. A hypermature cataract will have a wrinkled lens capsule, dystrophic calcification, and formation of multifocal subcapsular plaques. Lens capsule perforation or rupture will cause the edges of the ruptured capsule to curl and will have an associated intralenticular inflammatory response.

Classifying cataracts

Classifying cataracts and describing their location within the lens helps determine the cause and expected progression of the cataract in question. The different stages of cataract progression are incipient, immature, mature, and hypermature.

Incipient cataracts are early, clinically apparent cataracts that occupy less than 15% of the lens volume. They commonly involve the cortical, subcapsular, or Y-suture regions of the lens and, depending on etiology, may or may not progress.

The hallmark feature of an immature cataract is a tapetal reflection without evidence of hypermaturity. Often immature cataracts are osmotically active, resulting in an intumescent lens due to the influx of fluid.

Mature cataracts involve the entire lens structure, totally blocking the tapetal reflection. Mature cataracts almost always give rise to lens-induced uveitis. The complete formation of the cataract causes the lens protein to leak through the lens capsule and into the eye, causing lens-induced uveitis. Cloudiness in the anterior chamber together with prominent miosis and a darkened iris are the most common signs of lens-induced uveitis.

Hypermature cataracts occur as degenerative and ruptured lens fibers release enzymes, exacerbating proteolysis, especially in the cortical regions of the lens. Wrinkling of the anterior lens capsule occurs as degenerating lens proteins diffuse across the lens capsule, causing the lens to decrease in size. The anterior surface becomes flatter and the anterior chamber increases in depth. Lens associated inflammation called phacolytic uveitis is a common sequela to lens protein lysis and leakage into the aqueous humor. As resorption of the cataract continues, portions of the peripheral fundic reflex can be seen. Multifocal anterior and posterior subcapsular plaques are common. The Morgagnian cataract is a type of hypermature cataract in which the nucleus sinks ventrally within the capsule.

Cataracts and their selected causes

Hereditable or presumed hereditable cataracts are the most common type of cataract seen in juvenile to middle-aged pure bred dogs. Early developing and progressive inherited cataracts are recognized in a number of breeds. They are usually bilateral and symmetric. The mode of transmission has only been established in a minority of breeds, the majority being inherited as a simple autosomal recessive trait.

Diabetes mellitus is the most common systemic metabolic condition that causes cataracts in dogs. Hyperglycemia causes increased levels of glucose in the aqueous humor. This glucose enters the lens by facilitated diffusion and as the glucose concentration in the lens increases, the anaerobic glycolysis pathway that is catalyzed by hexokinase, becomes saturated, shifting glycolysis to the sorbitol pathway. The sorbitol pathway converts glucose to sorbitol via the aldose reductase enzyme. Unfortunately, sorbitol does not readily diffuse through the lens capsule, causing an accumulation of this compound within the lens. This increased intralenticular sorbitol concentration results in an osmotic gradient, causing an influx of water from the aqueous humor into the lens, resulting in structural changes, including lens fiber swelling and rupture, vacuole formation, and cataracts. These cataracts are normally rapidly progressive and become intumescent with wide suture clefts.

Hypocalcemic cataracts occur secondary to renal failure, or hypoparathyroidism. They present as multifocal, punctate cortical opacities and are bilaterally symmetric. Hypocalcemia causes a defect in the cation transport of lens epithelial cells. This leads to an increase in Na+ and a loss of K, causing an osmotic imbalance, resulting in lens fiber swelling and rupture. Treatment of hypocalcemia will generally stop the cataract progression but will not reverse existing lens opacities.

Toxin-induced cataracts develop at a variety of lens locations, depending on the toxic agent and its mechanism. Typically, however, most of these cataracts begin at the anterior and posterior cortices near the equator, or the Y-suture regions, and are often associated with vacuole formation. These vacuoles are able to be reversed if the toxic insult is removed. Toxic agents commonly cause derangements in the cell membrane permeability by affecting Na/K ATPase pump function. Agents that have been known to cause cataracts include ketaconozole (an anti-fungal agent) and disophenol (an anthelmintic agent).

Retinal degeneration, such as Progressive Retinal Atrophy and Sudden Acquired Retinal Degeneration syndrome (SARDs), is the most common cause of toxic cataracts in the canine. These cataracts develop due to alterations in the function of Na/K ATPase pumps from peroxidation of degenerative rod outer segment photoreceptor membranes and subsequent release of water-soluble dialdehydes. The cataracts are progressive and are characterized initially by an increased posterior subcapsular relucency, giving the cataract a lacy appearance.

Neonatal dietary cataracts have been reported in puppies, wolf pups, and kittens fed oral milk replacement products during the first week of life. In experimental conditions, puppies developed lens opacities by three weeks. These cataracts have a brown lamellar zone that separates the anterior and posterior nuclear and cortical junctions. This zone progresses to a dense white perinuclear opacity. The pathogenesis is related to arginine deficiency at a critical stage in neonatal lens development. These cataracts usually improve when the animal is placed on a proper diet.

