Vol.:(0123456789)
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G ae e's A chi e o Clinical and Expe imen al Oph halmology
h ps://doi.o g/10.1007/s00417-023-06163-5
GLAUCOMA
Incidence and ea men app oach o in aocula p essu e ele a ion
a e  a ious ypes o local s e oids o  e inal diseases
Aga aAnnaWyk o a1 · AlaaDinAbdin1· C is ianMun eanu1· U sulaLöw1· Be holdSei z1
Recei ed: 19 Feb ua y 2023 / Re ised: 13 June 2023 / Accep ed: 28 June 2023
© The Au ho (s) 2023
Abs ac
Pu pose Fo he ea men o macula edema, in addi ion o he use o an i ascula endo helial g ow h ac o s, s e oids a e
also used in a i eally and sub-Tenon. Side e ec s include among o he s ca a ac o ma ion and ele a ion o in aocula
p essu e (IOP). The aim o his e ospec i e s udy was o elici he IOP ele a ion a e adminis a ion o a ious s e oidal
medica ion, he ime o onse , and he e icacy o he adminis e ed IOP-lowe ing he apies.
Me hods We included 428 eyes wi h a pos ope a i e (n = 136), diabe ic (n = 148), u ei ic macula edema (n = 61), and
macula edema a e e inal ein occlusion (n = 83). These pa ien s we e ea ed wi h one o mo e di e se s e oidal agen s
once o mul iple imes. These d ugs included: iamcinolone ace onide (TMC) as in a i eal injec ion (TMC IVI) o sub-
Tenon (TMC ST), as well as dexame hasone (DXM) and luocinolone ace onide (FA) in a i eally. An inc ease o IOP
o ≥ 25mmHg was designa ed as pa hological. A s e oid esponse in anamnesis, he ime o onse o IOP ise om he i s
adminis a ion, and he he apy adminis e ed we e documen ed.
Resul s O 428 eyes, 168 eyes (39.3%) had IOP ele a ion up o a mean o 29.7 (SD ± 5.6) mmHg, which occu ed a a
median o 5.5mon hs. S e oids mos equen ly leading o ise o IOP included DXM (39.1% o all eyes ecei ing ha d ug),
TMC IVI (47.6%), TMC ST combined wi h DXM (51.5%), DXM wi h FA (56.8%), and TMC IVI wi h DXM (57.4%). A
Kaplan–Meie analysis and he Log Rank es showed a signi ican di e ence (p < 0.001). IOP ise was ea ed as ollows:
119 conse a i ely (70.8%), and 21 su gically (12.5%, cyclopho ocoagula ion 8.3%, il e ing su ge y 1.8%, in 4 he s e oidal
d ug implan was emo ed 2.4%), and 28 eyes ecei ed no he apy (16.7%). Su icien IOP egula ion was achie ed in 82
eyes (68.9%) wi h opical he apy. In 37 eyes (31.1%) wi h pe sis en ly ele a ed in aocula p essu e, opical he apy had o
be con inued o e he ollow-up o 20 ± 7mon hs.
Conclusions IOP inc eases a e any ype o s e oid applica ion a e no a e. Resul s o ou s udy le us suspec ha especially
he apy wi h in a i eal dexame hasone, ei he as a mono he apy o in combina ion wi h ano he s e oid, ends o inc ease
IOP mo e han o he s e oids. Regula IOP checks a e necessa y a e each s e oid adminis a ion, wi h possible ini ia ion
o long- e m conse a i e and/o su gical he apy i necessa y.
Keywo ds Macula edema· S e oidal agen s· Ocula hype ension· Seconda y ocula hype ension
* Aga a Anna Wyk o a
Aga a.wyk o [email protected]
1 Depa men o Oph halmology, Saa land Uni e si y Medical
Cen e (UKS), Hombu g/Saa , Ge many
G ae e's A chi e o Clinical and Expe imen al Oph halmology
1 3
In oduc ion
Glaucoma is conside ed o be he second leading cause o
isual impai men and blindness wo ldwide, a ec ing abou
70 million people [1]. The mos common o m o his disease,
conce ning 70% o cases, is p ima y open-angle glaucoma [2].
A majo isk ac o o he disease is an ele a ed in aocula
p essu e (IOP), al hough some cases p esen wi h no mal IOP
[3]. In any case, eyes wi h bo h high ension and no mal en-
sion glaucoma a e cha ac e ized by a p og essi e loss o e inal
ne e ibe cells wi h subsequen educ ion o he isual ield
[2] and educing IOP is conside ed an e ec i e ea men [4].
The apeu ic use o glucoco icoids can cause an ele a ion o IOP
called s e oid-induced ocula hype ension (SIOH) and he eby
s e oid-induced – seconda y – glaucoma (SIG) by ini ialing
signaling cascades a ec ing exp ession o genes, which causes
a highly pe sonalized pha macological esponse [5]. I was
i s in 1950 when an ele a ion o IOP was documen ed a e
sys emic adminis a ion o ad enoco ico ophic ho mone [6].
An inc ease o IOP a e he opical adminis a ion o co isone
was no iced i s in 1954 [7]. Since hen, he phenomenon o
SIOH and SIG has been s udied in ensi ely and isk ac o s, he
pa hophysiology, as well as ea men we e in es iga ed. Nowa-
days, s e oidal d ug implan s a e a known ea men op ion o
e inal diseases, such as macula edema [8]. An inc ease in IOP
unde s e oid he apy, esul ing in a seconda y glaucoma, can
be obse ed in abou 30% o he popula ion. This phenomenon
is called "s e oid esponse". In abou 5%, a "high- esponse" is
p esen , wi h a p essu e inc ease o mo e han 15mmHg abo e
he baseline p essu e [9]. I he s e oid-induced ocula hype en-
sion esul ing om he s e oid he apy is o a signi ican magni-
ude, and le uncon olled and un ea ed, i can lead o s e oid-
induced glaucoma wi h glaucoma ous op ic neu opa hy [10].
