GPEX nueva evidencia.pdf

1. Exfoliative glaucoma: new
evidence in the pathogenesis
and treatment
Stefano Miglior1
, Francesca Bertuzzi
Ophthalmology Department, Policlinico di Monza Hospital, University of Milano-Bicocca,
Monza, Italy
1
Corresponding author: Tel.: +39-039-2810620; Fax: +39-039-2810322,
e-mail address: smiglior@yahoo.com
Abstract
Exfoliation or pseudoexfoliation syndrome (PXF) is an age-related ocular and systemic dis-
ease in which abnormal extracellular material is produced and accumulates in many tissues.
PXF is the most common identifiable cause of open-angle glaucoma (OAG). PXFG is a par-
ticularly aggressive type of OAG, which runs with a faster rate of progression and poorer re-
sponse to medical therapy than primary OAG (POAG). The prevalence of the condition shows
huge variations among different population, Scandinavian and Mediterranean race being the
most affected. Many genetics and environmental factors are involved in the pathogenesis and
remarkable progresses in understanding the involved factors have been achieved in the past
years. Population-based studies have identified mutations on the lysil-oxidase-like 1(LOXL1)
gene as a risk factor for PXFS. Environmental and behavioral factors such as latitude of res-
idence, caffeine intake, and vitamins deficiency are under investigation for a possible involve-
ment in determining the disease in genetically predisposed individuals. Treatment options are
similar to those recommended for POAG. Exfoliation syndrome predisposes to capsular rup-
ture, zonular dehiscence, and vitreous loss during cataract extraction. Laser trabeculoplasty
has been demonstrated to show good clinical outcomes in PXF patients. A review of the cur-
rent literature and scientific evidences on pathogenesis and treatment is presented.
Keywords
Exfoliative glaucoma, Pseudoexfoliation syndrome, Lysil-oxidase (LOXL1) gene mutations,
Laser trabeculoplasty, Complicated cataract surgery
1 INTRODUCTION
“Exfoliation syndrome” refers to the anterior lens capsular delamination that occurs
at very high ambient temperatures and exposition to infrared radiation. Since the
condition of “true exfoliation” or capsular delamination is very particular and not
Progress in Brain Research, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2015.06.007
© 2015 Elsevier B.V. All rights reserved.
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2. frequent in clinical practice, the term “exfoliation” is currently used like a synony-
mous of “pseudoexfoliation.”
Pseudoexfoliation (PXF) syndrome is a strongly age-related systemic disease of
the extracellular matrix, characterized by multifocal production and deposition of
fibrillar extracellular material. In the eye, PXF could present unilaterally or bilater-
ally. The precipitation of disorganized basement membrane material affects various
ocular structures, mainly anterior lens capsule, iris, lens zonules, and trabecular
meshwork. This may subsequently lead to many intraocular problems like phacodon-
esis, poor pupil dilation, trabecular meshwork dysfunction (Ritch and Schlotzer-
Schrehardt, 2001a).
Pseudoexfoliative material has been identified by electron microscopy in many
visceral organs, such as lung, heart, kidney and gallbladder, liver and meninges, most
frequently in the fibrovascular septa, adjacent to elastic and oxytalan fibers (Streeten
et al., 1992). These findings led in the past to the hypothesis that pseudoexfoliation
syndrome (PXFS) could be associated with systemic cardiovascular and cerebro-
vascular diseases. At present, the existence of this association is controversial
(Anastasopoulos et al., 2011, French et al., 2012; Mitchell et al.; 1997; Ritch,
1994; Ritland et al., 2004).
The PXF fibrotic matrix process is characterized by excessive and abnormal
cross-linking of elastic microfibrils into fibrillar PEX aggregates.
Pseudoexfoliative material in the eye appears as white deposits on the anterior
lens surface and pupillary border, and in gonioscopic examination, a pigmented line
behind the Schwalbe’s line (Sampaolesi line) marks the accumulation of PXF material
in the angle; pigment deposition through the trabecular meshwork is visible, as well.
The deposition of pseudoexfoliative material in the trabecular meshwork can result
in aqueous outflow impairment, raised intraocular pressure (IOP), and glaucoma. PXF
is considered to be the most common identifiable cause of open-angle glaucoma
(OAG), accounting for approximately 25% of OAG worldwide (Ritch, 1994). How-
ever, most of people with PEX do not have pseudoexfoliative glaucoma (PXFG).
