Exfoliation glaucoma: clinicai perspective of a global challenge

Exfoliation syndrome (XFS) may be defined as a discrete clinicai entity characterised by the synthesis and deposition o f fine white granular material, upon and within ocular and orbital tissues 1 • 2• lt is now considered the most common identifiable specific entity leading to the development of glaucoma 3 • Recent evidence suggests that XFS may be a systemic condition 4 although, as yet, there is no conclusive evidence that XFS may cause damage systemically. The diagnosis of XF S is based on the incidental finding of "dandruff-like" material upon the pupillary margin, or "sugar frosting" o f the anterior lens capsule 5 . XFS is one o f the most controversial subj ects in the ophthalmic literature 6• 7 • Numerous reports have discussed the controversy over the morphology, origin and pathogenesis of the condition 1 • 5 • 8 • 9 . From the clinicai standpoint, controversy has arisen concerning both the epidemiological and the clinicai features ofXFS 5• 1 01 3 . Even the nomenclature o f XFS remain debatable: exfoliation, exfoliative, pseudoexfoliation syndrome are current terms used to describe the condition. A detailed account of the history, morphology, controversy and literature of XFS is beyond the scope of this short review. The reader is referred to detailed reviews ofthe early literature by Sunde 1 4, Tarkkanen 1 1 , Layden & Shaffer 7 and more recently by Ritch 4• The following description merely outlines a number of important clinicai features of exfoliation glaucoma (XFG), a clinicai challenge which is an important cause of visual loss worldwide.


INTRODUCTION
Exfoliation syndrome (XFS) may be defined as a discrete clinicai entity characterised by the synthesis and deposition o f fine white granular material, upon and within ocular and orbital tissues 1 • 2• lt is now considered the most common identifiable specific entity leading to the development of glaucoma 3 • Recent evidence suggests that XFS may be a systemic condition 4 although, as yet, there is no conclusive evidence that XFS may cause damage systemically. The diagnosis of XF S is based on the incidental finding of "dandruff-like" material upon the pupillary margin, or "sugar fro sting" o f the anterior lens capsule 5 . XFS is one o f the most controversial subj ects in the ophthalmic literature 6 • 7 • Numerous reports have discussed the controversy over the morphology, origin and pathogenesis of the condition 1 • 5 • 8 • 9 . From the clinicai standpoint, controversy has arisen concerning both the epidemiological and the clinicai fe atures ofXFS 5 • 1 0 -1 3 .
Even the nomenclature o f XFS remain debatable: exfoliation, exfoliative, pseudoexfoliation syndrome are current terms used to describe the condition. A detailed account of the history, morphology, controversy and literature of XFS is beyond the scope of this short review. The reader is referred to detailed reviews ofthe early literature by Sunde 1 4, Tarkkanen 1 1 , Layden & Shaffe r 7 and more recently by Ritch 4• The fo llowing description merely outlines a number of important clinicai fe atures of exfoliation glaucoma (XFG), a clinicai challenge which is an important cause ofvisual loss worldwide. some glaucoma cohorts 1 3 • 1 5 • 1 6• The important current and fu ture role o f XFG in causing visual disability in the elderly has been recently highlighted by some authors 3 • 5 • 1 2 • 1 7 • 1 8 • In Sweden, Thorburn 1 9 calculated that 2.5% of the population over the age of 70 years developed field loss due to XFG. Raivio 2 0 has estimated that the number of patients with glaucoma, especially XFG, in Finland will increase by 40% by the year 201 O. Consequently, h e calculated that a 40% increase of resources and glaucoma care fac ilities will be required for glaucoma patients by the year 20 1 O. Demogra phic trends in Europe suggest that the number ofXFG patients will steadily increase in the future due to increasing life expectancy in countries where the disease is most prevalent.
Unfortunately, general terms such as "primary open angle glaucoma" and "chronic open angle glaucoma" are often used to include both XFG and POAG and numerous studies fa il even to consider XFG. This approach is inappropriate since XFG and POAG are different entities. Clinicai and morpholo gical evidence supports the view that XFG is a true secondary open-angle glaucoma. The balance ofultrastructural evidence is in favour of XFG developing due to an accumulation of exfoliation material and pigment, or both, within the outflow system ofthe affected eye 1 • 9 • Clinically, XFG has a number of specific attributes which distinguish it fr om POAG 4 • 5 • 1 2•

Prevalence
The early literature, based on ophthalmic cohorts, advanced the notion that the XFS is common in Scandinavia and Greece, but rare in other countries e.g. Germany, Britain and the United States 1 5 • However, in the literature of the late sixties and seventies the concept of XFS being an uncommon disease in most ethnic groups was challenged. Aasved 2 1 provided convincing epidemiological evidence to suggest that the prevalence of XFS in population groups is first, much higher than previously thought and second, similar in all geographic areas. Subsequent studies, mostly in ophthalmic cohorts, have either supported, or contradicted Aasved's view.
