Hindawi Publishing Corporation

Journal of Ophthalmology
Volume 2014, rti!le "# 4$04%&, %
pages
http'((d)*doi*org(10*11++(2014(4$04%&
Clinical Study
,he -ffe!ts of ,opi!al ntiglau!oma #rugs as .onotherapy on
the O!ular /urfa!e' Prospe!ti0e /tudy
/e0da ydin 1urna,
1
/emih !i2go3,
1
hmet ltun,
1
4ur0er O3bay,
2
,omris /engor,
&
and Osman O2an Ol!aysu
4
1
Fatih Sultan Mehmet Education and Research Hospital, Ophthalmology Clinics, 347! "stan#ul,
$ur%ey
&
Fatih Sultan Mehmet Education and Research Hospital, 'athology Clinics, 347! "stan#ul,
$ur%ey
3
(ilim )ni*ersity, Florence +ightingale Hospital, Ophthalmology Clinics, 347&4 "stan#ul,
$ur%ey
4
Er,urum Region Education and Research Hospital, Ophthalmology Clinics, &--- Er,urum,
$ur%ey
Corresponden!e should be addressed to /e0da ydin 1urna5
s e 0 d a y din6yah o o *! o m
7e!ei0ed 11 .ar!h 20145 7e0ised 1+ .ay 20145 !!epted 1% .ay 20145 Published 8 June
2014
!ademi! -ditor' 9la0io .antelli
Copyright : 2014 /e0da ydin 1urna et al* ,his is an open a!!ess arti!le distributed under the Creati0e Commons
ttribution ;i!ense, whi!h permits unrestri!ted use, distribution, and reprodu!tion in any medium, pro0ided the original
wor2 is properly !ited*
'urpose* ,he aim was to !ompare the effe!ts of antiglau!oma eye drops on the tear fun!tions and o!ular surfa!e* Method* -ighty<
fi0e eyes of 4& patients with glau!oma were in!luded into this randomi3ed prospe!ti0e study* ,imolol without preser0ati0e =1>,
timolol with ben3odode!inium bromide =2>, latanoprost =&>, bimatoprost =4>, tra0oprost with ben3al2onium !hloride =+>, and
brimonidine with purite =$> were gi0en to $ groups* /!hirmer ", tear film brea2up time =,?@,>, staining s!ores, and impression
!ytology samples were e0aluated before and during 12<month<follow<up period* Results* t the end of 12 months, there was no
dete!ted !hange in /!hirmer " and ,?@, tests indi!ating dry eye* Corneal staining s!ores were higher in groups 1 and 2, while
!onAun!ti0al staining s!ores were higher in group $* Boblet !ell !ount de!reased in groups 1 and + in superior and inferior, group 2
in superior, and groups
& and $ in inferior !onAun!ti0a* /Cuamous metaplasia grades showed a signifi!ant in!rease in groups 1 and 2 at &rd, $th, and
12th month !ontrols = D 0*0+>* Conclusion* Ee obser0ed nonserious impa!t on tear fun!tions and o!ular surfa!e with
antiglau!oma monotherapy* ?eta blo!2ers indu!ed more damage on the o!ular surfa!e suggesting the role of the dosing and
a!ti0e substan!es beside preser0ati0es*
1* "ntrodu!tion
Blau!oma is the se!ond leading !ause of blindness world<
wide* -stimating a pre0alen!e of 2*$+F in the population
o0er
40, the o0erall number of glau!omatous subAe!ts is
e)pe!ted to in!rease in the !ourse of the present de!ade,
owing to both demographi! e)pansion and population
aging G1H* ,opi!al hypotensi0e drops are the standard
form of therapy, whi!h is often used for long time in
multiple dosing G2H*
-)perimental and !lini!al studies showed that the long<
term use of topi!al drugs may indu!e o!ular dis!omfort,
tear film instability, !onAun!ti0a inflammation,
sub!onAun!ti0al fibrosis, epithelial apoptosis, !orneal surfa!e
impairment, and the potential ris2 of failure for further
glau!oma surgery with a possible in!rease in 0isual loss G&,
4H* O!ular surfa!e disease
=O/#> demonstrates an o0erall pre0alen!e of 42F =range
20I
+8F> in glau!oma, whi!h is se0ere in &$F =range 14I$$F>
G+H* sso!iated symptoms are nonspe!ifi! to the anterior
surfa!e of the eye and may in!lude dry eye,
burning(stinging, it!hing, irritation, tearing, foreign body
sensation, red eye, and blurred 0ision* /igns also
generally are nonspe!ifi! and may in!lude !onAun!ti0al
staining with tear film abnormalities G$H* ,hese side
effe!ts !ould be attributable to the a!ti0e !omponent as
well as to the preser0ati0es in the !ommer!ial medi!ations
but the me!hanisms in0ol0ed and the respe!< ti0e roles of
