The incidence of patients with pseudoexfoliation in two different regions of

Serbia
Miroslav Stamenković 1,2, Tatjana Šarenac Vulović 3,4, Nenad Petrović 3,4, Jovana Srejović 3,4,
Katarina Ćupić 3,4, Dušan Todorović 3,4

1
University Eye Clinic, Medical Center Zvezdara, Belgrade, Serbia
2
Faculty of Special Education and Rehabilitation, University of Belgrade, Belgrade, Serbia.
3
Clinic of Ophthalmology, University Clinical Center, Kragujevac, Serbia;
4
Department of Ophthalmology, Faculty of Medical Sciences, University of Kragujevac, Serbia;

Correspondence to: Tatjana Sarenac Vulovic,

Pseudoexfoliation syndrome (XFS) is age related systemic disorder (1) (2). It can be presented in
the whole body, as well as in the eye (3). This disease is characterized by abnormal production
and accumulation of pseudoexfoliative material (4).

The prevalence of the PEX among different nations and regions is different (5). It is also more
common after the sixth decade of the life (6). Some studies suggested for the female
predomination, but the others suggested men. Certainly, there is no evidence with gender-related
inheritance. The highest incidence linked with geographical regions is in Scandinavian countries
and Greece (island Crete) (7).

Pseudoexfoliative material is made of abnormal fibrotic fibers (8). Histologically those fibers are
very similar to fibrous tissue fibers. According to some earlier examinations, inflammation is the
main process in the very beginning of XFS. Due to inflammation and accumulation of PEX
material in trabecular meshwork (TM) it can cause intraocular pressure rise. That condition in
known as pseudoexfoliation glaucoma (XFG) (9). It represents secondary open-angle glaucoma,
usually recorded in older patients. PEX material can be deposited in all parts of the eye, with
different consequences (10). Those consequences are very important for every ophthalmologist.
The most important are: pseudoexfoliative glaucoma and cataract surgery complications
(intraoperative and postoperative) (11). Detailed ophthalmological examination is necessary for
every ophthalmological patient, especially elder, to avoid many possible complications.
Pseudoexfoliations are most commonly present at iris pupillary margin (Figure 1) and anterior
lens capsule (Figure 2). In the body PEX is accumulated in visceral organs as well as in blood
vessels (8).

Cataract surgery is one of the most frequently performed operations in medicine, including
ophthalmology (12). The results of cataract surgery are very important for the patient, for the
surgeon and for the surroundings, at all.

The aim of this study was to determine an incidence of patients with pseudoexfoliation in two
different regions of Serbia.
MATERIAL AND METHODS

The study was designed as a multicentric, retrospective study with evaluation of the medical
records of all patients who underwent cataract surgery. It was conducted at Clinic of
ophthalmology, Clinical-Hospital Center Zvezdara and Clinic of ophthalmology, University
Clinical Center Kragujevac. It included 7451 patients scheduled for cataract surgery. The study
period was from November 2021 to Novembar 2023. The authors evaluated: incidence of PEX
syndrome and PEX glaucoma, age and gender of patients, ocular comorbidities, as well as
preoperative antiglaucomatous therapy and intraoperative and postoperative cataract surgery
complications. The main inclusion criterion was the presence of cataract, amd with no esclusion
criterions.

In the preoperative preparation of patients, the presence of ocular and systemic comorbidities,
antiglaucoma drugs was analyzed through a detailed review of the medical documentation . A
detailed ophthalmological examination was performed for every participant before and after the
cataract surgery. It included: best corrected visual acuity, intraocular pressure measurements
using Goldmann tonometry, slit lamp examination in mydriasis, indirect ophthalmoscopy.
Intraocular lens power for every patient was calculated using SRK T formula and using ocular
ultrasound A and B scan (Compact touch, Lumibird Medical, Cedex, France). The same
intraocular lens companies were used in both Clinics (navesti koje sočivo). The XFG was
diagnosed if the intraocular pressure was above 21mmHg, characteristic glaucoma damage of
optic nerve head and visual field defects were present, as well as PEX material noticed at iris
pupillary margin and/or lens anterior capsule during slit lamp examination.