The e a e many condi ions leading o macula edema,
ou o which a e men ioned in his pape : diabe es, e inal
Key messages
Wha is known:
Apa om ascula endo helial g ow h ac o s (an i-VEGF), s e oids a e also used in a i eally and
sub-Tenon o he ea men o macula edema wi h an ele a ion o in aocula p essu e (IOP) as one he
mos consequen ial side e ec s.
In his s udy, 39.3% o eyes had an IOP ele a ion up o a mean o 29.7 (SD ± 5.6) mmHg, which occu ed
a a median o 5.5 mon hs.
Wha is new:
S e oids which mos equen ly led o ise o IOP o ≥ 25 mmHg included dexame hasone (39.1% o all eyes
ecei ing ha d ug), iamcinolone in a i eal (47.6%), iamcinolone sub-Tenon combined wi h
dexame hasone (51.5%), dexame hasone wi h luocinolone ace onide (56.8%), and iamcinolone in a i eal
wi h dexame hasone (57.4%).
Rise in IOP could be ea ed in 70.8% wi h opical he apy.
ein occlusion, in lamma o y eye diseases (u ei is) and s a-
us pos eye su ge y. Al hough ha ing a ious pa hophysiol-
ogy, hey can be all ea ed wi h s e oidal d ugs.
The aim o his e ospec i e s udy was o elici he
in aocula p essu e inc eases a e s e oid adminis a ion
o e inal disease, he ime o onse , as well as he e i-
cacy o he adminis e ed eye p essu e-lowe ing he apeu ic
app oaches.
Me hods
S udy design andda abase
The da a collec ion was pe o med e ospec i ely on 428 eyes
o 349 pa ien s in he pe iod om 01.01.2016 o 31.08.2021.
The s udy was pe o med in a single cen e , he Depa men
o Oph halmology a he Saa land Uni e si y Medical Cen e
(UKS) in Hombu g/Saa . Pa ien s we e iden i ied using he
FIDUS (ou elec onic pa ien eco ds) [11] and SAP (Sys-
ems, Applica ions and P oduc s in da a p ocessing – ou
in e nal hospi al in o ma ion sys ems). Inclusion c i e ium
o his s udy was a diagnosis o macula edema as a esul o
s a us pos eye su ge y, diabe ic macula edema, e inal ein
occlusion, and u ei is. Pa ien s wi h con i med p ima y open-
angle glaucoma we e included. Mino s (pa ien s < 18yea s
old), howe e , we e excluded om he s udy. Pe o med su -
ge ies leading o seconda y macula edema included ca a ac
su ge y, pa s plana i ec omy (PPV), hese wo p ocedu es
combined, Desceme memb ane endo helial ke a oplas y
(DMEK), and pene a ing ke a oplas y (PK). Re inal ein
occlusion included bo h cen al (CRVO) and b anch e inal
ein occlusion (BRVO). Macula edema was diagnosed based
on undoscopy, op ical cohe ence omog aphy and luo escein
G ae e's A chi e o Clinical and Expe imen al Oph halmology
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angiog aphy, which we e pe o med be o e he i s s e oidal
d ug applica ion. Macula edema was ea ed wi h s e oidal
agen s once o mul iple imes, and wi h one o mo e s e -
oids. I a subjec p esen ed wi h a s e oid esponse, i.e. IOP
ise, we documen ed he ime a e i s s e oid adminis a-
ion and he he apy adminis e ed. An IOP ise was desc ibed
as ≥ 25mmHg [12]. The he apies adminis e ed in ou s udy
we e: (1) conse a i e wi h eye d ops and (2) su gical, includ-
ing cyclopho ocoagula ion, il e ing su ge y and emo al o
s e oidal d ug implan . A e wa ds, we documen ed whe he
he chosen ea men was bene icial o he eye p essu e o
no . IOP o ≤ 20mmHg was conside ed as well- egula ed and
he ime a e he in oduc ion o he apy was documen ed. In
case o conse a i e eye d op he apy, we also documen ed
whe he a pa ien was able o s op aking he medica ion.
This s udy and all in es iga ional p o ocols we e
app o ed by he Saa land Uni e si y Medical Cen e as
well as he E hics Commi ee o he Medical Associa ion
o Saa land, Ge many (N . 123/20, da e: 16.06.2020).
Ta ge igu es
All pa ien s had ollow-ups o 24mon hs wi h isi s a
day 1 ( i s s e oid adminis a ion), 6–8weeks, 6, 12, 18
and 24mon hs.
Oph halmological examina ions
A comple e oph halmological clinical e alua ion pe o med
o all pa ien s included he bes co ec ed isual acui y
(BCVA), in aocula p essu e (IOP) measu emen using
Goldmann applana ion onome y, and an e io and pos e-
io segmen examina ion wi h he sli lamp (Sli Lamp BX
900®, Haag-S ei , Köniz, Swi ze land). Macula edema
wi h i s cen al macula hickness (CMT) was measu ed wi h
macula op ical cohe ence omog aphy (M-OCT) (Spec a-
lis OCT, Heidelbe g Enginee ing, Heidelbe g, Ge many).
Fluo escein angiog aphy (FA, Heidelbe g Enginee ing,
Heidelbe g, Ge many) was usually pe o med once a he
ini ial p esen a ion o con i m he diagnosis. I necessa y – i
was epea ed.