the a!ti0e !ompounds and the preser0ati0es in indu!ing
allergi!, to)i!, or proinflammatory effe!ts of ophthalmi!
solutions are still being debated GJI10H* ,here are 0arious
!ommer!ially a0ailable antiglau!oma eye drops that a
!lini!ian must !hoose* ?eside the !lini!al effe!ti0eness,
o!ular
surfa!e !hanges that may affe!t patientKs !omplian!e
should also be ta2en into !onsideration during this !hoi!e*
,he purpose of this randomi3ed and prospe!ti0e study
was to !omparati0ely analy3e the effe!ts of 0arious
!ommer< !ially a0ailable antiglau!oma eye drops as
monotherapy on the tear fun!tions and o!ular surfa!e for
o0er the periods of
12 months*
2* .ethod
&.1. Su#/ects. -ighty<fi0e eyes of 4& patients with the diag<
nosis of primary open angle glau!oma that had ne0er used
topi!al antiglau!oma drugs before enrolled in this study*
,he resear!h was appro0ed by the -thi!s Committee and
followed the tenets of the #e!laration of Helsin2i*
"nformed !onsent was obtained from the subAe!ts*
Blau!oma was defined as intrao!ular pressure ="OP>
more than 21 mmHg without treatment, abnormal
automati! full threshold perimetry =&0(2 Humphrey, /an
;eandro< #ublin, C>, and abnormal opti! dis!
=in!reased 0erti!al to hori3ontal !up to dis! ratio, !up
to dis! asymmetry between the two eyes less than 0,2, and
peripapillary splinter hemorrhages>*
,he e)!lusion !riteria used were se0ere o!ular trauma
at any time, pre0ious history of intrao!ular surgery or
argon laser trabe!uloplasty, !urrent use of !onta!t lenses,
presen!e of eyelid or eyelash deformity, history of
re!ent o!ular inflammation or infe!tion, pre0ious or
!urrent use of other o!ular medi!ations in!luding artifi!ial
tear therapy, systemi! treatment 2nown to affe!t tear
se!retion, autoimmune dis< ease, and any history or slit<
lamp e0iden!e of eye surfa!e disorders*
&.&. 0roups. ,he patients were di0ided into si) groups and
started topi!al antiglau!oma drugs*
0roup 1 1! patients, 1 eyes2' 0,+F preser0ati0e<free
timolol maleate twi!e a day*
0roup & 17 patients, 14 eyes2' 0,+F timolol maleate
in!luding
0,012F ben3odode!inium bromide =?##> twi!e a
day*
0roup 3 17 patients, 14 eyes2' 0,00+F latanoprost
in!luding
0,02F ben3al2onium !hloride =?1> on!e a day at
night*
0roup 4 17 patients, 14 eyes2' 0,0&F bimatoprost
in!luding
0,00+F ?1 on!e a day at
night*
0roup 17 patients, 14 eyes2' 0,004 tra0oprost in!luding
0,01+F ?1 on!e a day at
night*
0roup 3 17 patients, 14 eyes2' 0,1F brimonidine in!luding
purite 0*00+F twi!e a day*
&.3. Follo45)p. ll patients re!ei0ed a !omplete eye
e)ami< nation in!luding measurement of "OP by
Boldmann appla< nation tonometry and 0iewing of
irido!orneal angle and opti! dis! before the study*
ConAun!ti0al impression !ytology was performed at &rd,
$th, and 12th months for ea!h eye*
2 Journal of Ophthalmology Journal of Ophthalmology 2
,o e0aluate the la!rimal fun!tion, tear film brea2up time
=,?@,>, staining s!ores =//>, and /!hirmer =/CH> " tests
were performed before the study, at 1st wee2 and at 1st,
&rd,
$th, and 12th months*
&.4. $ests 6 Studies. /CH " test with no topi!al anesthesia
was performed using /!hirmerKs paper strip pla!ed in the
lateral lower !onAun!ti0al sa!* ,he paper strip was remo0ed
after + minutes and the length of the moistened area was
re!orded*
,ear Cuality was measured with ,?@,* ,o
measure ,?@,, a drop of sodium fluores!ein dye was
instilled and the a0erage inter0al between the last
!omplete blin2 and the appearan!e of first dry spot on the
pre!orneal film was !al!ulated under !obalt blue filtered
light*
Corneal fluores!ein staining was e)amined with !obalt
blue illumination and lissamine green was then instilled
and interpalpebral !onAun!ti0al staining of temporal and
nasal !onAun!ti0a was graded using the O)ford /!heme $<
point s!ale =from 0 to +> G11H*
"mpression !ytology was performed after one drop of