The phacoemulsification was performed for all patients with the same phacoemulsification
machine (Stelaris, Bausch and Lomb, Rochester, NY, USA). The cataract surgery was done
under the topical anesthesia. After performing paracentesis and central corneal incision, cohesive
viscoelastic was injected in anterior chamber (AC). Then continuous capsulorhexis,
hydrodisection and nucleus rotation followed. The nucleus was cracked using “stop and chop”
technique and the remaining cortex was aspirated using bimanual irrigation and aspiration. After
fulfilling anterior chamber and capsular bag with cohesive viscoelastic intraocular lens was
injected. The remaining viscoelastic was aspirated and intracameral solution of cefuroxime (1
mg/0.1 ml balanced salt solution) was injected in AC. In the indicated cases, the procedure was
supplemented by preventive or therapeutic implantation of the capsular tension ring. Combined
eyedrops of dexamethasone and tobramycin (Tobradex®, Alcon, Vernier-Geneva, Switzerland)
were prescribed to all patients, in the same way. From the first postoperative day, patients also
applied a local non-steroidal anti-inflammatory drug (Nevanac®, Alcon, Vernier-Geneva,
Switzerland) in operated eye for prophylaxis of cystoid macular oedema. The patient was then
followed up by an external ophthalmologist. The presence of any intraoperative and
postoperative complications was recorded.

IBM SPSS version 22.0 was used for statistical analysis. According to the normality of
distribution, paired t-test, χ2, Mann-Whitney test was used in analysis of the incidence of XFS,
XFG, comorbidities, number of antiglaucomatous drugs, intra and postoperative complications,
as well as patients’ age and sex. Values p<0.05 and p<0.001 were considered to be statistically
significant.

RESULTS

The mean patients’ age was 71.4 ± 2.3 years (median 72, range 53 – 91 years). According to the
age of patients, most of them were in a range from 61 to 80 years old (5301 patients) (Figure 3).
3558 males and 3883 females participated in the study. No statistical significance was noticed
between the sexes (p<0.05).

Pseudoexfoliation syndrome was recorded in 676 patients. It represents 9,07% of all patients
who participated in the study. Among them, 407 were females and 269 were males (Figure 4).
Statistically significant difference was measured between sexes in XFS patients (p<0.001). The
mean age of XFS patients was 77.5 ± 3.4 years (median 74, range 58 – 90 years).

We recorded 243 patients with pseudoexfoliation glaucoma, which represents 3.26% of patients
who were inclued in the study. Mean age of XFG patients was 78.1 ± 2.1 years (median 73,
range 53 – 88 years). There was a statistically significant difference (p<0.05) among incidence of
XFG in females (n=157) compared to males (n=86). Mean number of used antiglaucomatous
drugs in XFG patients was 2.2 ± 0.7. No statistically significance was measured in number of
used antiglaucomatous drugs depending on patients’ sex (p>0.05). From these 243 XFG patients,
219 managed to successfully treat glaucoma using antiglaucomatous drugs, while argon laser
trabeuloplasty (ALTP) was performed in 19 and trabeculectomy in 5 patients during the study.

Intraoperative complications including poor mydriasis (less than 5mm), posterior capsule
rupture, zonular dehiscence, CTR implantation were significantly more often presented in PEX
patients (Table 1). Postoperative complications also occurred more commonly in patients with
pseudoexfoliations (Table 2).

DISCUSSION

Senile cataract is the blurring of the lens after the age of 65 (13). Its development can be in
relation to different conditions in the eye, and in the body, as well. Our results also indicate that
older people are in positive correlation with cataract incidence, with no statistical significancy
with sex predomination.

Cataract surgery is the only effective way of its treatment (13). Phacoemulsification is the most
performed method for cataract surgery (14). Ultrasound energy is used to emulsify and aspirate
the crystalline lens in the eye through the small corneal incision. For good results some
precursors must be fulfilled: dilatated pupille, stability of the iridolental diaphragm, manual
dexterity, and the experience of the surgeon (15).

Our study established that PEX presentation in our group of patients was 9.07%. This result is
the similar as in the other studies (16) (17), where incidence in studies ranges from 4-10%. We
must notice that it is not same if the incidence is 4% or 10%, because for surgeon it is very
important to be beware during and after surgery if PEX material is presented in the eye.
According to our results, older female was more common. This result is also like some of the
earlier studies (10) (18). It was also very important to notice that mean age of patients with PEX
was higher in comparison to patients without PEX. According to these findings, some
suggestions to ophthalmologists are to pay attention to older female patients, recruited for
cataract surgery.