Applica ion p ocess
In his s udy, macula edema was ea ed wi h iamcinolone
ace onide sub-Tenon (TMC ST) o in a i eally (TMC IVI),
dexame hasone in a i eally (DXM) and luocinolone ace-
onide in a i eally (FA) used in mono he apy o di e -
en combina ions in ou Macula Ou pa ien Depa men
(IVI cen e [13]). Physicochemical cha ac e is ics o each
d ug a e summa ized in Table1. Pa ien s we e examined
be o e each s e oidal d ug applica ion o check o possible
con aindica ions o he injec ion, such as any kind o eye
in lamma ion o o he pa hologies. We examined he BCVA,
IOP, an e io and pos e io ocula segmen and educa ed he
pa ien s abou he injec ion, possible isks and complica ions
as well as had hem sign he consen o m. A e wa ds, he
eye o be injec ed was ma ked and d opped wi h opicamide,
phenyleph ine, o dila e he pupil, and polyhexanide 0.02%
eye d ops, as an an isep ic. Al oge he , he eye was d opped
wi h polyhexanide wice be o e and once a e an injec ion.
The anamnesis and cu en he apy we e also asce ained,
o ind ou abou possible changes in medica ion applied
om an oph halmologis o , o example, an ele a ed IOP
ha had o be ea ed. We pe o med an OCT o check he
macula edema be o e he i s injec ion and hen acco ding
o he ea men plan e e y one, h ee o ou appoin men s.
We applied iamcinolone ace onide, dexame hasone and
luocinolone ace onide in a i eally and iamcinolone ace-
onide sub-Tenon unde a d op/gel anes hesia wi h p opa-
acaine eye d ops and xylocaine gel o a leas 10min be o e
he injec ion. 0.05ml o TMC, 700μg o DXM o 190μg
o FA was en e ed empo-in e io ly wi h displacemen o
he conjunc i a a 4mm om he limbus. A e wa ds, he
ligh pe cep ion was checked and when posi i e – he pa ien
was eleased om ou ou pa ien depa men . A e he s e -
oid applica ion in a i eally, we always ecommended a
Table 1 Compa ison o each s e oid d ug wi h i s ac i e subs ance, applica ion o m, ime o ac ion, maximal concen a ion (i a ailable), con-
cen a ion a he end o ac ion ime (i a ailable), i s app o ed and o label use [12, 15–24]
DME = diabe ic macula edema, RVO = e inal ein occlusion, PME = pos ope a i e macula edema, NI = no in o ma ion
T ade name Ac i e subs ance Applica- ion Time o ac ion Maximal concen a ion
(day/ alue)
Concen a ion a he end o
ac ion ime (day/ alue)
App o ed use
VOLON A T iamcinolone ace onide In a i eal injec ion 12weeks o cou-
ple o mon hs
2.15 o 7.20μg/ml -
VOLON A T iamcinolone ace onide Sub-Tenon injec ion 12weeks NI -
OZURDEX Dexame hasone In a i eal implan 6mon hs 0.094ng/ml 0.05ng/ml DME
RVO
U ei is
ILUVIEN Fluocinolone ace onide In a i eal implan 36mon hs 7 h day 100pg/mL DME
U ei is
G ae e's A chi e o Clinical and Expe imen al Oph halmology
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check-up appoin men in he nex wo o h ee days a ou
depa men o a ex e nal doc o s´ o ices. A dose o 0.15ml
o TMC was adminis e ed sub-Tenon unde he empo-in e-
io conjunc i a in d op/gel anes hesia wi h p opa acaine
eye d ops and xylocaine gel o a leas 10min be o e he
applica ion.
Fo DME and macula edema a e ein occlusion, we
adminis e ed one TMC IVI as s anda d, and i no complica-
ions occu ed, we pe o med in a i eal injec ion o DXM
a e a leas 8weeks. DXM was usually applied e e y
4–6mon hs, while FA e e y 2–3yea s. In he absence o
imp o emen a e opical and sys emic he apy o UME
(u ei ic macula edema), TMC sub-Tenon ollowed by in a-
i eal injec ion o DXM was adminis e ed. Pos ope a i e
macula edema was p incipally ea ed wi h TMC sub-Tenon
[14]. No s anda d pos ope a i e he apy was adminis e ed,
especially no an ibio ics o s e oids.
The apy o s e oid‑induced ocula hype ension
applied in his s udy
The i s -choice in aocula p essu e-lowe ing he apy applied
in ou depa men we e opically adminis e ed d ugs. The ec-
ommended ea men mos ly included alpha-2(α2)ad ene gic
ecep o agonis s 2 o 3 imes pe day, ca bonic anhyd ase
inhibi o s 2 imes pe day, be a (β-) blocke s 2 imes pe day
as single medica ion, o as combina ion medica ion. I he IOP
was no low enough, we p esc ibed ace azolamide 250mg
in doses o 0.5, 1, 2 o 3 pe day, acco ding o needs o he
pa ien , adminis e ed o ally. P os aglandin analogues we e
no ecommended as hey migh igge an an e io chambe
in lamma ion and macula edema, as well as i s p og ession
h ough a achidonic acid and p o-in lamma o y p ocess ac i a-
ion [25]. A i s , we p esc ibed a he apy wi h one medica ion
(= mono he apy). I he d ug was no ole a ed i was swi ched.
In con as , i he a ge IOP could no be eached – ano he
d ug was added. I a pa ien s ill p esen ed wi h inc eased IOP,
we decided o un a su gical, IOP lowe ing in e en ion.
P ocedu es ca ied ou in ou s udy included a cyclopho o-
coagula ion, abeculec omy and i ec omy o emo e a s e-
oidal d ug implan and ensu e a no maliza ion o an ele a ed
IOP. Anes hesia applied o pa ien s in ou s udy included a
opical, e obulba , sub-Tenon and gene al anes hesia.
