LASER TREATMENT IN

GLAUCOMA
Efficacy and Safety

Erika Rasmuson

Department of Clinical Sciences, Ophthalmology

Umeå 2023
This work is protected by the Swedish Copyright Legislation (Act 1960:729)
Dissertation for PhD
ISBN: 978-91-8070-012-2 (print)
ISBN: 978-91-8070-013-9 (pdf)
ISSN: 0346-6612
New Series Number: 2239
Cover photo: Johan Rasmuson
Electronic version available at: http://umu.diva-portal.org/
Printed by: Cityprint Norr AB
Umeå, Sweden 2023
Dedicated to my wonderful family
Table of Contents
Abstract ...................................................................................................... iii

Svensk sammanfattning ............................................................................. v

Abbreviations............................................................................................ vii

Original papers .......................................................................................... ix

Introduction................................................................................................ 1
Background ....................................................................................... 1
Aqueous humor dynamics and intraocular pressure ............. 2
Pathophysiology ...................................................................... 3
Epidemiology ........................................................................... 3
Glaucoma types ....................................................................... 4
Primary open-angle glaucoma (POAG) .................................. 4
Pseudoexfoliation glaucoma ................................................... 4
Secondary glaucoma................................................................ 5
Risk factors for open-angle glaucoma..................................... 6
Diagnostics and monitoring of glaucoma ............................... 6
Glaucoma treatment and compliance ..................................... 9
Laser treatment in glaucoma .......................................................... 10
Laser trabeculoplasty ............................................................ 10
Transscleral cyclophotocoagulation ..................................... 12
The Glaucoma Intensive Treatment Study (GITS) ............... 14
Need for further laser treatment research? .......................... 14

Hypotheses and aims ................................................................................15

Materials and Methods............................................................................. 16

Subjects ........................................................................................... 16
IOP measurements ..........................................................................17
Laser treatments ............................................................................. 18
Transscleral cyclophotocoagulation ..................................... 18
Laser trabeculoplasty ............................................................ 18
Visual acuity .......................................................................... 19
Statistical methods.......................................................................... 20
Definitions of treatment success and failure ........................ 20
Study drop-out ...................................................................... 20
Ethical considerations .................................................................... 21

i
 Consent .................................................................................. 21
Risk of harm .......................................................................... 21

Results ...................................................................................................... 23
Transscleral cyclophotocoagulation ............................................... 23
IOP – first 24 hours after TCP .............................................. 24
IOP – 2-year retrospective follow-up after TCP ................... 25
Visual acuity after TCP, short- and long-term evaluation .... 27
Complications of TCP ............................................................ 28
Laser trabeculoplasty ...................................................................... 29
IOP change after LTP ............................................................ 29
Complications after LTP....................................................... 35

Discussion and clinical implications ........................................................ 36

Efficacy of TCP ................................................................................ 36
Safety of TCP ................................................................................... 37
TCP – effect on visual acuity ................................................. 39
TCP - place in glaucoma management ........................................... 39
Efficacy of LTP ................................................................................ 40
Safety of LTP ................................................................................... 41
LTP in glaucoma care ..................................................................... 42
Study population and patient selection .......................................... 42
Strengths and limitations ............................................................... 43

Conclusions............................................................................................... 44

Acknowledgements................................................................................... 45

References ................................................................................................ 48

ii
Abstract
Glaucoma is a progressive optic neuropathy and the major cause of irreversible
blindness worldwide. Although the pathogenesis of glaucoma is not completely
understood, the most important risk factor for development and progression of
the disease is an elevated intraocular pressure (IOP). Current glaucoma
treatment aims to reduce the IOP in the affected eye. This can be achieved by
topical drops, laser therapy or surgery. Laser treatment is used at different stages
of the glaucoma disease. Some types of laser procedures are used as first-line
treatments or as complement to topical medications or surgery, while other types
are used in advanced glaucoma as a last option when other therapies have failed.
Although laser therapy has long been used to reduce the IOP in glaucoma,
knowledge gaps remain. The aim of this thesis was to evaluate the efficacy and
safety, in both a short- and long-term perspective, of two of the most frequently
used laser procedures in glaucoma: laser trabeculoplasty (LTP) and transscleral
cyclophotocoagulation (TCP).

In the first study, a retrospective analysis, the long-term efficacy and safety of
TCP was evaluated in 300 eyes of 300 glaucoma patients in northern Sweden. We
found an overall substantial IOP reduction of more than 10 mmHg that was
maintained at least 2 years in various types of glaucoma. Following TCP, the
patients could reduce their treatment with an average of one substance of topical
glaucoma medication in the treated eye. No case of phthisis bulbi, the most feared
complication of TCP, was reported. However, a general decline in visual acuity
(VA) was noted during the two-year follow up period, and the cause of this finding
was difficult to assess due to the retrospective nature of the study.