Approximately, 20% of newly diagnosed PEX have glaucoma, and overall, 50%
of patients with PEX are ultimately diagnosed with glaucoma. Many genetics and
environmental factors are involved in the pathogenesis and remarkable progresses
in understanding the involved factors have been achieved in the past years. The prev-
alence of the condition shows huge variations among different populations, Scandina-
vian and Mediterranean races being the most affected. Given the wide epidemiological
spread of this disease, any new result in research on this topic would be particularly
relevant. PXFG is a particularly aggressive type of OAG, which runs with a faster rate
of progression and poorer response to medical therapy than primary OAG (POAG).
2 PATHOPHYSIOLOGY AND GENETIC FEATURES
PXFG is a major type of secondary glaucoma characterized by the production, ag-
gregation, and accumulation of abnormal extracellular fibrillar material in the ante-
rior segment of the eye. Histochemically, pseudoexfoliative material is made of
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3. glycoconjugates surrounding a protein core. These aggregates are synthesized intra-
cellularly in multiple different cell types in the anterior segment including nonpig-
mented ciliary epithelial cells, trabecular endothelial cells, and pre-equatorial lens
epithelial cells. This is thought to be the result of an oxidative stress (Ritch and
Schlotzer-Schrehardt, 2001b).
Many research efforts have been addressed to identify genetic risk factors for
XFS in the most recent years. Population-based studies have identified mutations
on the lysil-oxidase-like 1 (LOXL1) gene as a risk factor for PXFS. This gene en-
codes an enzyme that is involved in elastin synthesis.
Thus, it is biologically plausible that defects in the LOXL1 gene may cause
aberrant production of elastin and accumulation of fibrillar material leading to
increased outflow resistance in the trabecular meshwork. On the other hand, dysre-
gulation on the LOXL1 gene expression may lead to degenerative tissue alterations,
particularly the lamina cribrosa, adversely affecting the biomechanical properties of
this structure and making it more vulnerable to high IOP.
In 2007, Thorleifsson and associates conducted a large study in patients from Ice-
land and Sweden on the specific genes which may be associated with glaucoma. 594
patients and 14,672 control subjects were genotyped at more than 300,000 single-
nucleotide polymorphism (SNP) markers. A strong association was found between
exfoliation and two nonsynonymous polymorphisms (Thorleifsson et al., 2007).
In 2008, a study conducted by Pasutto et al. (2008) investigated the association
between three LOXL1 common-sequence variants and PXF/PXFG in patients of
German and Italian descent. 726 patients with PXF/PXFG (517 Germans and 209
Italians) and 418 healthy subjects were genotyped. Strong association was found be-
tween the three SNPs common-sequence variants in both PXF and PXFG patients
groups, independent of their geographic origin.
A similar study was repeated in a population from Iowa (Fingert et al., 2007),
where PXFG is epidemiologically less relevant than in Scandinavian populations
(9% of OAG caused by PXF). 72 patients and 75 ethnically matched controls were
genotyped for LOXL1 common sequence variants and a strong association was con-
firmed between LOXL1 and PXF/PXG.
In a recent paper from Anastasopoulos et al. (2014), the association between
SNPs of the LOXL1 gene and PXF, PXFG, and POAG was investigated in a Greek
population. 233 subjects (93 controls, 40 PXF, 34 PXFG, and 66 POAG) were gen-
otyped and one SNP (G153D) was found to be strongly associated with both PXF and
PXFG. However, according to this study’s findings, the presence of gene variants of
LOXL1 would not help to identify who, among PXF subjects, has increased risk to
develop PXFG.
In general, LOXL1 variants are extremely common and carried by many people
without the disease, so genetic testing at present does not show significant diagnostic
value because of poor positive predictive value.
The association found between genetic variants and disease is similar in popula-
tions of different ancestry; nevertheless, the prevalence of PXF/PXFG varies consid-
erably across different countries, so environmental and behavioral factors are
probably strongly involved in the development of the disease, as well.
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4. At present, despite PXF has a well-established genetic component, genetic
counseling for patients is not recommendable to improve diagnostic accuracy
throughout the population.
In an interesting paper, Izzotti et al. (2011) examined the amount of mitochon-
drial damage in a cohort of 38 patients with various types of glaucoma. Their results
show that oxidative damage arising from mitochondrial dysfunction was present
only in POAG (3-fold increase in mitochondrial DNA deletion) and PXFG (6.3-fold
increase in mitochondrial DNA deletion). Some subjects carrying particular genetic
assets are more susceptible to this event. This issue may help to understand why be-
havioral and environmental factors may interact with genetic alterations to promote
the development of the disease in conditions of increased oxidative stress.