S a is ics
Da a was collec ed in a Mic oso Excel 365 sp eadshee .
Desc ip i e analysis o he pa ien collec i e was al eady pos-
sible using Excel. Absolu e (numbe o cases) and ela i e e-
quencies (pe cen age) we e calcula ed. In addi ion, maximum,
minimum, mean, and s anda d de ia ion could be calcula ed
o some pa ame e s o be e desc ibe he pa ien g oups. The
a i hme ic mean was always calcula ed and documen ed as
he mean alue.
Fo he s a is ical analysis we used IBM SPSS S a is ics
27. The Pea son Chi-Squa ed es was used o compa e ca -
ego ical and o dinal a iables as well as o show a signi ican
associa ion be ween g oups and ca ego ies. Fo he compa i-
son o he con inuous a iable o e ime be ween numbe s
o ca ego ies he Gene al Linea Model was used. Also, he
pai wise compa ison be ween ime poin s was adjus ed wi h
Bon e oni co ec ion. A p- alue o < 0.05 was conside ed o
show a signi ican esul .
Bo h eyes we e included in 79 pa ien s o 349 (22.6%), he e-
o e he in e class co ela ion coe icien (ICC) [26] be ween
he le and igh eye o he same pa ien was calcula ed o all
pa ame e s o exclude a signi ican e ec due o co ela ed da a.
Resul s
S udy collec i e
Demog aphic da a, gene al andeye anamnesis (Table2)
The s udy included 428 eyes o 349 pa ien s, o which 188
(53.9%) we e male and 161 (46.1%) we e emale wi h an
a e age age o 68.4 (± 11.9). The gene al anamnesis showed
ha 251 (71.9%) subjec s p esen ed wi h hype ension, 146
(41.8%) wi h diabe es melli us wi h an a e age HbA1c o
7.5% and 159 (45.6%) ook an an icoagulan a ha ime.
Ou o 428 eyes, we coun ed 236 (55.1%) igh eyes
and 192 (44.9%) le ones. The p- alue o ICC o all main
Table 2 Demog aphic da a, gene al and eye anamnesis o 349 pa ien s
Demog aphic da a and eye anamnesis
Numbe o pa ien s To al 349
Male 188 (53.9%)
Female 161 (46.1%)
A e age age 68.4 ± 11.9yea s
Hype ension 251 (71.9%)
Diabe es melli us 146 (41.8%)
An icoagula ion 159 (45.6%)
Numbe o eyes 428
Righ eyes 236 (55.1%)
Le eyes 192 (44.9%)
Eyes wi h p ima y open-angle glaucoma 65 (15.2%)
Eye p essu e lowe ing eye d ops 58 (13.6%)
Posi i e amily his o y o glaucoma 7 (2%)
Amblyopic eyes 14 (3.3%)
His o y o auma 8 (1.9%)
S a us pos ca a ac su ge y 328 (76.6%)
S a us pos pa s plana i ec omy 236 (31.5%)
G ae e's A chi e o Clinical and Expe imen al Oph halmology
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ou come measu es be ween le and igh eyes was > 0.35,
which indica ed a non-signi ican co ela ion be ween he
wo eyes in examined pa ien s. Acco ding o he eye anam-
nesis, 65 (15.2%) eyes p esen ed wi h p ima y open-angle
glaucoma using only one ocula p essu e lowe ing eye d op,
ou o which 7 (2%) had a posi i e amily his o y o glau-
coma. 14 eyes we e amblyopic (3.3%), 8 eyes had a his-
o y o auma (1.9%), 328 eyes (76.6%) had unde gone
ca a ac su ge y p e iously and 135 eyes (31.5%) pa s plana
i ec omy.
All eyes ha expe ienced auma (n = 8, 1.9%) su e ed
om a pos ope a i e macula edema la e on.
Classi ica ion acco ding odiagnosis
We included 136 eyes (31.8%) wi h a pos ope a i e macula
edema (PME), 148 (34.6%) wi h diabe ic macula edema
(DME), 83 (19.4%) wi h macula edema a e a e inal ein
occlusion (RVO, bo h cen al e inal ein occlusion – CRVO,
and b anch e inal ein occlusion – BRVO) and 61 (14.3%)
wi h u ei ic macula edema (UME).
Classi ica ion acco ding os e oids adminis e ed
As a as adminis a ion o single d ug and d ug combina-
ions was conce ned, he exac da a is p esen ed in Table3.
Pe iod o  ollow‑up
A ollow-up a 6–8weeks was done o all he pa ien s,
386 (90.2%) pa ien s we e con olled a e 6mon hs, 323
(75.5%) o hem had a ollow-up a 1yea , 256 (59.8%) o
hem came in o a con ol isi a e 18mon hs, while a
ull ollow-up o 24mon hs was eached by 220 pa ien s
(51.4%). We conside ed he unscheduled isi s as well, as
he pa ien s we e o en e e ed om a doc o because o
p oblems a e s e oid adminis a ion, mos ly because o
IOP ele a ion.
Visual acui y (VA)
The BCVA imp o ed in pa ien s wi h pos ope a i e macu-
la edema wi h an a e age o 0.26 (± 0.2) decimal be o e
he i s s e oid applica ion, 0.4 (± 0.26) a e 12mon hs
and 0.4 (± 0.26) a e 24mon hs o ollow-up, as well as in
pa ien s wi h u ei ic macula edema wi h 0.25 (± 0.13) p e-
ope a i ely, 0.37 (± 0.2) a e 12mon hs and 0.42 (± 0.28)
a e 24mon hs. Subjec s su e ing om diabe ic macula
edema had an a e age BCVA o 0.43 (± 0.22) be o e he
s e oid applica ion, 0.46 (± 0.25) a e 12mon hs and 0.38
(± 0.25) a e 24mon hs. Pa ien s a e a e inal ein occlu-
sion p esen ed wi h an a e age BCVA o 0.34 (± 0.2) p e-
ope a i ely, 0.37 (± 0.24) a e 12mon hs and 0.31 (± 0.26)
a e 24mon hs.