Blunt trauma to the globe can result in cataract formation as a result of compressive forces causing rupture of lens fiber membranes along the anterior cortex, thus disrupting the precise spacing between the lens fibers. Initial cataractous changes occur at the anterior and posterior lens sutures and appear stellate in shape. Rupture of the lens capsule by blunt trauma is rare.

Perforation of the lens capsule cause focal to diffuse cataract formation. Small rents in the anterior lens capsule < 1.5mm may seal by fibrous metaplasia. Dogs, rabbits and cats typically have a fibrinous neutrophilic response and are better able to seal small rents in the lens capsule than humans. Rents larger than 1.5mm are associated with phacoclastic uveitis and secondary glaucoma. Thus, prophylactic lensectomy is necessary in these cases, not only to preserve vision, but also to protect the globe.

In cats, primary ocular sarcoma is an aggressive malignant ocular neoplasm that is often associated with lens trauma. Time from trauma to detection of the tumor is approximately five years. After detection, even with early orbital exenteration, most cats die of metastatic disease within several months. Therefore it is imperative that these lenses be removed early.

Cataract treatment

Cataracts cause uveitis as a consequence of lens proteins leaking into the eye. Chronic inflammatory lens-induced uveitis leads to glaucoma or retinal detachments if not addressed. Therefore, it is important to treat animals with cataracts as soon as possible with anti-inflammatories to control the onset of sequela.

Recently, products (such as Ocluvet) containing an antioxidant formula including N-acetyl Carnosine have been marketed as providing a medical cure for cataracts. As of yet, these claims have not been scientifically proven and thus far have been no more effective in dissolving cataracts than natural cataract degeneration and degradation, as seen in hyper-mature cataracts. Furthermore, when these neutraceuticals are used, the concern is that the potential sequela of cataracts, which are not benign, might be left untreated.

Topical aldose reductase inhibitors have been shown experimentally to reduce the onset of cataracts in dogs with diabetes. This potential future medical modality might decrease or even prevent the onset of diabetic cataracts.

Cataracts can be removed surgically to restore vision. Historically, extracapsular cataract extractions were delayed until cataracts were mature. However, with new advancements in cataract surgery and the advent of phaco-emulsification, cataract surgery is now performed much earlier and with higher success rates (upwards of 90%). Today, newer phacoemulsification machines allow for more settings and power adjustments than were previously available. These machines allow the surgeon to fine tune the instrumentation during surgery to provide the right amount of ultrasonic power for safe and efficient cataract extraction.

To ensure the most successful outcome of cataract surgery, patients must be carefully screened. A minimum ophthalmic database includes a complete ophthalmic examination, qualitative and quantitative tear film assessment, tonometry, gonioscopy (to evaluate the iridocorneal angle and thus predisposition to glaucoma), an electroretinogram (to detect retinal degeneration) and/or ocular ultrasound (to detect retinal detachment).

Bimanual surgical techniques for removing cataracts, such as the phaco chop, have recently been adopted. The phaco chop technique uses less phaco time and energy to remove the cataract, thus decreasing the chance for secondary complications. Other advantages of phaco chop include reduction of zonular and capsular stress (because forces are directed toward an opposing instrument) and the phaco tip being kept in a central 'safe zone' in the middle of the pupil.

Potential complications after cataract surgery include trauma (exogenous or self induced), which is a major concern, particularly immediately after surgery. Hence, temporary tarsorrhaphy sutures are placed, and patients go home with an Elizabethan collar.

Corneal edema due to endothelial damage can occur, especially when a significant amount of phaco power has been used to remove the cataracts. This occurs most commonly in older dogs that have marginal endothelial cell reserves and in breeds that are predisposed to endothelial dystrophy, such as Boston Terriers. Dispersive viscoelastics (that coat the endothelium) and the two-handed phaco technique help decrease this complication.

Posterior capsular opacification (PCO) is the most common long-term complication of cataract surgery in dogs, with smaller- and medium-sized breeds developing PCO earlier than larger breeds.

Postoperative hypertension and glaucoma is always a concern. This condition can occur due to swelling and hydration of the iridocorneal angle trabecular meshwork or due to residual viscoelactic agents clogging the iridocorneal angle. Irrigation of the anterior chamber and use of Carbachol and Tissue Plasminogen Activator help prevent this.

The frequency of retinal detachment post cataract surgery is 4% for immature cataracts, 6.5% for mature cataracts and 19% for hypermature cataracts. The majority of postoperative detachments and tears involve the peripheral retina, suggesting that there is tension on the peripheral retina as shrinkage of the lens and its capsule occurs.

In conclusion, early cataract removal requires less ultrasonic power, thus less ocular trauma and less surgical time. The end result of early cataract removal is less postoperative inflammation and higher long-term success rates. Referring patients early in the course of their disease and educating owners that the referral is for a complete ocular examination may better define which patients are candidates for surgery and the optimal timing for this surgery.