The most important characteristic of exfoliation syndrome (XFS) is that it involves a greater risk of developing glaucoma.1,2 In a community-based study in Minnesota, 16% of all XFS patients required antiglaucomatous treatment upon presentation. Of the remaining XFS patients, 44% received glaucoma therapy over the next 15 years.3 The glaucoma onset is 2 to 3 times higher in XFS with ocular hypertension than in patients with ocular hypertension without XFS.4–6 Previous reports have shown that, in comparison with other forms of open-angle glaucoma, exfoliation glaucoma (XFG) is more resistant to medical therapy and progresses faster.7,8 XFG basically presents as secondary open-angle glaucoma with elevated intraocular pressure (IOP), however, due to the anterior shift of the crystalline lens as a result of zonular weakness and changes in the iris, it may also present as acute or chronic secondary angle-closure glaucoma.9
Possible pathologic mechanisms of glaucoma development in XFS comprise (Fig. 1):
- Elevated IOP caused by functional impairment of aqueous humor outflow due to deposition of exfoliation material (XFM) in the trabecular meshwork (TM) and trabecular cell dysfunction.
- Connective tissue elastosis due to XFS, leading to structural and functional alterations and increased vulnerability of the lamina cribrosa (LC) toward elevated IOP, thereby facilitating the progression of glaucomatous optic neuropathy.
- Elevated IOP due to closure of the anterior chamber angle accompanied by forward displacement of the crystalline lens due to zonular weakness.
- Presumable primary functional impairment of retinal ganglion cells.
MECHANISMS OF IOP ELEVATION IN XFS
The following factors contribute to functional impairment of aqueous humor outflow:
- The deposition of XFM in the anterior chamber angle.
- Dysfunction of trabecular endothelial cells.
- Degenerative alterations of the TM, juxtacanalicular connective tissue (JCT), and Schlemm canal (SC).
The range of fluctuations in IOP was 15 mm Hg or greater in 35% of patients with XFG.10 This amount of fluctuation was found in only 7.5% of patients with primary open-angle glaucoma (POAG). In 45% of XFG and 22.5% of POAG, peak levels of IOP were observed outside of regular office hours. This significantly large magnitude of IOP fluctuation in XFG seems to be related to its specific pathologic changes in the angle-drainage system, leading to a higher rate of transition to glaucoma and the progression of glaucoma. The XFG-associated histopathologic alterations in the outflow tissues clearly differ from those observed in POAG tissues.
The main pathologic features associated with POAG are:
- Decrease in the cellularity of the TM.11
- Abnormal accumulation of extracellular plaque material in the JCT.12,13
- Decrease in giant vacuoles in the inner wall of SC.14
- Collapse of SC.15
Richardson and Epstein16 reported that the accumulation of XFM in the JCT leads to the destruction of SC architecture and a profound impairment of aqueous outflow. However, according to electron microscopic studies by Futa,17 the amount of XFM in the JCT showed considerable interindividual variability with only a few cases revealing large amounts (Fig. 2). Furthermore, the majority of TM specimens, obtained by trabeculectomy in medically uncontrollable XFG, showed little XFM deposition beneath the inner wall of SC.18
Schlötzer-Schrehardt and Naumann19 extensively studied the TM in 5 eyes with end-stage XFG, 10 eyes with XFS without glaucoma, and 6 age-matched control eyes by electron microscopy. They described the following histopathologic alterations associated with XFS/XFG:
- The XFG specimens showed no increase in extracellular plaque material in the JCT,19 although a significant increase in juxtacanalicular plaque material has been reported in POAG specimens.13
- Reduced cellularity of the TM was not recognized as a feature of XFG in contrast to POAG.11
- XFM preferentially accumulated within surface invaginations of endothelial cells lining the inner and outer walls of SC. The authors suggested that the primary pathologic events of XFM production involved the subendothelial regions of SC (Fig. 3).19 They considered it unlikely that XFM passes through the TM and becomes passively trapped beneath the endothelium, because no XFM has been observed in other parts of the TM in early stages of the disease. Accordantly, Inomata et al20 demonstrated that exfoliation aggregates are physically too large to pass through the TM into SC by using tracer substances of various diameters.
- The functional capacity of giant vacuole formation by endothelial cells for the purpose of aqueous drainage appeared disturbed.19
Schlötzer-Schrehardt and Naumann19 concluded that the primary pathologic process appears to be a metabolic disorder involving abnormal production of XFM in the outer portions of the TM, which leads to subsequent structural alterations and development of glaucoma. Other reports have shown that the structural integrity of SC and JCT are maintained in the early and middle stages of XFG21,22 suggesting that elevation of IOP occurs before disorganization of the TM. Elevation of IOP may be related to the amount and the location of XFM near the inner wall of SC. Histopathologic findings also showed that, unlike in pigmentary glaucoma, the deposition of pigment granules in the TM did not seem to increase the resistance to the outflow of aqueous humor (Fig. 2).17,23
MECHANISMS OF INCREASED VULNERABILITY OF THE LC IN XFS
The role of the LC in the pathophysiology of glaucoma is well recognized.24 Considerable elastosis in the LC of patients with XFG has been demonstrated, suggesting dysregulation of elastin synthesis and/or turnover in the optic nerve head tissue of patients with XFG.25 The structural weakness of the LC in XFS eyes is considered a predisposing factor for the development and progression of glaucomatous optic neuropathy, even when the IOP is within normal range.25,26 A histopathologic study on human donor eyes including 37 eyes with XFS, 5 eyes with XFG, and 5 eyes with POAG, showed that the dysregulated expression of lysyl oxidase-like 1 (LOXL1) and elastic fiber proteins are associated with structural alterations of the LC, which may predispose to a reduced resistance to IOP and thus to the development and progression of glaucomatous optic neuropathy.27
The use of enhanced depth imaging spectral-domain optical coherence tomography (OCT) enables the visualization of deeper structures in the LC and the optic nerve head in vivo.28,29 The LC has been reported to be significantly thinner in patients with normal tension glaucoma than in those with hypertensive POAG.30 This imaging technique was used to compare 21 patients with XFG and 35 patients with POAG, displaying equivalent severity of disease. The findings showed that the LC was significantly thinner in patients with XFG than in those with POAG.31 This observation supports the notion that the optic nerve head is more severely damaged in XFG than in POAG.