S a is ical analysis showed no signi ican di e ence
be ween BCVA in eyes wi h an ele a ed IOP as opposed
o eyes wi hou an IOP ele a ion. VA in 168 eyes wi h an
ele a ed IOP was as ollows: 0.34 (± 0.21) decimal be o e
he i s s e oid applica ion, 0.4 (± 0.25) a e 12mon hs and
0.35 (± 0.24) a e 24mon hs o ollow-up.
Cen al macula hickness (CMT)
As a as he CMT is conce ned, i was educed in all
g oups unde he s e oid he apy. I amoun ed on a e age
465μm be o e he i s s e oid adminis a ion, 380μm a e
6–8weeks, 384μm a e 6mon hs, 382μm a e 12mon hs,
370μm a e 18mon hs, and 369μm a e 24mon hs.
Rega ding CMT in di e en g oups be o e he s e oid appli-
ca ion and a las con ol o 24mon hs, we measu ed 504μm
(± 109) and 384μm (± 105) in he pos ope a i e g oup,
420μm (± 119) and 362μm (± 97) in diabe ic pa ien s,
Table 3 Ele a ion o in aocula
p essu e in eyes ea ed wi h
mono he apy o combina ion
o s e oidal agen s (TMC
ST = iamcinolone sub-Tenon;
FA = luocinolone ace onide;
DXM = dexame hasone; TMC
IVI = iamcinolone in a i eal)
S e oidal d ug as mono he apy
and d ug combina ion
F equency (n, % o all
d ug combina ions)
IOP ele a ion (n, % o
each d ug combina ion)
Time un il IOP ise
in median (mon hs)
TMC ST 130 (30.4%) 30 (23.1%) 5
FA 16 (3.7%) 5 (31.3%) 11
DXM 133 (31.1%) 52 (39.1%) 5
TMC IVI 21 (4.9%) 10 (47.6%) 1
TMC IVI + DXM 47 (11%) 27 (57.4%) 7
DXM + FA 37 (8.7%) 21 (56.8%) 6
TMC ST + DXM 33 (7.7%) 17 (51.5%) 4
TMC IVI + DXM + FA 6 (1.4%) 4 (66.7%) 8
TMC IVI + TMC ST + DXM 3 (0.7%) 1 (33.3%) 8
TMC ST + DXM + FA 1 (0.2%) 1 (100%) 8
TMC IVI + TMC ST 1 (0.2%) 0 (0.0%) 8

G ae e's A chi e o Clinical and Expe imen al Oph halmology
1 3
429μm (± 129) and 386μm (± 144) in subjec s a e e inal
ein occlusion and 497μm (± 108) and 356μm (± 125) a
u ei ic pa ien s.
In aocula p essu e (IOP)
An IOP was measu ed a e e y isi , wi h an a e age o 14.3
(SD ± 3.3) mmHg be o e he i s s e oid adminis a ion, 15.7
(SD ± 4.6) mmHg a e 6–8weeks, 15.8 (SD ± 4.6) mmHg
a e 6mon hs, 15.3 (SD ± 4.0) mmHg a e 12mon hs,
15.2 (SD ± 4.6) mmHg a e 18mon hs, and 15.5 (SD ± 5.4)
mmHg a 24mon hs.
S e oid esponse
I a subjec p esen ed wi h an IOP ise o ≥ 25mmHg, we
documen ed he ime a e i s s e oid adminis a ion and
he he apy adminis e ed. Ou o a o al o 428 eyes, 168
p esen ed wi h an IOP ele a ion o ≥ 25mmHg, wi h a mean
alue o 29.7 (SD ± 5.6) mmHg. The ise o ocula p essu e
occu ed on a e age a e 7.5mon hs (SD ± 6.2) om he i s
s e oid adminis a ion, wi h a median o 5.5mon hs. Subjec s
p esen ed wi h an ele a ed ocula p essu e o ≥ 25mmHg
a e a minimum o 2weeks and a maximum o 24mon hs.
When i came o he ise o IOP a e adminis a ion
o s e oids in a mono he apy o as a d ug combina ion,
s e oids mainly leading o a ise in IOP included DXM
(39.1% o all eyes ecei ing ha d ug), TMC ST (23.1%),
TMC IVI combined wi h DXM (57.4%), DXM wi h FA
(56.8%), and TMC ST wi h DXM (51.5%) (Table3 and
Fig.1). Kaplan–Meie analysis and he Log Rank es
showed a signi ican di e ence (p < 0.001) in be ween
ypes o s e oidal medica ion used and he momen he
pa ien had an IOP ele a ion. IOP ise was documen ed
a e a median o 1mon h in case o TMC IVI and up o
11mon hs a e applica ion o FA (Fig.2). Addi ionally,
57.7% ou o all eyes wi h an IOP ele a ion we e ea ed
wi h a s e oidal d ug mono he apy. Fu he mo e, he
Fig. 1 Ele a ion o in aocula
p essu e in eyes ea ed wi h
mono he apy o combina ions
o s e oidal medica ion (TMC
ST = iamcinolone sub-Tenon;
FA = luocinolone ace onide;
DXM = dexame hasone; TMC
IVI = iamcinolone in a i eal)
Fig. 2 Median ime o an IOP
ele a ion (in mon hs) a e he
i s s e oidal agen applica ion
in mono he apy, mos applied
s e oid combina ions, and he
es o s e oid combina ions
(TMC ST = iamcinolone
sub-Tenon; FA = luocinolone
ace onide; DXM = dexame ha-
sone; TMC IVI = iamcinolone
in a i eal)
G ae e's A chi e o Clinical and Expe imen al Oph halmology
1 3
s e oid combina ions simila ly led o he IOP inc ease.