In any assessment ofthe true prevalence ofXFS it must be remembered that figures based on ophthalmic patients show a http://dx.doi.org/10.5935/0004-2749.19980036    biased prevalence for this disorder 1 3 • 22• On the other hand, XFS is a chronic disorder with a slow and insidious onset and subtle signs which are difficult to see clinically 10· 12• Epidemiological data collected by the same investigator from different ethnic cohorts may prove helpful. We conducted a recent epidemiological study in a Greek surgical cohort 2 3 and compared these data with that obtained in a prospective study with a similar protocol in Scotland 2 4 • In the Scottish surgical cohort the prevalence of XFG was 26%, a prevalence which was significantly lower than that in the Greek study 74%. The latter prevalence is similar to the figures reported in Scandinavian cohorts (50-62%). Therefore, XFG appears to be subject to significant geographic variation. Nevertheless, there is often a tendency for underdiagnosis and this problem may be partly due to the subtlety of the  diagnostic signs and the poorly defined early stages of XFS. Thus, the true prevalence ofthe condition remains uncertain in many countries 4• 1 3 • In the present state of knowledge it is possible to say that XFS is age-dependent, its prevalence increases uniformly with age and a significant proportion ofthe elderly population is affected. In certain countries such as Greece, Finland, Norway and Iceland available data suggest that 12-30% ofthe population over the age of 70 years show evidence of exfoliation material on clinicai examination 1 3.
The percentage of patients with XFS who have XFG, or ocular hypertension on initial examination ranges fr om 22 to 94% depending on the sampling method 2 • 1 5 • 2 5 • 26• A retrospec ti v e American study 27 has shown that in patients with XFS and normal intraocular pressure (IOP), 5% developed raised IOP o ver 5 years, while 15% did so over 1 O years. Some authors fe lt that XFG occurred shortly after the development ofXFS, otherwise the risk was small 2 8 , however, the general consensus is that XFG may ensue at any time in a patient with XFS and unilateral involvement constitutes an earlier stage in the evolution of the disorder 6• 2 9 • Whether XFG can occur without an interval o f normality, i.e. without the initial development ofXFS, is not known. There is a significant risk to the unaffected eye with XFS developing XFG, related to the duration o f the condition 3 0 • 3 1 . A retrospective study 29 has indicated that 21-26% of patients with bilateral XFS and unilateral XFG may develop XFG in the fe llow eye within 5 years . In a series o f 519 patients, Brooks & Gillies 32 established that in unilateral XFG the presence o f XFS in the fe llow eye was a serious risk fa ctor. Raised IOP developed in approximately 75% of these eyes.
In the literature there is conflicting evidence on the influence o f sex on the prevalence and severity o f EXG. The impressions of previous workers 1 2 • 3 1 that XFG may affe ct more severely males have not been entirely confirmed by a recent study comparing XFG and POAG 23• Although more males with XFG required surgery in this study, the same trend was evident amongst POAG patients. This implies that other fa ctors like compliance to antiglaucoma therapy contribute to the higher prevalence of male patients in surgical cohorts. This is also supported by the absence ofsex-related difference in the levei of iOP prior to surgery.
The heredity pattern for XFG remains unknown but the maj ority of cases are sporadic. Tarkkanen  Interestingly, XFS patients without glaucoma exhibit a higher mean IOP compareci with age matched control subj ects 36• lt is thus possible that XFS increases outflow resistance even in "normal" eyes. Whether this fe ature is explained by the incomplete handling o f the influx o f pigment and exfoliation material by the self-cleaning filter mechanism of the angle, is speculative.