topi!al anesthesia with the 4 L + L $ mm si3ed re!tangular
shaped !ellulose a!etate filter papers of 0,02+ m pore si3e
=.illipore<B/EPO 4&00> in superior<!entral and inferior<
nasal bulbar !onAun!ti0a* ,he spe!imens were stored in
8+F ethanol and stained a!!ording to Papani!olauKs
modifi!ation of BillKs te!hniCue and periodi! a!id</!hiff*
,he spe!imens were e)amined under a light mi!ros!ope in
a mas2ed fashion and were graded on a s!ale of 3ero to
three a!!ording to 4elsonKs method* Boblet !ell !ount was
!ounted in + neigh< boring areas at L400 magnifi!ation
under light mi!ros!opy
and mean goblet !ell !ount of mm
2
area was !al!ulated*
,he same pathologist e)amined the spe!imens in a mas2ed
manner G12H*
&.. Statistical 7nalysis. ll the data were analy3ed using
the 4C// 200J software* #es!ripti0e statisti!al methods
=mean, standard de0iation> were used for the
demographi! and !lini!al !hara!teristi!s of !ases* Varian!e
analysis was used for the repeated measures of multiple
groups5 4ewman 1euls post ho! multiple !omparison test
was used for subgroups analysis5 one<way 4OV test was
used for the !omparison of the groups and ,u2ey H#/ test
was used for the subgroups and Chi<sCuare and 9isher tests
were used for the !omparison of the !ategori!al 0ariables* M
0alues of D0*0+ were !onsidered statisti!ally signifi!ant*
&* 7esults
/tudy in!luded %+ eyes of 4& patients with the diagnosis of
PB* .ean age of the patients was +0,$J N +,% in group
15
+1,&$ N +,+ in group 25 ++,+J N $,0% in group &5 +%,14 N %,$8 in
group 45 +J,4& N 8,8& in group +5 and +%,&& N 11,24 in group $
=M O 0*08>* 9emale to male ratio was 4(4, 4(&, &(4, 4(&, &(4,
and 4(& in groups 1, 2, &, 4, +, and $, respe!ti0ely =M O 0*%4>*
"OP signifi!antly de!reased in all of the groups at 1st
wee2 and at 1st, &rd, $th, and 12th months 0isits !ompared
to baseline =M O 0*0001, M D 0*0+>*
& Journal of Ophthalmology Journal of Ophthalmology &
,able 1' /CH " =mm> 0alues and tear brea2up time =,?@,> of the tear film =se!ond> a!!ording to the groups during the beginning, 1st
wee2,
1st month, &rd month, $th month, and 12th month !ontrols*
? eginni ng 1 st w e e2 1st m ont h &r d m ont h $t h m ont h 12 t h m ont h
/CH " =mm>
Broup 1 11*+& N 4*4+ 1&*J& N 11*&% 10*2 N +*4% 11*$J N 4*$8 11*&& N 4*8J 11*2J N &*$J 0*$8 0*$&$
Broup 2 12*%$ N 4*+$ 1&*0J N &*+2 12*8& N &*22 11*%$ N 2*1% 11*28 N &*%J 12 N &*01 0*%1 0*+4J
Broup & 1$*14 N J*0& 1&*J1 N 4*J$ 1&*J1 N +*4J 1&*14 N 4*8& 1+*+ N 4*8J 14 N $*&1 1*+0 0*204
Broup 4 10*8& N 10*11 10*8& N %*+& 8*J8 N J*%1 11*14 N %*&% 11*28 N %*04 10*J8 N %*18 0*4J 0*J8$
Broup + 10*8& N &*1J 8*4& N &*+2 10*+ N &*2& %*J8 N 4*48 8*4& N &*%% 8*14 N &*4% 2*08 0*0JJ
Broup $ 11*%$ N 4*&J 11*21 N +*+% 11*21 N +*%8 1&*4& N 4*$+ 12*+ N J*+ 11*4& N J*1+ 0*J+ 0*+82
1*+0 0*82 1*21 1*%% 2*22 2*2J
M
?@, =se!>
0*188 0*4J4 0*&1& 0*10$ 0*0$1 0*0++
Broup 1 14*+J N &*$& 11*$J N 4*&8 10*2J N &*+$ 11 N 4*&1 11*4J N &*% 12*0J N &*%% 1*04 0*402
Broup 2 14*+ N 4*88 12*21 N &*+% 12*&$ N &*8J 10*21 N 2*84 10*J1 N 2*& 10*21 N &*04 1*8$ 0*08$
Broup & 1% N 4*1+ 1%*%$ N 2*+1 1% N 4*$$ 1%*+ N 2*0J 1%*$4 N 4*08 18*J1 N 2*%J 0*J& 0*$02
Broup 4 1$*+ N 4*0& 14*14 N 4*08 14*&$ N 4*4J 1+*&$ N 4*&4 1$*+ N 4*J 1%*28 N 4*2+ J*0$ 0.001
Broup + 18*28 N 2*1& 1$*+J N &*&2 1+*$4 N 2*8& 1$*4& N 2*&4 1+*$4 N &*$& 1$*21 N 2*88 +*J$ 0.001
Broup $ 1$ N 2*84 1$*J1 N 2*1$ 1J*&$ N 2*J$ 1$*+J N 4*+2 1J*$4 N 4*$J 1%*21 N +*&J 1*04 0*40&
M %*+% 8*+% %*%J 12*28 8*%& 1&*88
M 0.051 0. 0 0 0 1 0. 0 0 0 1 0 . 0 0 0 1 0. 0 0 0 1 0. 0 0 0 1
3.1. $ear Functions. ,here was no statisti!ally signifi!ant
differen!e in mean /CH " test results between the groups
at any time of the study = P 0*0+> =,able 1>* ,here was
no signifi!ant ,?@, !hange in groups 1, 2, &, and $ before
and after the treatment, while ,?@, de!reased
signifi!antly in group 4 at 1st wee2 and 1st month !ontrols
=M O 0*04%,
M O 0*0018> and in group + at 1st wee2 and 1st, &rd, $th,