Se en y-one eyes (42.3%) we e ea ed wi h s e oid com-
bina ions ha esul ed in IOP ele a ion in 51 o 57%
o eyes. The mos used combina ions included TMC ST
wi h DXM, DXM wi h FA, and TMC IVI wi h DXM.
Glaucoma pa ien s be o es e oid applica ion
As a as eyes wi h p ima y open-angle glaucoma a e
conce ned, we no ed 65 o hem. 30 (46.2%) had no
IOP ele a ion a e applica ion o a s e oid agen and
35 (53.8%) p esen ed an inc eased IOP, which makes
20.8% o all 168 eyes wi h an ele a ed IOP in his s udy.
Thus, eyes wi h p e ious glaucoma had a signi ican ly
(p < 0.009) inc eased isk o de eloping an IOP ele a ion
a e s e oid applica ion.
Rubeosis i idis
Rubeosis i idis, as an addi ional pa ame e ha may cause a
ise in ocula p essu e, was documen ed in one pa ien be o e
he s e oid he apy and addi ionally in wo pa ien s a e
6mon hs. The i s pa ien p esen ed wi h a diabe ic macula
edema and p oli e a i e diabe ic e inopa hy; she also had an
IOP ele a ion o 40mmHg maximum. The second subjec wi h
he same diagnosis addi ionally had an ischemic maculopa hy,
and IOP ose o mo e han 25mmHg. The hi d pa ien , who
de eloped ubeosis i idis a e 6mon hs, had u ei is in e me-
dia wi h asculi is, wi h IOP ele a ions o up o 50mmHg.
Lens s a us – IOP ele a ion inphakic e suspseudophakic
eyes
Lens s a us showed o be s a is ically signi ican
(p < 0.01) as a as ise o IOP is conce ned. Ou o 100
phakic eyes in gene al popula ion, 61% (n = 61) showed
an ele a ed IOP a e s e oid applica ion. In compa ison,
IOP ele a ion was documen ed only in 32.6% (n = 107)
o pseudophakic eyes (n = 328) (Fig.3). Thus, lens s a-
us could be a p edic i e ac o o IOP ele a ion a e
s e oid adminis a ion.
Gene al linea model (GLM) analysis o in luence o
lens s a us on IOP ele a ion showed, ha i came slowe
o IOP spike in phakic eyes, wi h a peak IOP o 18.4 (an
a e age, ± 0.7) mmHg a 6mon hs. In pseudophakic eyes
IOP spike o 18.0 (± 0.5) mmHg could be obse ed a
6–8weeks (p = 0.019, Fig.4).
The apy
In o al, 119 (70.8%) pa ien s ecei ed a conse a i e he apy
wi h IOP-lowe ing eye d ops. The e was no s anda d scheme
Fig. 3 Pe cen age o eyes wi h and wi hou IOP ele a ion in phakic
and pseudophakic eyes (0 = no ise o IOP; 1 = ise o IOP)
Fig. 4 A e age IOP in phakic
and pseudophakic eyes (0 = no
ca a ac su ge y; 1 = s a us pos
ca a ac su ge y)
G ae e's A chi e o Clinical and Expe imen al Oph halmology
1 3
o p esc ibing he eye d ops, nei he in ou depa men no
a ex e nal doc o ´s p ac ices. P esc ip ions included alpha
agonis s, be a blocke s and ca bonic anhyd ase inhibi o s.
When he ollow-up exams showed an IOP o ≤ 20mmHg,
we conside ed his as well egula ed, and a conse a i e
he apy could be discon inued.
Su icien IOP egula ion was achie ed in 82 eyes (68.9%)
ea ed wi h opical he apy. In 37 eyes (31.1%) wi h pe sis-
en ly ele a ed in aocula p essu e, opical he apy had o
be con inued pas he ollow-up.
Su gical in e en ion was pe o med in 21 eyes wi h
pe sis en ly ele a ed IOP and inc ease in cup- o-disc a ion
(CDR). Ou o hese 21 cases, we pe o med a cyclopho o-
coagula ion in 14 eyes (8.3%), a il e ing su ge y in 3 eyes
(1.8%) and we emo ed a s e oidal d ug implan – FA – om
4 eyes (2.4%). S e oidal d ug implan s we e emo ed in 1
eye ea ed o a pos ope a i e macula edema (25%), in 2
eyes ea ed o a diabe ic macula edema (50%) and in 1 eye
su e ing om a e inal ein occlusion (25%).
28 eyes ecei ed no he apy (16.7%).
Discussion
Common side e ec s o in aocula glucoco icoids may
include pos injec ion in ec ious endoph halmi is, second-
a y ocula hype ension, o seconda y s e oid-induced
open-angle glaucoma, hegma ogenous e inal de ach-
men , pos injec ion s e oid-induced ca a ac , cen al se ous
cho io e inopa hy, and oxic e ec s [27–30]. Howe e , an
inc ease in IOP is one o he mos widely discussed opics
in e ms o i s possible u u e implica ions, i.e. de elopmen
o a seconda y s e oid-induced glaucoma. When compa ed
o in a i eal injec ion, sub-Tenon applica ion o TMC has
a lowe isk o IOP ele a ion due o a lowe in aocula con-
cen a ion and sho e du a ion o ac ion [31, 32].