The short-term effect of TCP on IOP was further investigated in a prospective

study of 58 eyes of 58 glaucoma patients. IOP was measured at baseline before
TCP and at five additional time-points up to 24 hours after the treatment. The VA
was measured before TCP and at the 24 h examination. The results showed a
transient IOP spike with a peak at six hours after TCP in approximately 40% of
the eyes. Spikes were more common in eyes with pseudoexfoliation glaucoma.

The last two studies of the thesis focused on the short- and long-term efficacy of
LTP. One-hundred fifty-two eyes of 122 newly diagnosed glaucoma patients that
had been randomized to the multi-treated arm in the Glaucoma Intensive
Treatment Study (GITS) were included. All studied eyes were treated with three
different IOP-lowering substances and after one week, LTP was performed. We
demonstrated that there was an additional IOP-lowering effect of LTP but that
this effect was strongly associated with the level of IOP before the laser, where a
higher IOP pre-LTP yielded a greater IOP reduction. Eyes with pre-laser IOP ³15

iii
mmHg showed a significant IOP reduction that was maintained during four years
of follow-up. However, in eyes with pre-LTP IOP <15 mmHg, the effect of laser
treatment was limited.

In summary, this thesis investigated the efficacy and safety of TCP both
retrospectively in a longer perspective and prospectively during the first 24 hours
after treatment. An overall high efficacy without serious complications was
shown, but a possible decline in VA must be considered in the long run.
Furthermore, the risk of IOP spikes after TCP implies that additional IOP-
lowering treatment should be considered during the first 24 hours, especially in
eyes with pseudoexfoliation glaucoma or severe glaucoma damage. Finally, LTP
may provide a valuable long-lasting IOP-lowering effect despite medical multi-
treatment in eyes with a pre-LTP IOP ³15 mmHg.

iv
Svensk sammanfattning
Glaukom är en långsamt fortskridande ögonsjukdom som drabbar synnerven.
Sjukdomen är den vanligaste orsaken till obotbar blindhet. Varför man får
sjukdomen är inte helt klarlagd, men ett förhöjt ögontryck utgör en viktig
riskfaktor för både utveckling och försämring av glaukom. All hittillsvarande
behandling vid glaukom syftar till att sänka ögontrycket i det drabbade ögat.
Vanliga alternativ är trycksänkande ögondroppar, laserbehandling eller kirurgi.
Trots att laserbehandlingar länge har använts både som förstahandsval och som
ett komplement till annan behandling finns det fortfarande kunskapsluckor.
Syftet med denna avhandling var att utvärdera effektivitet och säkerhet både på
kort och lång sikt vid två av de mest använda lasermetoderna vid
glaukomsjukdom; transskleral cyklofotokoagulation (TCP) och
lasertrabekuloplastik (LTP).

I den första studien undersöktes den långsiktiga effektiviteten och säkerheten

efter TCP-behandling hos 300 glaukompatienter från norra Sverige genom en
tillbakablickande journalgenomgång. TCP gav en generellt god trycksänkning, i
genomsnitt drygt 10 mmHg, som höll i sig under en uppföljningstid på två år.
Efter TCP-behandlingen kunde patienterna minska på sin trycksänkande
medicinering med i genomsnitt en trycksänkande substans i det behandlade ögat.
Under uppföljningstiden förekom inget fall av ftis, den mest fruktade
komplikationen efter TCP där ögat skrumpnar ihop och slutar fungera. Däremot
sågs en försämring av synskärpan under de två uppföljande åren. Eftersom detta
var en tillbakablickande studie det var svårt att klargöra huruvida
synskärpeförlusten var en följd av laserbehandlingen eller av andra faktorer
såsom exempelvis försämring av glaukomsjukdomen eller utveckling av grå starr.

Vidare studerades hur ögontrycket påverkades kortsiktigt efter TCP i en

framåtblickande studie av 58 ögon. Här mättes ögontrycket strax innan
laserbehandlingen och därefter vid ytterligare fem tidpunkter under det första
dygnet. Synskärpan kontrollerades innan behandling och efter 24 timmar.
Resultaten från mätningarna visade att ca 40% av de behandlade ögonen fick en
tryckstegring som var mest uttalad efter 6 timmar. Tryckstegring var vanligast
hos patienter med exfoliationsglaukom, en glaukomtyp som är vanlig i norra
Sverige och Skandinavien.

Nästföljande två studier fokuserade på effekterna av LTP på både kort och lång
sikt. Patienterna som studerades ingick i Glaucoma Intensive Treatment Study
(GITS) där patienter med nyupptäckt glaukom slumpats till att, i det här fallet, få
multibehandling vilket innebar tre trycksänkande droppar och därefter LTP en
vecka senare. Våra resultat visade att LTP kunde ha en ytterligare trycksänkande

v
effekt trots att ögontrycket redan var sänkt pga dropparna. Effekten av LTP var
dock starkt kopplad till trycknivån, där ett högre ögontryck innan
laserbehandlingen gav en större trycksänkning efter LTP. Om man hade ett
ögontryck som var ³15 mmHg innan LTP så sågs en trycksänkning som varade
upp till fyra år, men om trycket däremot var lägre än 15 mmHg innan
behandlingen var effekten av LTP minimal.