and 12th month !ontrols =M O 0*01%, M O 0*0045 M D 0*0+>
=,able 1>*
3.&. Staining Scores. ,here was no signifi!ant differen!e in
!orneal and temporal !onAun!ti0al // in the baseline =M O
0*1205 M P 0*0+>* Corneal // were higher in groups 1 and 2
at &rd, $th, and 12th month !ontrols =M O 0*04, M O 0*025
M D 0*0+>* ,emporal // showed signifi!ant in!rease to s!ore
2 in group $ at 12th month !ontrol =M O 0*0115 M D 0*0+>*
4asal !onAun!ti0al staining was higher in group 4 at
baseline =M O 0*0$, M O 0*0+$5 M D 0*0+>* /ignifi!ant
differen!e was obser0ed between the groups at 1st, &rd, and
12th month !ontrols =M O 0*001, M O 0*02%, M O 0*02$5 M D
0*0+>* 4asal // were higher =s!ore 2> in group 1 at 1st
month, in groups 1 and 2 =s!ore 2> at &rd month and in
group 2 =s!ore &> at $th month, and in groups 4 =4 eyes> and
1 =1 eye> =s!ore 2> at 12th month !ontrols*
3.3. "mpression Cytology. #uring impression !ytology in
the superior Cuadrant, sCuamous metaplasia grades showed
signifi!ant differen!es between the groups in the &rd, $th,
and 12th month !ontrols* Broups 1 and 2 showed higher<
grade 0alues =M D 0*0+>* #uring the follow<up, sCuamous
metaplasia grades showed a signifi!ant in!rease in groups 1
and 2 at &rd, $th, and 12th month !ontrols when !ompared
to the beginning =M D 0*0+>* Highest grade re!orded in
the superior Cuadrant was grade 2, whi!h was obser0ed in
two eyes in group 1 =1&,&F> in superior<!entral !onAun!ti0a
=,able 2>*
"n the inferior Cuadrant, sCuamous metaplasia grades
showed a signifi!ant in!rease in groups 1 and 2 at &rd, $th,
and 12th month !ontrols when !ompared to the beginning
=,able &>* Howe0er, group $ showed a signifi!ant in!rease
in sCuamous metaplasia grades in &rd and $th month
!ontrol and group + showed a signifi!ant in!rease in
sCuamous metaplasia grade only in &rd month !ontrol when
!ompared to the beginning* Highest grade re!orded in
the inferior Cuadrant was grade 2, whi!h was obser0ed in
one ea!h eye in groups 1 =$,JF> and $ =J,1F> in inferior<
nasal !onAun!ti0a at 12th month !ontrol =9igures 1=a><1=b>>*
,he !ount of goblet !ells in superior<!entral !onAun!ti0a
showed a statisti!ally signifi!ant differen!e at &rd, $th, and
12th month !ontrols =M D 0*0+>* ,he mean !ount of goblet
!ells in superior<!entral !onAun!ti0a in groups 1 and 2 at
&rd and 12th months and in group + at 12th month was
signifi!antly lower than beginning =M D 0*0+> =,able &>* ,he
mean !ount of goblet !ells in superior<!entral !onAun!ti0a in
group 1 was signifi!antly lower than groups &, +, and $ at
&rd month !ontrol =M O 0*021+, M O 0*0415 M D 0*0+>* ,he
mean !ount of goblet !ells in superior<!entral !onAun!ti0a in
groups
1 and 2 was signifi!antly lower than group & at $th month
!ontrol =M O 0*028, M O 0*025 M D 0*0+>* ,he mean !ount
of goblet !ells in superior<!entral !onAun!ti0a in group 1
was
lower than groups 4 and + at 12th month !ontrol =M O 0*0&1,
M O 0*0&25 M D 0*0+>*
,here was statisti!ally signifi!ant differen!e in !ount of
goblet !ells in inferior<nasal !onAun!ti0a at &rd, $th, and 12th
month !ontrols =M D 0*0+>* ,he mean !ount of goblet !ells
,able 2' /Cuamous metaplasia grades in the superior !onAun!ti0a a!!ording to the groups*
/Cuamous metaplasia
Broup 1
@pper Cuadrant
Broup 2 Broup & Broup 4 Broup + Broup $ M
?efore 0*0$ N 0*2+ 0*14 N 0*&$ 0*42 N 0*+1 0*14 N 0*&$ 0*0J N 0*2$ 0*&+ N 0*48
M
2
' 10*28
M O 0*0$J
&rd month 0*J& N 0*4+ 0*42 N 0*$4 0*42 N 0*+1 0*14 N 0*&$ 0*2% N 0*4$ 0*$4 N 0*$&
M
2
' 12*40
M O 0.030
$th month 0*J& N 0*4+ 0*%+ N 0*&$ 0*+0 N 0*+1 0*0J N 0*2$ 0*2% N 0*4$ 0*&+ N 0*48
M
2
' 2&*81
M O 0.0001
12th month
M
0*J& N 0*J0
0.0001
0*$4 N 0*48
0.0001
0*42 N 0*+1
0*&82
0*0J N 0*2$
0*184
0*14 N 0*&$
0*0$1
0*42 N 0*+1
0.019
M
2
' 18*+%
M O 0.001
?efore &rd month 0.002 0.046 1*00 1*00 0*0%& 0*4$
?efore $th month
0.002 0.002 0*&1J 0*&1J 0*0%& 1*00
? e fo r e 1 2 t h m o n t h
0.