3 GEOGRAPHIC AND EPIDEMIOLOGIC FEATURES
Prevalence rates of PXF are highly variable worldwide, ranging from <1% in the
Northern Mongolia (Foster et al., 1996) to 17% and higher in Scandinavian popula-
tions (Ekstrom, 1987), and much higher in the elderly people (40.6% in subjects aged
>80 years in a survey performed in Iceland (Arnarsson et al., 2007)).
Both racial ancestry and latitude of residence have a role in determining preva-
lence variation. Among Africans, prevalence of PXF is much higher in African sub-
jects living in South Africa (6–7.7%) than in African Americans living in the
Southern United States (0.5%) (Ball, 1988). An interesting survey about the geo-
graphic variability of the PXF prevalence has been performed in the United States
(US), as well (Stein et al., 2011). The continental US territory overlays across 15°
of latitude, the condition of PXF/PXFG were identified by means of ICD-9 coding.
In multivariable analysis accounting for age, sex, race, and other factors, the risk of
PXF was found to be progressively higher in the Northern states (the country was
stratified into northern, middle, and southern tiers). The analysis was repeated taking
off the sample populations of Scandinavian origin, which could possibly have higher
concentration in the northern tiers, and the relative risk did not change. Kang and
coworkers made a similar multivariable analysis on the sample of two population-
based study Kang et al. (2012), where more detailed information about residential
history were available, and the results showed that lifetime residence in the middle
and southern tier carried, respectively, a 47% and 75% reduced risk of PXFG com-
pared to lifetime living in the northern tier.
Then, latitude of residence is an important issue to consider when assessing risk
factors for PXF/PXFG.
In different studies (Kang et al., 2012, 2014a; Stein et al., 2011), solar exposure
was associated with PXF, possibly because the effect of reflected light. In Northern
countries solar exposure is obviously less than at the equator, where the PXF prev-
alence is much lower; however, reflected light could be the determinant of this lat-
itude effect, being determined by reflected light either from water or from snowpack.
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5. Stein and associates indicated an increased number of sunny days as a risk factor,
while Kang and coworkers found an association between the amount of time spent
outdoors and PXF. A study in the island of Rab found fishermen to be much more at
risk to have PXF than urban workers (Vojnikovic et al., 2007).
Dietary issues have been investigated as well, in association with PXF preva-
lence. Kang et al. (2014b) made a prospective study assessing folate, vitamin B6,
and B12 intake in PXF/PXFG. They found a trend between low folate intake and
incident PXF. Pasquale et al. (2012) in a prospective study of two large cohorts
(78,977 women from the Nurses Health Study and 41,202 men from the Health Pro-
fessionals Follow Up Study) investigated the association between caffeine consump-
tion and PXFG or glaucoma suspect. They observed a positive association between
heavier caffeine consumption and PXFG/PXFG suspect. High rate of coffee con-
sumption increases homocysteine blood levels.
Scandinavians are the population which has the highest coffee consumption in the
world, so this is another issue to take into consideration while investigating PXF/
PXFG pathogenesis.
4 CLINICAL OUTCOME AND TREATMENT
PEX is known to be a strong independent risk factor for progression of glaucoma in
patients with ocular hypertension (OH). The EMGT (Hejil et al., 2009) showed that
after a mean of 8.7 years without treatment, glaucoma conversion rate was twice as
high in patients with OH and PXF as in control patients (OH without PXF). Progres-
sion rate and time to progression were worse in PXF patients compared with other
glaucomas, as well, in the same report.
Topouzis and associates (2009), in a large population-based study performed in
the Greek city of Thessaloniki, found that the likelihood of having glaucoma, at the
same screening IOP, was three times higher among participants with PXF than
among those without PXF. This finding may suggest that additional factors, other
than high IOP, could play a role in determining increased vulnerability of the optic
nerve in patients with PXF.
Due to high IOP level, marked diurnal IOP variations and spikes, and fast optic
nerve damage and visual field deterioration, hard and quick lowering of IOP is
necessary.
4.1 MEDICATIONS
To achieve target IOP, in PXFG more medications are needed than in POAG. Al-
though the IOP reduction may be greater than in POAG subjects at the beginning
of medical treatment, to achieve the target pressure is more challenging (Hejil
et al., 2009), and adjunctive therapy with other medications or laser is often needed.