Li e a u e desc ibes a hype ensi e ocula esponse in up
o 50% o eyes ha a e injec ed wi h a co icos e oid [10,
33]. In ou s udy, 57.7% ou o all eyes wi h an IOP ele a ion
had been ea ed wi h a s e oidal d ug mono he apy. Acco d-
ing o he o icial summa y o p oduc cha ac e is ics, an IOP
ele a ion o ≥ 10mmHg om baseline occu ed in 28% a
any isi , while an IOL o ≥ 30mmHg occu ed in 15% o
pa ien s who we e subjec s o an obse a ional s udy and
ecei ed DXM. In ou s udy, an IOP ise, de ined as a single
measu emen o ≥ 25mmHg [12], was documen ed in 39.3%
o all eyes. Simila ly, Rezkallah e al. [34] analyzed 494 eyes
a e an in a i eal injec ion o a dexame hasone-implan ,
ou o which 32.6% p esen ed wi h ocula hype ension
(OHT). The main indica ions o ea men in hei s udy
we e e inal ein occlusion, diabe ic macula edema, pos -
su gical macula edema and u ei is. The SAFODEX s udy
[12] showed ha dexame hasone-implan s, injec ed in 421
eyes o e inal ein occlusion, diabe ic macula edema, pos -
su gical macula edema and u ei is, caused OHT in 28.5%
o cases. In he ZERO s udy, conduc ed by Schmi z e al.,
less han 20% o he eyes a e dexame hasone injec ions o
e inal ein occlusion p esen ed wi h ele a ed IOP.
As a as in a i eal injec ions wi h luocinolone ace o-
nide a e conce ned, main ad e se e ec s include he isk o
aised in aocula p essu e, as well as ca a ac de elopmen
[23]. Acco ding o ILUVIEN’s summa y o p oduc cha -
ac e is ics, IOL ele a ion is a e y common ad e se e en
wi h IOP > 25mmHg a 21% and > 30mmHg a 14% o
pa ien s in an obse a ional s udy. 38% o subjec s equi ed
an IOP-lowe ing medica ion, whe eas 5.6% had su ge y o
lowe IOP. In ou s udy, 5 o 16 eyes (31.3%) wi h FA mono-
he apy had an ele a ed IOP which occu ed a e a median
o 11mon hs. In he FAME s udy, IOP inc eased in 37.1%
o eyes a e ecei ing an FA-injec ion [23]. In compa ison,
Al aqawi e al. [35] documen ed an IOP ise o ≥ 10mmHg
in 3 eyes (11%). Fallico e al. [36] epo ed ha 27% o hei
subjec s equi ed IOP-lowe ing d ops and 3% glaucoma su -
ge y. In e es ingly, 1.8% o ou pa ien s’ eyes unde wen a
il e ing glaucoma su ge y and 2.4% had a s e oidal d ug
implan – luocinolone ace onide in all cases – emo ed.
In an a icle by Tao e al. [28], abou 40% o eyes de el-
oped a seconda y OHT a e an in a i eal iamcinolone
he apy, whe eas in ou s udy 47.6% o eyes p esen ed wi h
ocula hype ension. Fu he mo e, sub-Tenon iamcinolone
ace onide caused an IOP ele a ion in 23.1% o eyes. Handzel
e al. [37] as well as Ca dillo e al. [31] s a ed, ha he e was
no signi ican ise in IOP a e sub-Tenon iamcinolone ace-
onide, wi h Ca dillo p esen ing no di e ence be ween he
2 ypes o iamcinolone ace onide applica ion (in a i eal
e sus sub-Tenon).
The mos common s e oid combina ions ha esul ed in
an inc ease in IOP we e in a i eal iamcinolone ace on-
ide combined wi h dexame hasone (57.4%), dexame hasone
wi h luocinolone ace onide (56.8%), and sub-Tenon iam-
cinolone ace onide wi h dexame hasone (51.5%) (Table3
and Fig.1). These esul s le us suspec ha he apy wi h
dexame hasone, ei he as a mono he apy o in combina ion
wi h ano he s e oid, ends o inc ease IOP.
The ise o ocula p essu e occu ed on a e age a e
7.5mon hs om he i s s e oid adminis a ion, wi h a
median o 5.5mon hs. Subjec s p esen ed wi h an ele a ed
ocula p essu e o ≥ 25mmHg a e a minimum o 2weeks
and a maximum o 24mon hs. IOP ise was documen ed
a e a median o 1mon h in case o in a i eal iamci-
nolone ace onide, wi h he i s IOP ele a ion occu ing a e
no mo e han 2weeks. This co ela es wi h esul s by Jonas
e al. [30] who showed IOP ise al eady du ing he i s week
a e he in a i eal injec ion. The longes mean inc ease o
IOP wi h 11mon hs was obse ed a e he applica ion o
luocinolone ace onide. In compa ison, Al aqawi e al. [35]
G ae e's A chi e o Clinical and Expe imen al Oph halmology
1 3
documen ed an IOP ise a e a mean o 3mon hs a e he
applica ion.
In ou s udy, in 28 eyes (16.7%) wi h a single IOP ise,
he e was spon aneous no maliza ion o IOP a e discon-
inua ion o s e oidal he apy, wi hou p essu e-lowe ing
opical he apy. Gi en a s e oid induced ele a ed IOP, no -
maliza ion is possible a e simply s opping he s e oidal
he apy. Howe e , o p e en s uc u al and/o unc ional
de e io a ion due o con inuously inc eased IOP, pa ien s
su e ing om SIOH, o SIG can be success ully managed
wi h opical glaucoma medica ion, jus he same as pa ien s
wi h p ima y open-angle glaucoma and ocula hype en-
sion, wi hou he impac o s e oids. I hese ea men s
ail o con ol he IOP, pa ien s mus unde go a adi ional
glaucoma su gical in e en ion, which is only equi ed in
less han 2% o cases [30]. Acco ding o he o icial sum-
ma y o p oduc cha ac e is ics o OZURDEX®, opical
IOP lowe ing medica ion was applied in 42%, while su gi-
cal in e en ion o ele a ed IOP was needed in 1.2% o
pa ien s who we e subjec s o an obse a ional s udy [38].