0

0

4





0.

0

08





0*1+J





0*1+J





0*

&

1J





0*

&

1J





,able &' /Cuamous metaplasia grades in the inferior<nasal !onAun!ti0a a!!ording to the groups*
2
? e fo r e 1 2 t h m o n t h
0.

0

08





0.

0

2

5





0*0

%

&





0*

&

1J





0*0

%

&





0*0

%

&





in inferior<nasal !onAun!ti0a in group 1 at &rd, $th, and 12th
months, in groups & and $ at 12th month, and in group + at
$th and 12th months was signifi!antly lower than beginning
= D
0*0+> =,able 4>* ,he mean !ount of goblet !ells in
inferior< nasal !onAun!ti0a in group 1 at &rd month was
signifi!antly lower than groups &, 4, +, and $ = O 0*044,
M O 0*00+5
M D 0*0+>* ,he mean !ount of goblet !ells in inferior<nasal
!onAun!ti0a in group 1 at $th month was signifi!antly
lower than groups + and $ =M O 0*04&, M O 0*0&$5 M D
0*0+>* ,he mean !ount of goblet !ells in inferior<nasal
!onAun!ti0a in group 1 at 12th month was signifi!antly lower
than groups
4, +, and $ =M O 0*01$, M O 0*00+5 M D 0*0+> =,able 4>*
4* #is!ussion
;ong<term use of topi!al medi!ations in !hroni!
ophthalmi! !onditions, su!h as glau!oma, may ad0ersely
affe!t the o!ular surfa!e G10H* Howe0er, the me!hanisms
of o!ular surfa!e damage as well as the respe!ti0e role of
the a!ti0e !ompound and the preser0ati0es in ophthalmi!
solutions are still being in0estigated G$, 10H*
?1 is the most !ommonly used detergent preser0ati0e
in topi!al ophthalmi! preparations while ?## and
o)idants
su!h as stabili3ed o)y!hloro !omple) =/OC> or purite are
other alternati0es G4, %I10H* ?1 has been shown to !ause
tear film instability, loss of goblet !ells, !onAun!ti0al
sCuamous metaplasia, apoptosis, disruption of the !orneal
epithelium barrier, and damage to !orneal ner0es G1&,
14H* nother alternati0e is ?##, whi!h is also a
Cuaternary ammonium surfa!tant, and may ha0e
properties similar to ?1* "t is formulated with timolol as
a gel<forming solution, whi!h has a longer residen!e time
G4H* Purite is an o)idati0e preser0ati0e whi!h is usually
used in brimonidine topi!al drops and artifi!ial tears
G1+H* Clini!al studies showed that purite !aused the least
amount of damage to !orneal epithelial !ells G8H and the
number of inflammatory !ells in the !onAun!ti0a was sig<
nifi!antly lower with brimonidine<purite G1$H* Preser0ati0e<
free drugs were less asso!iated with o!ular surfa!e
symptoms and signs in the literature G+, 1JH*
!ti0e !ompounds as well as preser0ati0es may affe!t
the o!ular surfa!e* ?eta blo!2ers ha0e been reported to
inhibit proliferation of !orneal epithelial !ells G1%H and lead
to a de!rease in goblet !ell density and tear produ!tion
G18, 20H* Howe0er prostaglandin analogues are !laimed for
inflammatory damage in the o!ular surfa!e of glau!oma
patients !ombining allergy with to)i!ity G21, 22H*
/Cuamous metaplasia
Broup 1
"nferior Cuadrant
Broup 2 Broup & Broup 4 Broup + Broup $
?efore 0*1$ N 0*2+ 0*21 N 0*42 0*42 N 0*+1 0*2% N 0*4$ 0*11 N 0*2$ 0*2% N 0*4$