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6. When PXFG is unilateral, the EGS Guidelines recommend careful follow-up of
the fellow eye because there is high probability of development of PXFG over time
(Arnarsson et al., 2013)
4.2 LASER
Usually, PXFG responds well to trabeculoplasty, probably due to the increased pig-
mentation of the angle, which make the laser treatment more effective. The
Glaucoma laser trial research group (1989, 1995a,b) demonstrated that initial treat-
ment with argon laser trabeculoplasty had a greater effect than medication (Timolol
Maleate 0.5%) at 2 years of follow-up. The Selective laser trabeculoplasty is a dif-
ferent kind of laser procedure (532 Q-switched Nd: Yag laser) which has been more
recently developed, characterized by selective targeting of pigmented trabecular
meshwork cells, without collateral thermal damage to the adjacent nonpigmented
trabecular meshwork cells and underlying trabecular beams (Latina and Park,
1995, Latina et al., 1998). In a paper published in 2011, Ayala and Chen (2011) com-
pared IOP lowering and inflammation (measured by means of a laser flare meter)
after SLT in a sample of 60 eyes, 30 with POAG and 30 with PXFG. The results
showed that inflammation had not significantly different rating between the two
groups and good IOP lowering was reached in both groups (6.87 mmHg in POAG
patients and 6.19 mmHg in PXFG patients) 1 month after SLT. PXFG did not seem
to be a risk factor for post-laser complications.
A recent meta-analysis of six random controlled trials compared SLT to ALT
(Wang et al., 2013) in treatment of OAG. The results were in favor of SLT, which
showed a numerically larger IOP reduction compared with ALT. Patients who re-
ceived SLT took fewer glaucoma medications than those who received ALT. The
difference in tolerability between the two lasers was not significant.
4.3 CATARACT SURGERY
PXF eyes show many structural issues which have to be taken into account when
considering cataract surgery: poor pupil dilation, zonular weakness, earlier cataract
formation (Ritch and Schlotzer-Schrehardt, 2001a). Cataract extraction, due to the
above described features, implies a higher degree of technical difficulty and a larger
rate of complications in PXF subjects.
Then, it is recommendable not to delay cataract surgery in these patients. More-
over, several studies demonstrate an IOP-lowering effect following cataract surgery,
particularly in patients with PXF (Dosso et al., 1997; Gillies, 1973; Rao, 2012;
Shingleton et al., 2003).
In a paper of 2006, Damji and associates described a prospective multicenter
study on 183 subjects (Damji et al., 2006), to determine 2 years clinical outcome
of cataract extraction in patients with POAG, PXF, PXFG, and controls. The results
confirmed a generalized IOP-lowering effect of the surgery in all of the patients, sig-
nificantly greater in PXF and PXFG patients than in non-PXF (POAG, controls) at all
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7. time points ( 2.51 mmHg vs. 0.89 mmHg). The reasons of the better IOP lowering
effect in PXF/PXFG group are still not perfectly clear, plausible theories include:
washing out of fibrillar material from the angle, structural alterations such as deep-
ening of anterior chamber angle, decrease in irido-lenticular contact, inflammation
leading to better aqueous outflow (trabeculoplasty-like effect).
For all these reasons, and given the higher rate of bleb failure when cataract sur-
gery is performed after filtering surgery (Patel and Danesh-Meyer, 2013), when lens
opacity is diagnosed in a PXFG patient, cataract extraction is highly recommendable
before any other surgical option. Cataract is very common indeed, among PXF pa-
tients, because of the strong correlation between PXF prevalence and older age.
Moreover, a large population study demonstrated that PXF is an independent risk
factor for nuclear cataract development at 10-year follow-up, and the association be-
tween PXF and nuclear cataract persisted after multivariate analysis adjusted for age
gender, diabetes, smoking, steroid use, myopia, socioeconomic status, and glaucoma
(Kanthan et al., 2013). Cataract surgery provides a better IOP control in the short to
medium term and is often useful in order to avoid, or at least delay, more invasive
filtering surgery.
4.4 GLAUCOMA SURGERY
The most widely used surgical procedure in PXFG is by far the trabeculectomy with
antimetabolites. Given the higher mean IOP in PXFG compared to other types of
glaucoma and the larger diurnal fluctuations, nonpenetrating surgeries, which are
less efficient in IOP reduction, are not recommended for these patients.
Clinical outcomes and postoperative rate of success and complications are very
similar to other OAGs.
The postoperative management, either after cataract, or, even more, glaucoma
surgery, should involve the use of aggressive anti-inflammatory treatment with ste-
roids and nonsteroidal medications, due to weak brain–blood barrier in PXF (Kuchle
et al., 1995).
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