Signs and Symptoms
Exfoliation syndrome and exfoliative glaucoma occur in high rates throughout northern Finland, Iceland, Saudi Arabia, Great Britain and Greece. The condition has a predilection for northern climates.1-4 Exfoliation occurs in 5% of older Americans.5 This condition is considered uncommon in patients of African descent, though it does occur.6,7 The true overall prevalence of exfoliation may be underestimated, as 15% of cases may be missed clinically.8
Exfoliative glaucoma is predominately a disease of the elderly and is rarely found in patients younger than 50.4,9 The lowest age of onset reported thus far occurred in a 17-year-old girl.10 The highest prevalence rates have been found in patients over the age of 70.11-15
Patients present with a fine, flaky material on the anterior lens capsule at the pupillary margin. Over time, this will coalesce into the characteristic “bull’s-eye” pattern typically seen in exfoliation syndrome. On the lens capsule, there will be a central area of exfoliative material, surrounded by a clear area where the material has been eroded by the iris contracture, which itself is surrounded by a peripheral area of exfoliative material. This classic pattern is usually only observable when the patient’s pupil is dilated. Beyond the anterior lens surface, exfoliative material is most commonly seen accumulating at the pupillary margin. This may be visible in an undilated state. Pigment loss from the pupil margin with subsequent pigment granular deposition on anterior chamber structures is a hallmark of the condition.9 This leads to increased transillumination of the iris at the pupillary margin, termed peripupillary transillumination defects. There may be pigment granules on the corneal endothelium and iris surface. Within the angle there may be observable pigment, clear flaky material, or both.16-18 Gonioscopically, the trabecular meshwork pigmentation is often not as solid as seen in pigment dispersion syndrome, as there is more than just pigment in the exfoliative angle.
Initially, intraocular pressure is unaffected in exfoliation syndrome; however, elevated intraocular pressure can develop, and characteristic glaucomatous cupping and visual field loss may ensue. In one report, 16% of patients with clinically apparent exfoliative material required treatment upon presentation, with 44% developing a need for therapy over the next 15 years.13 Roughly a 32% conversion rate from exfoliation syndrome to exfoliative glaucoma occurred over a 10-year period in another study.14 One report noted a 45% conversion rate from exfoliation syndrome to exfoliative glaucoma over a mean time frame of five years.19 Clinically, exfoliative glaucoma is markedly asymmetric with biomicroscopically unilateral involvement in many cases.4,5,13,14,20
Patients with exfoliation are more prone to developing cataracts as well as surgical complications during extraction.21-25 Complications include poor pupillary mydriasis, poor zonular integrity and intraoperative zonular dialysis, spontaneous lens dislocations and vitreous loss during surgery. Occasionally lens displacement with pupil block and angle closure may occur.26,27
Exfoliation involves the production and accumulation of an abnormal fibrillar extracellular material within the anterior chamber of the eye.28,29 The accumulated material consists of a fibrillar component and an amorphous component, though the exact chemical composition remains unclear.30-34 It appears that the material represents abnormal basement membrane secreted by all structures within the anterior chamber and deposited on the anterior lens capsule, iris surface and trabecular meshwork.30-34 Due to accumulation of material at the pupillary margin, there is increased lenticular apposition with the iris and subsequent erosion of iris pigment as the pupil dilates and constricts. This leads to increased iris transillumination and deposition of pigment granules on the endothelium, iris surface and trabecular meshwork similar to PDS. The iris will also rub this material off the lens surface, with a mid-peripheral clear zone. As this is a condition that involves deposition of material on the anterior lens capsule, and not flaking off of the lens capsule, lensectomy is not curative.
There has been conjecture as to whether this condition should be called exfoliative glaucoma or pseudoexfoliative glaucoma, and both terms are often used interchangeably. True exfoliation of the lens capsule is a rare disorder in which the lens capsule is thickened and the superficial portion of the lens capsule splits from the deeper layer, often due to exposure to intense heat or infrared radiation. Because material is laid down upon the surface of the lens, and the lens capsule is not being rubbed off, many prefer to use the term pseudoexfoliation. However, iris contracture is rubbing the material off the lens, so exfoliative glaucoma seems a more appropriate term.