2
' J*82
O 0*1$1
&rd month 0*+& N 0*+1 0*+0 N 0*$+ 0*+J N 0*+1 0*21 N 0*42 0*&+ N 0*48 0*+J N 0*J+
M
2
' 4*+0
M O 0*4J8
$th month 0*40 N 0*+0 0*$4 N 0*48 0*+J N 0*+1 0*21 N 0*42 0*2% N 0*4$ 0*+J N 0*J+
M
2
' J*28
M O 0*200
12th month
M
0*+& N 0*$&
0.001
0*+J N 0*+1
0.013
0*J1 N 0*4$
0*08$
0*21 N 0*42
0*&82
0*2% N 0*4$
0.029
0*+0 N 0*$+
0.019
M ' %*%J
M O 0*114
?efore &rd month 0.008 0.046 0*1+J 0*&1J 0.046 0.046
?efore $th month
0.025 0.014 0*1+J 0*&1J 0*0%& 0.046
,able 4' ,he mean !ount of goblet !ells in superior<!entral and inferior<nasal
!onAun!ti0a*
B

ob

let



!e

l l

!

o

u

n

t




? e ginni n g & r d m o n t h $ t h m o n t h 1 2 t h m o n t h
Broup 1
/uperior 8&*4 N 4%*8+ %$*4J N 44*14 %$*8& N +&*$2 J8*8& N 42*J+ +*$% 0.002
"nferior 84*1& N 4%*$J %J*2J N 4&*4% %%*&& N +4*$ %1*4J N 4J*42 $*$2 0.001
Broup 2
/uperior 110*0J N 41*48 88*21 N &+*++ %&*J8 N 4&*+4 %+ N 41*8+ 11*12 0.001
"nferior 120*4& N &8*J+ 11$*&$ N &+*08 11&*28 N &8*44 11+*8& N &4*1% 0*$1 0*$1$
Broup &
/uperior 12%*+J N &4*2& 128*8& N 2J*+8 1&$*J1 N &J*1+ 114*J8 N 24*2J 2*21 0*10&
"nferior 1&2*%$ N 2+*JJ 1&1*$4 N 28*+2 12J*+J N &+*44 11&*+ N &8*8$ 2*8$ 0.044
Broup 4
/uperior 124*+ N &0*+% 10+*+ N 4+*0J 11+*J1 N &%*J8 118 N 28*8+ 2*1& 0*112
"nferior 1&2*21 N 4$*08 128*+ N 42*&& 12$*21 N 4+*24 1&&*14 N &+*8J 0*&& 0*%02
Broup +
/uperior 1&2*%$ N 20*J% 12J*4& N 18*+J 12+*+ N 1+*JJ 118*14 N 1+*04 4*&$ 0.01
"nferior 14%*%$ N 18*J1 140*14 N 1J*84 1&4*J8 N 18*8J 12%*14 N 1J*8+ 10*0$ 0.047
Broup $
M
0*0$$
0.004 0.004 0.003
M
0*0J 0.0 02 0.0 4 4 0.004
=a> =b>
9igure 1' =a> ,he impression !ytology of a patient in group $ showing grade 0 metaplasia in the inferior<nasal !onAun!ti0a before treatment*
=b> ,he impression !ytology of the same patient in group $ showing grade 2 metaplasia in the inferior<nasal !onAun!ti0a after using
brimonidine< purite for 12 months*
"n the present study, we measured tear Cuality with
,?@, and tear produ!tion with /CH " test and e0aluated
the o!ular surfa!e by !orneal and interpalpebral
!onAun!ti0al staining* Ee obser0ed no statisti!ally
signifi!ant differen!e in mean /CH " test results between
the groups at any time of the study or after* Howe0er,
,?@, de!reased signifi!antly in groups
4 =bimatoprost> and + =tra0oprost> during their !ontrols*
4one of the patients had /!hirmer 0alue less than + mm
or ,?@, 0alue less than 10 mm indi!ating dry eye* ,he
most signifi!antly affe!ted o!ular sign of O/# was
reported to be de!reased ,?@,, indi!ating tear film
instability while !orneal and !onAun!ti0al staining was a
reliable indi!ator of
se0erity in the literature G+H* 7ossi et al* showed abnormal
,?@, and pun!tuate 2eratitis, whi!h was more freCuent
with in!reasing number of eye drops and number of
instillations per day in the patients with topi!ally treated
glau!oma G2&H* /hima3a2i et al* G18H ha0e reported in a
prospe!ti0e study that timolol !aused signifi!ant
impairments in tear produ!< tion and turno0er, while no
ad0erse effe!ts were obser0ed on the !orneal epithelial
integrity and tear fun!tion with prostaglandin analogue
unoprostone eye drops5 /tewart et al* showed that timolol
maleate demonstrated in!reased staining in the !ornea and
nasal !onAun!ti0a from baseline to hour 0 and hour 1 on the
healthy subAe!ts G24H* -yes being instilled
/uperior 118*8& N 41*+1 1&0*J8 N 40*8& 12J*21 N ++*&2 114*21 N 40*2% 1*+$ 0*21$
"nferior 1J4*0J N 10+*+1 144*28 N +1*+8 1&+*$4 N +%*&8 128*+J N 4&*14 2*%8 0.001