Dilatated pupile can be reached, using combined installation of mydriatic eye drops: tropicamid,
phenylephrine, homatropine. In some cases, it is demanded to prescribe the using of NSAID
eyedrops preoperative to reach and maintain dilatated pupile (16). Patients with uveitic, diabetic
or traumatic cataract, patients with PEX deposits or patients which are using tamsulosin is very
difficult to reach good dilalated pupile (17). In that case, cataract surgery becomes very
complicated, and needs experienced surgeon or using some devices intraoperative to get dilatated
pupile (ring) (18).

Stability of the iridolental diaphragm is also very important because of the zonula’s weakness,
which provoke very serious complications during and after the phaco surgery (18). This
condition is very often related to PEX deposits in the eye. PEX deposits in the eye predict harder
nuclear form of the cataract. Dense and hard cataracts are related to a greater number of
intraoperative complications (20).

Based on the facts above, PEX presentation in the eye is very important for every phaco surgeon.
In order to avoid difficult intra and postoperative complications, detailed clinical examination of
every eye of patients must be performed (12).

Earlier investigations suggested that some PEX deposits were not recorded because of the poor
dilatated pupile (21). During the surgery, PEX can be detected using the capsular stain.

In the literature, complications of cataract surgery in PEX patients are more common than in
patients without PEX. The most common intraoperative complications of the phaco surgery in
patients with PEX are: posterior capsule rupture, vitreous body loss, zonula dehiscense,
intraoperative miosys; postoperative complications are: cystoid macular edema, nuclear fragment
dislocation, posterior lens capsule opacification, corneal edema, retinal detachment, anterior
chamber inflammation and hyphema, as well as IOL decentration (22).

Our study established that the elder patients had more frequent PEX. It seems to be in correlation
with earlier epidemiological ane experimental studies. Oxidative stress which is increased in
elder ages is the main cause of PEX production (23). It provokes inflammation and start fibrous
tissue production (9) (24). Increased production and accumulation of some abnormal fibrous
fibres in anterior segment of the eye result as PEX deposits in the all parts of the eye. PEX
material deposits in the iridocorneal angle, and in the retinal vessels, which make conditions to
provoke XFG development. According to our findinngs, approximately 3% of oue patients had
XFG. Considering thet this type of glaucoma is very hard to treat and control, and that it has
advanced damage of the RNFL, we have to pay more attention on making the decission for the
cataract suregry. Some earlier studies suggested that IOP can be reduced after phaco suregry in
pateitns with XFG. Personalized, patient and detailed approach to every patient with PEX is
demanded.

Every patient which comes for the cataract surgery must be detailed ophthalmological examined,
to determine PEX presence in anterior segmentt of the eye. That finding will help surgeon to
make good choice and strategy for future surgery.

Pseudoexfoliative material is one of the risks factor for the glaucoma development-XFG. XFG
treatment demands very intensive antiglaucomatois therapy, because of its unpredictable course
of the disease. Using antiglaucomtous drugs with preservative provokes ocular surface chages,
and can have impact on the IOL calculation, as well as on cornael clearness during the surgery.
Also, Pex material in lamina criborsa of optic nerve head and in the retinal vessels