Patients with XFG often present with a particularly high levei o f IOP 37• Tarkannen 11 reported that o ver 60% o f the affected eyes in patients with unilateral XFG exhibited an IOP higher than 35 mmHg, at diagnosis. Lindblom & Thorburn 34 surveyed the hospital records of a well defined glaucoma population in Halsingland, Sweden. Their cohort consisted of 245 cases with XFG and 75 cases with POAG. Both glauco mas showed the same degree o f visual field loss at diagnosis, despite the fa ct that the mean IOP at diagnosis was considerably higher in the XFG group (42.9 mmHg for XFG versus 34.8 mmHg for POAG). In XFG these authors noted a significant increase in the mean IOP with every stage of progression in their classification for glaucomatous damage. This was not observed in the POAG cases. lt is remarkable that, according to their findings, the mean IOP at diagnosis for patients with legal blindness due to advanced XFG was almost 60 mmHg. This is also supported by the observation that low IOP is extremely rare in XFG. In one study, only 2 out of 245 patients (0.8%) with XFG and visual field loss had an IOP below 20 mmHg at diagnosis 3 5 • Therefore, there is nearly universal agreement in the literature that XFG is a hyperten sive glaucoma. Indeed, a number o f studies h ave described an acute form of XFG. Up to 25% of patients with XFG may present with an acute ri se in IOP in excess o f 50 mmHg, and a varied degree of corneal oedema 37• The majority of these cases have open angles, although cases o f acute angle closure glaucoma with exfoliation have also been described 4. Extreme cases of so called "absolute XFG" can occasionally present with high IOP and no perception of light. In an Australian series, 5 cases o f absolute XFG were identified in a cohort of 72 cases with acute open angle XFG 37• There are data indicating a higher prevalence ofnarrow/closed angle in association with exfoliation 4• Furthermore, documentation of the degree of angle pigmentation is considered a reliab le indicator of the severity of XFG. In one study, 81% of the more heavily pigmented eyes showed the more severe XFG 3 8 . In contrast, exfoliation material deposition within the angle in not a reliable indicator of the risk of development, or the severity ofXFG. A characteristic gonioscopic fe ature termed Sampaolesi's line, defined as a single wavy pigmented line superior to Schwalbe' s !in e, has also been documented in nearly ali cases with XFG and is a reliable diagnostic in di cato r 12• 39• Characteristically, patients with XFG may suffer a transient acute IOP elevation after mydriasis. Gifford 1 0 described the appearance of a "pigment cloud" in the anterior chamber fo llowing mydriasis in 6 out of 62 cases. Among the differences between XFG and POAG one of the most interesting is the lack o f a change in IOP fo llowing the use o f topical steroids. Steroid-induced ocular hypertension occurs in approximately a third o f the normal population, but occurs in the majority of patients with POAG. lt is reversible, reproducible and genetically determined, the trabecular meshwork is the site of pathoiogy responsibie for the IOP elevation and the response is abolished fo llowing fi ltering surgery 26 19• In the same study, it was established that almost 0.8% of individuais aged 70 or more lost vision in one eye and 0.3% were visually handicapped by bilateral XFG before death.
In a recent prospective study we evaluated the diurnal iOP in XFG compared to POAG 4 5 •46 to determine its potential role in the course and management of this disease. Patients with XFG showed significantly higher mean diurna! range of IOP (13.5 mmHg versus 8.5 mmHg for POAG), higher maximum IOP (mean 38.2 mmHg versus 26.9 mmHg fo r POAG) and higher minimum IOP (mean 24.7 mmHg versus 18.4 mmHg for POAG). When compared to POAG, patients with XFG demonstrated more often an IOP range higher than 15 mmHg (35% vs only 7.5% for POAG). Importantly, in 45% of XFG patients and in 22.5% of POAG patients the peak ievelle pigmentation is considered a reliable pathognomic fe ature of XFG. Furthermore, gonioscopic documentation ofthe degree of angle pigmentation o f a glaucomatous eye is considered a rn XFG the worse IOP characteristics may account for the more rapid glaucomatous degeneration compared to POAG. Weber et ai. 47 have suggested that in patients with secondary glaucomas, as opposed to POAG, good correlation between visual field decay and both mean IOP and maximum IOP existed. Stewart et ai. 48 have demonstrated the importance of low variance in IOP over time in preserving visual function in advanced glaucoma.