2*1J &*J+ &*%1 &*8%
&*4& 4*&2 2*40 &*J+
with any type of beta blo!2er had more !orneal epithelial
pun!tate erosion and a shorter ,?@, in a study by ;ee et
al* G1%H* 1uppens et al* demonstrated that ,?@, was
signifi!antly lower in patients treated with preser0ed and
preser0ati0e<free timolol than in !ontrols and did not differ
signifi!antly from ea!h other, suggesting that the a!ti0e
!ompound may alter the tear film, while ?1 may ha0e
other side effe!ts G2+H* ,hese !hanges in tear fun!tion and
tear turno0er may in!rease both !on!entration and
e)posure time of drugs and preser0ati0es* 9urthermore,
!orneal anestheti! effe!t of timolol maleate may also be
attributed to signifi!ant !orneal to)i!ity in beta blo!2er
instilling patients G20H* /upporting the findings of "noue et
al* and /tewart et al*, we dete!ted more !orneal and
nasal !onAun!ti0al staining in the patients in groups 1 and
2 =preser0ed and nonpreser0ed groups> re!ei0ing timolol
suggesting the role of a!ti0e !ompound timolol on !orneal
to)i!ity but on the opposite to ;ee et al* and 1uppens et
al*, we did not dete!t a !hange in /!hirmer " and ,?@, tests
with beta blo!2er eye drops*
1o3obolis et al* showed that !entral !orneal
me!hani!al sensiti0ity was redu!ed signifi!antly in the
patients re!ei0ing latanoprost, tra0oprost, and bimatoprost
!orrelating with /!hirmer and ,?@, test s!ores G2$H*
Howe0er, .artone et al* ha0e obser0ed that !lini!al
s!ores of !orneal sensiti0ity, /!hirmer " test, and la!rimal
film brea2up time were sig< nifi!antly lower in the
preser0ati0e medi!ation groups than in the preser0ati0e<
free group with no signifi!ant differen!e between patients
treated with timolol and latanoprost in the monotherapy
group G10H* "n our study, ,?@, de!reased signifi!antly in
patients using bimatoprost and tra0oprost monotherapy
during their !ontrols, while none of the patients using
prostaglandin analogue showed signifi!ant staining o0er
s!ore 2* ,ear fun!tions were not affe!ted in the patients
using latanoprost although it represents a ?1
!on!entration twi!e that of most other glau!oma drops*
"mpression !ytology is a simple and nonin0asi0e
method* 4elson et al* de0ised a &<stage !lassifi!ation
based on nu!lear(!ytoplasmi! ratio and goblet !ell density
to e)amine !onAun!ti0al epithelium G2J, 2%H* ,he time
reCuired for onset of the metaplasia has been suggested to
be less than three months G28H* lso in this study we
dete!ted sCuamous metaplasia mostly at &rd month
!ontrols* Hong et al* e0alu< ated the !onAun!ti0al !hanges in
bulbar !onAun!ti0al impres< sion !ytology spe!imens from
patients re!ei0ing timolol, latanoprost, dor3olamide,
timolol Q latanoprost, and timolol
Q dor3olamide medi!ations a!!ording to 4elsonKs method*
,he impression !ytology s!ores were signifi!antly higher
in the medi!ation groups mostly in the fi)ed<!ombination
therapy groups than in the monotherapy groups with no
signifi!ant differen!e between the different types of med<
i!ation after at least si) months of treatment G&0H* "n the
present study, sCuamous metaplasia grades did not
show a signifi!ant differen!e between the groups at the
end of
12th month !ontrols in the inferior Cuadrant, while in the
superior Cuadrant groups 1 and 2 showed higher<grade
0alues =M D 0*0+>* /Cuamous metaplasia grades showed a
signifi!ant in!rease only in groups 1 and 2 at &rd, $th, and