Phacoemulsification is the most commonly performed cataract procedure in the developed world,
[18]
but the high capital and maintenance costs of a phacoemulsification machine and of the
associated disposable equipment, have made ECCE and MSICS the most commonly performed
procedures in developing countries.[2] Cataract surgery is commonly done as an out-patient or
day-care procedure, which is cheaper than hospitalisation and an overnight stay, and day surgery
has similar medical outcomes.[19]It occurs due to metabolic changes in the crystalline lens which
occur over the years (1). The only effective way to treat cataract is the surgical one (2). Through
the centuries the surgical technique was improving. In the last few decades cataract surgery is
based on usage of ultrasound energy to aspirate the cataract. This technique is known as
phacoemulsification (3). Cataract still remains the worlds’ leading cause of reversible blindness
in the elderly population. Knowing that senile cataract begins to develop in every person above
the 65 years old, explains why the phacoemulsification is the most common surgical procedure
worldwide (4). Pseudoexfoliation (PEX) is an age related systemic disorder. It affects many
visceral organs and blood vessels. PEX represents the accumulation of fibrillar material in the
extracellular matrix of the tissue (5). PEX shows a strong geographic presentation. It is a very
common condition in Scandinavia, where its incidence is over 22%, while in Chine its rate is
about 0.5% (6). In the eye, PEX is found in the conjunctiva, cornea, anterior chamber, iris,
anterior lens capsule, ciliary body, zonules (Figure 1). This condition is described as a
pseudoexfolation syndrome (7). The most known ocular manifestations of PEX are the
accumulation at iris pupillary margin and anterior lens capsule. By blocking the trabecular
meshwork PEX aggravates the aqueous humour outflow, which leads to the intraocular pressure
(IOP) rise. That is followed by a characteristic visual field defects and optic nerve damage. This
condition in known as pseudoexfolation glaucoma (XGF) (8). It is also reported that patients
with PEX are in a higher risk to develop a senile nuclear cataract (5). The presence of PEX in
conjunctival goblet cells, corneal endothelium, iris and zonule can have a huge effect at cataract
surgery. The accumulation of PEX in these tissues is associated with many intraoperative and
postoperative complications in patients scheduled for cataract surgery (9) (10) (11). The aim of
this study was to investigate the prevalence of the surgical complications during
phacoemulsfication in patients with PEX. Pseudoexfoliation syndrome is a systemic disease with
varying frequency, depending on latitude. It is most often described in the Scandinavian
countries. A population-based study evaluating the prevalence of PEX syndrome in people over
the age of 66 reports that one in four individuals is affected out of a total of 339 participants [15].
At the end of the 21-year follow-up period, the incidence of PEX syndrome observed rose from
23% in 66 year-olds to 61% at the age of 87 [16]. Ariga states in his article that the incidence of
PEX syndrome varies, depending on the population, between 6-10% [17], which corresponds to
the results among our patients (6.0%). A retrospective study by Vazquez-Ferreiro et al.,
monitoring the incidence of PEX syndrome in patients undergoing cataract surgery, reports 120
eyes affected out of a total of 681 operated eyes (17.6%) [18]. However, comparable work
evaluating the incidence of PEX syndrome and related secondary glaucoma in terms of file size
was not found. While the results of European studies report a more frequent presence of
unilateral disability, American studies tend to report a higher incidence of bilateral PEX
syndrome [19]. However, our patient sample showed a ratio of almost 1:1 (423: 429). Due to the
systemic nature of the disease, a thorough observation of the second eye, which is still
macroscopically intact, is necessary even in the presence of unilateral PEX syndrome. This is
especially important for the possible early detection of secondary glaucoma associated with this
pathognomonic unit. This glaucoma was first described in 1917 by Lindberg in Finland [20].
Kuchynka states that glaucoma occurs in up to 20 % of patients with PEX syndrome [1].
Obuchowska et al. in their work described glaucoma in 28 of 82 eyes with PEX syndrome
(34.1%) [21]. Potocky observed an association Graph 3. Gender distribution in patients with
pseudoexfoliation syndrome Graph 4. Occurrence of secondary glaucoma in patients with
pseudoexfoliation (PEX) syndrome Graph 5. Therapy of patients with pseudoexfoliation
glaucoma 65% 35% Gender distribution in patients Female Male 76% 24% Occurrence of
secondary glaucoma Eyes without PEX glaucoma Eyes with PEX glaucoma 89% 11% Therapy
of patients Medication Anti-glaucoma surgery CZECH AND SLOVAK OPHTHALMOLOGY
2/2022 61 with secondary glaucoma among his operated patients in even 39.1 % of cases out of a
total of 2 916 eyes [22]. In our cohort, patients reported diagnosed glaucoma in 23.94% of eyes,
which corresponds to the range reported by Kanski (15-30%) [4]. However, all these studies
involve smaller cohorts of patients compared to our cohort. The cataractogenic effect of the
pseudoexfoliation material is also described, but the exact pathophysiology of this association is
not yet completely clear [11]. The Reykjavik eye study followed up 1 045 patients with PEX
syndrome over a 12-year period and revealed a higher probability of indicating cataract surgery
in these patients [23]. Similarly, other research with a follow-up period of 30 years confirmed
PEX syndrome as a strong predictive factor of cataract surgery, compared to subjects without
diagnosed PEX syndrome [24]. Numerous studies have shown a positive effect of
phacoemulsification on postoperative intraocular pressure and deepening of the anterior chamber
of the eye [10,25,26,27]. Improving the anatomical parameters of the anterior segment of the eye
after phacoemulsification can have a major impact on patients with pseudoexfoliation glaucoma.
PEX syndrome is not only associated with an increased risk of developing cataracts, but also
with an increased risk of these complications during the procedure and in the postoperative
period. To reduce possible perioperative complications, it is advisable to minimise the zonular
stress when manipulating the nucleus and cortex. For example, a larger capsulorhexis, which is
also a prophylaxis of the development of capsular phimosis in the postoperative period, can help
us to do this. In the case of a small pupil, the use of viscomydriasis or the establishment of iris
hooks is appropriate. Another mechanical helper used to stabilise the capsular bag is CTR [28,
29]. The question remains whether CTR should be implanted prophylactically in the other eye,
which is still without signs of PEX syndrome [30, 31]. In our experience, we do not agree with
this view, because in most of our patients a distension ring was not necessary. With consistent
preoperative preparation, perioperative and postoperative care and, at the same time, thanks to
the progress of the surgical techniques, instruments and materials used, the postoperative result
in patients with PEX syndrome is almost comparable to the healthy population [11].
Pseudoexfoliation (PEX) syndrome is an ocular manifestation of a systemic disorder with a
certain genetic basis (autosomal dominant inheritance with incomplete penetration) [1,2].
Currently, several genes have been identified that may be involved in the development of PEX
syndrome (LOXL 1, CACNA 1A) [3]. The disease rarely occurs before the age of 50. The
prevalence of 50-59 years is reported to be only 0.4% [3]. The incidence and severity of the
disease increase rapidly after the 6th decade of life [4]. It is more common in women, but there is
a higher incidence of PEX-induced glaucoma in men [3]. Worldwide, up to 70 million people
suffer from PEX syndrome, with geographi