MECHANISM OF IRIDOCORNEAL ANGLE CLOSURE IN XFS
Open-angle glaucoma is the most common glaucoma associated with XFS, but due to zonular weakness, the crystalline lens may be displaced anteriorly and may lead to development of angle-closure glaucoma. In Asian individuals, who naturally have a particularly high prevalence of narrowed iridocorneal angles, caution is needed in regards to XFS-associated chronic angle-closure glaucoma, because it might progress faster than primary angle-closure glaucoma.
Clinical evaluation of the morphologic changes in the anterior segment of patients with unilateral XFS was carried out by using anterior segment-OCT.32 When the affected eyes and unaffected contralateral eyes were compared, the eyes with XFS had a significantly shallower anterior chamber and a significantly greater iris convexity than the fellow eyes. Compared with healthy eyes, eyes with XFS also had a narrower angle opening distance at 500 μm. The anterior chamber depth might be shallower in patients with XFS.32 According to estimations by Day and colleagues, among patients with European ancestry, the frequency of primary angle-closure glaucoma in subjects aged 70 years or older is 0.96%. This shows that the condition is more common than previously thought. The authors of this study also noted that gonioscopy is absolutely necessary to confirm the absence of angle closure when diagnosing POAG.33 In Japan, a previous report using gonioscopy in 305 eyes from XFS outpatients showed that 3.6% of patients were classified as Shaffer grade 1, 13.1% as Shaffer grade 2, and ∼10% as XFG with a closed iridocorneal angle.23
One needs to keep in mind that the mechanism of angle closure can sometimes be hidden by chronic XFG. In XFG with closure of the iridocorneal angle, glaucoma may progress even faster than in XFG with open angle. In light of this risk, patients with XFG need to be examined by gonioscopy on a regular basis to confirm that there is no narrowing or closure of the iridocorneal angle. Further studies of larger populations are needed to determine the increased risk for angle closure in XFS patients.
RETINAL GANGLION CELL DYSFUNCTION
Using OCT, the retinal nerve fiber layer and the thickness of the ganglion cell complex were examined in 30 eyes of patients with unilateral XFS, whose conventional ophthalmological examination showed no other abnormalities, as well as in the fellow eyes and healthy controls. Eyes with XFS had significantly thinner retinal nerve fiber layer and ganglion cell complex than those of the healthy controls. On the basis of these findings, reports have stated that XFS itself might be an independent risk factor for glaucoma development.34 The results of the study suggest that eyes with XFS have significantly higher IOP than the fellow eyes without XFS, even though the measurements were within the normal range; therefore, the effect of IOP and its fluctuations might be undeniable. Since the aforementioned weakness of the LC might also contribute to the observed differences, detailed molecular genetics and pathologic research studies on a large number of cases will be needed to determine whether the dysfunction of retinal ganglion cells is caused by XFS-associated mechanisms.
Large-scale Genome Wide Association Study data has shown that, in addition to LOXL1, a single nucleotide polymorphism in the calcium channel, voltage-dependent, P/G type alpha 1A subunit (CACNA1A) gene was associated with XFS.35 CACNA1A is involved in calcium transport and may be important for ganglion cell homeostasis.
Recently, based on the analysis of Tenon’s capsule fibroblasts obtained from patients with XFS, dysfunctional autophagy processes and mitochondrial abnormalities have been reported.36 The malfunction of intracellular breakdown processes may be involved in XFS pathophysiology due to the accumulation of dysfunctional mitochondria and interference with microtubule dynamics.36 In age-related macular degeneration, decreased lysosomal activity leads to the accumulation of intracellular waste products causing cell swelling. This may correlate with other retinal and neurodegenerative diseases.36 Autophagy dysfunction is more pronounced in cells derived from XFG patients than from POAG patients.36 In addition to being involved in the production of XFM, dysfunction of autophagy and mitochondrial abnormalities may also affect the function of retinal ganglion cells.
In summary, due to accumulation of XFM in the TM and structural weakness of the LC of the optic nerve head, patients with XFS may eventually develop secondary open-angle glaucoma with elevated IOP. In addition to the discovery of LOXL1, further genetic associations, for example with CACNA1A, have been identified and knowledge related to XFS etiology and pathophysiology has markedly increased over the past 10 years. However, the disease state of XFS cannot be completely replicated in cultured cells or animal models yet; thus, many aspects of XFS and XFG remain unexplained. Further cell biological investigations navigated by the molecular genetics underlying XFS will eventually lead to a better understanding of the mechanisms of XFG.
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