Once medicai treatment o f XFG is started severa! authors have noted that, in comparison with POAG, the response to medicai therapy is poorer 5• 28• 3 1 • Another fe ature stressed by some writers is that an initial good response to medicai therapy is fo llowed upon by a rising IOP and sometimes abrupt fa ilure in IOP control 49 • Airaksinen 50 compared the hypotensive effect oftimolol to that ofpilocarpine in patients with POAG and XFG. He concluded that in XFG a good hypotensive effect with timolol was fo llowed by a rise in IOP !ater, so adjunctive medicai therapy had to be added more fr equently in XFG. Aasved et ai. 49 fo und that the percentage ofinitial successful control (defined as IOP < 22 mmHg) with timolol in patients with XFG was only l i%. Blika & Saunte 5 1 reported that after 3 years on timolol drops alone successful control was obtained in 33% ofthe POAG cases compare in 6 out o f 8 patients wi. Granstrom 42 documented retrospectively a greater risk of visual field loss in patients with XFG, compared with POAG patients, treated with piiocarpine 4% three times a day. Overall monotherapy is less successful in XFG compared to POAG.
We documented the diurna! IOP variation in XFG and POAG subjects treated with timolol maleate solution 0.5% b.i.d. 46. Despite a greater percent reduction in IOP in XFG than POAG the absolute leve1s ofiOP still remained higher in XFG after timolol treatment. Only 13% of XFG patients vs. 32% ofPOAG patients achieved a levei ofiOP consistently 18 mmHg o r below throughout the 24 hour period. Considering a higher target for treated IOP we fo und that 37% XFG versus 58% of POAG patients maintained treated IOP values 21 mmHg o r below. The time o f maximum IOP elevation in XFG patients receiving timolol generally was observed at 22:00 and 6:00 hours and importantly, 57% of EXG and 53% of POAG patients had their peak IOP outside office hours. Consequently, relying on a single office measurement to assess treatment response in XFG may not accurateiy reflect the diurna! range of IOP. These IOP fi ndings fo llowing timolol treatment may provide a reason why treated XFG patients progress more quickly and eventually suffer more often fr om severe visual loss.
The Argon Laser Trabeculoplasty (AL T) has certain characte ristic attributes in XFG mainly due to the excess pigmentation in the angle which often obscures the location ofthe trabecular meshwork . An acute elevation of IOP in the immediate postoperative period was shown to be more common in XFG. Severa! studies have suggested that AL Tis more successful in XFG, but this view is not universally shared 1 2• Most authors have claimed a better initial response to AL T in XFG, due to the increased pigmentation of the trabecular meshwork. Tuulonen et al. 52 reported fo ur fa ctors which fa vour the use of AL T; older age, lower pre-treatment IOP levei, XFG and pigmented meshwork. Advancing age and XFG are fa ctors consistently reported to influence positively the outcome of AL T 4. Svedbergh 53 reported a 70% initial success rate in 55 eyes with XFG and late fa ilure only in 2 cases. Psilas and coworkers 54 obtained an average initial reduction of 46% ( 13.4 mmHg) in XFG compared to a reduction o f 22% (9.2 mmHg) in POAG. Nevertheless, despite the higher initial IOP reduction there was no difference in the success rate o f AL T between the two glaucomas approximately 2 years after treatment.
Higginbotham & Richardson 55 reported that despite having a large immediate IOP response to AL T exfoliation patients fa iled at a fa ster rate. A high rate of fa ilure in XFG, compared to POAG, has been reported with longer fo llow up periods. In his review article in 1988 Svedbergh revised his view on the outcome o f AL T in XFG on account o f the increased rate of late fai lures. His 5 year retrospective analysis o f 74 patients treated by AL T showed similar fa ilure rates at the end ofthe first year in both XFG and POAG (19%) but, after 5 years late fa ilures were significantly more common in the XFG group (69% versus 45% for POAG).
There are few studies on the results of surgery in POAG and XF G. Jerndal & Lundstrom 56 documented a similar rate of complications with that seen in POAG and a fa vourable IOP lowering effect in XFG. Tornqvist and Drolsum 57 provided a retrospective comparison with POAG after trabeculectomy . They identified better fi eld preservation fo llowing surgery in XFG patients in comparison with comparable POAG patients. A recent prospective study in Glasgow 24 identified a significantly lower postoperative IOP for XFG than in comparable POAG patients, at approximately 6 months after surgery. A characteristic preoperative fe ature in XFG 2 3 , was that despi te treatment with more antiglaucoma drops fo r a shorter duration o f time, at the time o f surgery the mean treated IOP was still significantly higher than that for comparable POAG patients. Furthermore, XFG patients were more often treated surgically due to unacceptably high IOP, whilst progressive loss ofvisual field without recognised high IOP was more fr equent in POAG. It was evident fr om our study that in many cases surgery is delayed. Therefore, early surgical intervention should be the course of action in XFG when initial medicai and laser responses are deemed inadequate.