cal location playing a significant role in incidence. The highest incidence is usually reported in
Scandinavia and Greece [3]. The disease is characterised by the formation of pathological
pseudoexfoliation masses. Histologically, it is an amorphous eosinophilic microfibrillar material
(Figure 1) [1], which is found in the tissues of the eye, ocular adnexa, orbit, but also in the
vascular system and visceral organs of the body (e.g. lungs, heart, kidneys, liver, skin) [3]. There
are studies showing a link between PEX syndrome and general diseases (e.g. stroke, Alzheimer's
disease, coronary heart disease, aortic aneurysm, homocystinuria) [5,6]. Deposits of this material
are evident on the cornea, iris (Figure 2), lens, ciliary protrusions, zonular apparatus, and
trabecular meshwork of the anterior chamber angle [1]. PEX may occur both unilaterally and
bilaterally with lateral asymmetry [7]. In the early stages of the disease, it can be easily
overlooked when examined on a slit lamp (Figure 3) [4]. At the lens capsule, this grey-white
material typically forms two concentric circles with a central zone in the area of the unexpanded
pupil (Figure 4) [3]. Atrophy of the iris, pigmentation of its anterior surface and pigmentation of
the anterior chamber angle structures are also evident. A typical gonioscopic finding is the
formation of a hyperpigmented Sampaolesi line before the Schwalbe line (Figure 5) [4]. The
Sampoalesi line, together with deposits of material in the pupillary margin of the iris and
deposits on the anterior capsule, is one of the most specific symptoms of PEX syndrome in
pseudophakic eyes [8]. Clinically, the disease may manifest by higher fragility of the lens
capsule and zonular apparatus. After mydriatics application, a difficult dilatation of the pupil may
occur (Figure 6) [1]. Pseudoexfoliation syndrome is also the most common identifiable cause of
secondary open-angle glaucoma [4,7]. Due to the deposition of PEX material and pigment
dispersion, there is a mechanical obstruction of the outflow of the ventricular fluid, which results
in an increase in IOP with a possible pseudoexfoliation glaucoma [3]. This type of glaucoma has
a higher level of IOP, faster progression and more difficult stabilisation of IOP with drug therapy
than primary open-angle glaucoma [3,9]. Several studies have shown a significant reduction in
IOP after cataract surgery in patients with glaucoma, averaging at 3-6 mmHg [3,10]. Cataract
surgery in PEX syndrome is associated with a higher risk of perioperative and postoperative
complications [3] (Table 1) [11]. The higher incidence of complications is due to a combination
of poor mydriasis, increased fragility of the capsule and a weak zonular apparatus of the lens
[1,3,9]. Compared to patients without PEX syndrome, a higher incidence of posterior capsule
rupture, vitreous prolapse, vitreous dislocation or intraocular lens dislocation is reported [3,12].
Other risks include postoperative corneal decompensation for keratopathy and capsule phimosis
[4]. Patients should be closely monitored in the postoperative period, due to longer postoperative
healing, a demonstrably higher risk of prolonged inflammation, cystoid macular oedema, and
IOP elevation [4,13]. Decentration,

can be included among the most common late complications, even after uncomplicated surgery
(Figure 7) [14]