The development of glaucoma typically occurs due to a buildup within the trabecular meshwork of pigment granules and exfoliative material. The primary cause of IOP elevation appears to be phagocytosis of accumulated pigment and material by the trabecular cells and Schlemm’s canal cells with subsequent degenerative changes of Schlemm’s canal and trabecular meshwork tissues. Thus, this is a secondary open angle glaucoma mechanism.26,27 However, due to zonular dehiscence from accumulations of exfoliative material, there can be lens displacement with secondary pupil block and angle closure mechanisms.26,27
Patients with exfoliation have demonstrated aggregates of similar material in the fibrovascular connective tissue septa of the skin as well as in some internal organs (e.g., heart, lung, liver and kidney). Some evidence suggests an association with transient ischemic attacks, aortic aneurysm formation and systemic cardiovascular diseases.27,33 Thus, exfoliation syndrome is considered to be a generalized systemic disorder rather than solely an ocular condition.33
Genetic studies have identified a highly significant association between several polymorphisms in the lysyl oxidase-like 1 (LOXL1) gene in both exfoliation syndrome and exfoliative glaucoma, occurring in almost 100% of exfoliative patients worldwide. LOXL1 is a pivotal crosslinking enzyme in extracellular matrix metabolism and seems to be specifically required for elastic fiber formation and stabilization. This suggests that LOXL1 enzyme function and expression are abnormal and thereby play a role in glaucoma development, possibly due to abnormalities in the lamina cribrosa.35 There is evidence for an exfoliation-specific elastinopathy of the lamina cribrosa resulting from a primary disturbance in LOXL1 regulation, possibly making exfoliative eyes more vulnerable to pressure-induced optic nerve damage and glaucoma development and progression.35,36
There also appear to be significant differences in corneal biomechanical properties in eyes with exfoliation syndrome and glaucoma compared to normal eyes and those with primary open angle glaucoma (POAG). Exfoliative eyes have been measured with the Ocular Response Analyzer (Reichert) to have a lower corneal hysteresis (CH) and corneal resistance factor (CRF) than nonexfoliative eyes.37-39 While this information may not be clinically necessary to make a diagnosis of exfoliative glaucoma, it can help to partially explain the reason for this condition being a more aggressive form of open angle glaucoma.
Exfoliation syndrome without intraocular pressure rise requires periodic monitoring of the IOP, discs, nerve fiber layer and visual fields due to possible later development of IOP elevation.13,14,19 Establishing a diurnal pressure curve with multiple IOP readings is especially important, as patients with exfoliation syndrome and exfoliative glaucoma demonstrate great variations in IOP.40,41 Patients with exfoliative glaucoma, more than POAG, exhibit a diurnal range greater than 15mm Hg. Forty-five percent of exfoliative glaucoma patients demonstrate a peak IOP, at times, outside normal office hours.42
Exfoliative glaucoma is medically treated in the same manner as POAG. It can be a particularly aggressive form of open angle glaucoma, possibly due to an abnormal elastinopathy of the lamina cribrosa, lowered CH and CRF, or both. It appears that exfoliative eyes are more likely to show progressive disease than eyes with POAG, even at similarly treated IOP levels.
If not systemically contraindicated, the clinician may use topical beta-blockers, topical carbonic anhydrase inhibitors, prostaglandin analogs and alpha adrenergic agonists. However, the IOP in exfoliative glaucoma is typically higher than in POAG and is more difficult to temporize. Typically, a greater amount of medical therapy is needed to control patients with exfoliative glaucoma compared to POAG patients.43-45 Selective laser trabeculoplasty is a viable treatment option for exfoliative glaucoma, often showing a greater effect than in eyes with POAG.46,47 It was shown that both forms of laser trabeculoplasty (selective and argon) had equal IOP reduction through six months.48 Invasive procedures such as trabeculectomy, drainage implant surgery, cataract surgery and ab interno trabeculectomy are viable management options.49
• Peripupillary iris transillumination defects are a common and important finding in patients with exfoliation. In fact, they may precede the development of clinically observable exfoliative material on the lens surface. This finding mandates a careful inspection of the anterior lens surface following dilation.
• A pigment shower in the anterior chamber can occur following diagnostic dilation.
• Eyes with exfoliation typically do not dilate well due to subclinical posterior synechiae. Radial streaks of pigment on the surface of the lens seen after dilation are a strong indicator of exfoliation.
• Exfoliative glaucoma can be especially difficult to control. Give special care to earlier, aggressive pressure reduction when exfoliation is present.
• While exfoliation can appear unilateral, it is likely bilateral and asymmetric.
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