In he MEAD S udy o e 40% o eyes equi ed a opical
an iglaucoma he apy and 0.3% o eyes we e ea ed wi h
incisional glaucoma su ge y [39]. Mo eo e , he Re ise -
FA implan s udy epo ed an IOP ele a ion o ≥ 30mmHg
in mo e han 60% o eyes. As a esul , one hi d o hese
eyes equi ed glaucoma il a ion su ge y o explan a ion
o he de ice [40]. Ou s udy showed 168 eyes (39.3%)
wi h an OHT a e s e oid injec ion, which we e ea ed
conse a i ely wi h opical an iglaucoma he apy (70.8%
o eyes wi h ele a ed IOP). In compa ison, 10% o eyes
equi ed opical glaucoma ea men a e an IOP ele a ion
in he EMR-s udy [41]. We conside ed an IOP o be well
con olled when eaching an IOP o ≤ 20mmHg unde op-
ical he apy, which was achie ed in 82 eyes (48.8%) a e
4.5mon hs on a e age. Li e al. [42] eached IOP con ol
simila ly by mon h 4. Su gical in e en ion was needed in
21 eyes (12.5%) wi h cyclopho ocoagula ion pe o med in
14 eyes (8.3%), glaucoma il a ion su ge y pe o med in 3
eyes (1.8%) and s e oidal d ug implan emo al in 4 cases
(2.4%). The IRSS S udy showed ha 2% o eyes equi ed
incisional glaucoma su ge y [43], whe eas in he EMR-
s udy, his was only necessa y in 0.3% [41].
As a as eyes wi h p ima y open-angle glaucoma
a e conce ned, 35 ou o 65 (53.8%) p esen ed wi h an
inc eased IOP, which is 20.8% ou o all 168 eyes wi h
an OHT and showed o be s a is ically signi ican wi h a
p- alue < 0.009. Simila ly, in a s udy by Chin e al. [44],
ou o 13 eyes wi h p e-exis ing p ima y open-angle glau-
coma, 6 de eloped OHT (46.2%). Mo eo e , Le in e al.
[45] analyzed pa ien s wi h a his o y o co icos e oid
induced IOP ele a ion and his o ical non- esponde s a e
sub-Tenon co icos e oid injec ions. Thei esul s showed
ha a highe a e o ecu en IOP ele a ion de eloped in
his o ical esponde eyes (44%) compa ed wi h 13% in
non- esponde s.
Lens s a us migh be a p edic i e ac o o IOP ele a ion
a e s e oid applica ion, as IOP inc eased in 61% o phakic
eyes, compa ed o 32.6% o pseudophakic eyes.
One o he majo limi a ions o ou s udy is he e o-
spec i e design which is he cause o some missing da a.
The e o e, p ospec i e designs should be c ea ed o be e
esea ch on and unde s and his opic. Mo eo e , as ou
clinic is loca ed in a u al a ea wi h a poo ly de eloped pub-
lic anspo sys em and some o he pa ien s a e mul imo -
bid, he connec ion o a egula check-up, which is decisi e
o he success o il e ing ope a ions, was no gi en. Fo his
eason, we p e e ed cyclopho ocoagula ion because o he
educed need o pos ope a i e ollow-up.
Conclusions
In conclusion, e e y s e oid he apy, ega dless o he agen
o indica ion, can lead o he de elopmen o ocula hype -
ension. The isk may a y acco ding o he s e oids and he
ea men (e.g. mono he apy e sus d ug combina ion) used.
Resul s o ou s udy le us suspec ha especially he apy
wi h in a i eal dexame hasone, ei he as a mono he apy o
in combina ion wi h ano he s e oid, ends o inc ease IOP
mo e han o he s e oids. An ele a ed IOP p edisposes he
pa ien o de elop seconda y s e oid-induced hype ension,
as well as seconda y s e oid-induced glaucoma wi h all o
he disease’s sigh - h ea ening aspec s. Each pa ien should
be in ensi ely in o med abou he possible isks o he apy
and a end egula IOP con ols du ing ollow-up o ini ia e
an ea ly in e en ion i necessa y.
Funding Open Access unding enabled and o ganized by P ojek
DEAL. No unding was ecei ed o his esea ch.
Decla a ions
E hical app o al All p ocedu es pe o med in his s udy we e in
acco dance wi h he e hical s anda ds o he Saa land Uni e si y Medi-
cal Cen e and he E hics Commi ee o he Medical Associa ion o
Saa land, Ge many (N . 123/20, da e: 16.06.2020), as well as wi h
he 1964 Helsinki decla a ion and i s la e amendmen s o compa able
e hical s anda ds.
This a icle does no con ain any s udies wi h animals pe o med by
any o he au ho s.
In o med consen Fo his ype o s udy o mal consen is no equi ed.
Con lic o in e es All au ho s ce i y ha hey ha e no a ilia ions
wi h o in ol emen in any o ganiza ion o en i y wi h any inancial in-
e es (such as hono a ia; educa ional g an s; pa icipa ion in speake s'
bu eaus; membe ship, employmen , consul ancies, s ock owne ship,
o o he equi y in e es ; and expe es imony o pa en -licensing a -