12th month !ontrols when !ompared to the beginning in
the superior and inferior Cuadrants* ?eta blo!2ersK
e)hibition of higher
grade of sCuamous metaplasia might be related to a!ti0e
substan!e timolol and in!reased number of instillations per
day in group 1 =nonpreser0ed timolol> and longer residen!e
time of the gel<forming solution in group 2 =timolol Q
??#>*
,he de!rease in !onAun!ti0al goblet !ell density is
a!!epted as an important parameter in assessing the O/#*
,he !onAun!ti0al inflammation and redu!ed goblet !ell
density of dry eye are e)a!erbated by use of preser0ed
topi!al agents G21, &1H* "n our study, the mean !ount of
goblet !ells showed a signifi!ant de!rease in groups 1
=nonpreser0ed timolol>, 2 =timolol Q ??#>, and +
=tra0oprost> in the superior Cuadrant while in the inferior
Cuadrant in groups 1 =nonpreser0ed timolol>, &
=latanoprost>, + =tra0oprost>, and $ =brimonidine> showed a
de!rease at the end of 12th month !ontrol* ?au< douin et
al* showed in the impression !ytology spe!imens that
!lass "" antigen H;<#7 e)pression showed slight and
nonsignifi!ant in!reases in the glau!oma patients re!ei0ing a
beta blo!2er as monotherapy or treated with a
prostaglandin analogue alone =latanoprost, tra0oprost, and
bimatoprost>, while H;<#7 positi0ity was at the
highest le0el in the multitreatment group G21H* Pisella et
al* demonstrated that ?1<!ontaining latanoprost and
timolol e)hibit higher inflammatory mar2er e)pression and
de!reased .@C+C e)pression and proapoptoti! effe!ts on
!onAun!ti0al !ells than does nonpreser0ed timolol*
;atanoprost !aused less to)i!ity, howe0er, than preser0ed
timolol, and both drugs were less to)i! than ?1 alone
in a study with flow !ytometry in impression !ytology
spe!imens G&2H* On the other hand, 4oe!2er et al* found
less damage in the !ornea and lower inflammatory
infiltrates in the !onAun!ti0a with those drugs !ontaining
the least preser0ati0e !on!entrations, espe!ially
brimonidine<purite and bimatoprost using s!anning ele!tron
mi!ros!opy and light mi!ros!opy in rabbits G&&H* "n the
present study, we obser0ed a de!rease in goblet !ell !ount
in the timolol, latanoprost, and tra0oprost groups but not in
bimatoprost group* Our obser0ation of goblet !ell de!rease
in these patients may refle!t the role of inflammation
a!!ord< ingly*
,his study has se0eral limitations* Our number of
patients for ea!h group was limited and there was no
!ontrol group for ea!h a!ti0e !ompound or preser0ati0e*
;onger and larger s!ale prospe!ti0e studies in!luding
!ontrol groups may be benefi!ial to impro0e glau!oma
treatment and for a better understanding of o!ular surfa!e
disease in glau!oma*
+* Con!lusion
"n this study, we obser0ed nonserious impa!t on tear
fun!tion tests and low<grade metaplasia with topi!al
antiglau!oma monotherapy at the end of 12th month
!ontrol* Ee also obser0ed that preser0ed and nonpreser0ed
beta blo!2ers indu!e more damage on the o!ular surfa!e
!ompared to prostaglandin analogues and brimonidine<
purite suggesting that beside preser0ati0e substan!es, the
number of daily administrations and a!ti0e substan!es
might also be responsible for the o!ular surfa!e !hanges
obser0ed*
Confli!t of "nterests
,he authors report no !onfli!t of interests* ,he authors
alone are responsible for the !ontent and writing of the
paper*
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. - # " ,
O 7 /
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