Sammanfattningsvis så undersöktes effektiviteten och säkerheten hos TCP både

under det första dygnet såväl som under en två-årsuppföljning. En god och
varaktig sänkning av ögontrycket påvisades. Inga allvarliga biverkningar sågs,
men en försämring av synskärpan på längre sikt kan inte uteslutas. Förekomsten
av tryckstegring timmar efter TCP-behandlingen gör även att ytterligare
trycksänkande medicinering bör övervägas under det första dygnet. Detta för att
förebygga glaukomförsämring, speciellt hos patienter med exfoliationsglaukom
eller allvarlig glaukomskada. Slutligen kan LTP sänka trycket ytterligare hos
multibehandlade personer. Effekten är dock avhängig trycknivån innan
laserbehandlingen. Ett ögontryck på 15 mmHg eller högre ger en varaktig
trycksänkning i upp till fyra år medan ett lägre tryck ger en mycket begränsad
effekt.

vi
Abbreviations
ACG angle-closure glaucoma

ALT argon laser trabeculoplasty

ANOVA analysis of variance

CCT central corneal thickness

EGS European Glaucoma Society

EMGT Early Manifest Glaucoma Trial

ETDRS Early Treatment Diabetic Retinopathy Study

GAT Goldmann applanation tonometry

GEE generalized estimated equations

GITS Glaucoma Intensive Treament Study

ICP intracranial pressure

IOP intraocular pressure

J Joule

LiGHt Laser in Glaucoma and ocular Hypertension Trial

LOXL-1 lysyl oxidase like -1

logMAR logarithm of the minimum angle of resolution

LTP laser trabeculoplasty

mmHg millimeter mercury

NTG normal tension glaucoma

NVG neovascular glaucoma

OAG open-angle glaucoma

vii
OH ocular hypertension

OCT optical coherence tomography

OSG other secondary glaucoma

PEX pseudoexfoliation

PEXG pseudoexfoliation glaucoma

PGA prostaglandin analogue

POAG primary open-angle glaucoma

SAP standard automated perimetry

SD standard deviation

SLT selective laser trabeculoplasty

TCP transscleral cyclophotocoagulation

TM trabecular meshwork

VA visual acuity

viii
Original papers
The thesis is based on the following publications which will be referred to in the
text by their Roman numerals:

I. Rasmuson E, Lindén C, Lundberg B, Jóhannesson G. Efficacy and

safety of transscleral cyclophotocoagulation in Swedish glaucoma
patients. Acta Ophtalmologica Scandinavica 2019; 97: 764-770

II. Rasmuson E, Lindén C, Lundberg B, Jóhannesson G. Changes in

intraocular pressure during the first 24 hours after transscleral
cyclophotocoagulation. Manuscript.

III. Rasmuson E, Bengtsson B, Lindén C, Heijl A, Aspberg J,

Andersson-Geimer S, Jóhannesson G. LTP in newly-diagnosed
multi-treated glaucoma patients. Acta Ophtalmologica
Scandinavica 2021; 99: 269-274

IV. Rasmuson E, Bengtsson B, Lindén C, Heijl A, Aspberg J,

Andersson-Geimer S, Jóhannesson G. Long-term follow-up of laser
trabeculoplasy in multi-treated glaucoma patients. Submitted
manuscript.

Papers I and III were reprinted with kind permission from the publisher.

ix
Midjourney AI attempting to interpret the etymology of glaucoma in
the style of the English 19th century painter William Turner.

x
 Introduction
Background
Glaucoma is a progressive disease of the optic nerve that causes permanent loss
of the visual field, and in severe cases, blindness. The most common type, open-
angle glaucoma (OAG), is sometimes referred to as “the silent thief of sight” since
the optic nerve damage is initially asymptomatic and hence may go unnoticed for
several years before diagnosed. By then, the disease may have caused a
considerable and irreversible reduction of the patient’s visual field. Glaucoma is
characterized by gradual thinning of the nerve fiber layer of the retina, most
evident in the optic nerve head. Other structures in the eye that are involved in
glaucoma (described in detail further below), are the ciliary body and the
drainage structures of the anterior chamber angle. Figure 1 shows the different
parts of the eye.

Figure 1. Basic anatomy of the eye. Illustration by Erika Rasmuson.

1
Aqueous humor dynamics and intraocular pressure
The non-vascularized parts of the eye receive oxygen and nutrients via the
aqueous humor. The aqueous humor is produced by the inner non-pigmented
epithelial cells lining the ciliary body, see Figure 2.

Figure 2. Cross-sectional image of the anterior chamber of the eye. Arrows indicate the flow of
aqueous humor from the posterior to the anterior chamber. Illustration by Erika Rasmuson.

Approximately 2-3 µl of aqueous humor is produced every minute, but the

production varies as it follows a circadian rhythm, and the production is lower
during sleep [1]. The aqueous humor is transported from the posterior chamber
through the pupil to the anterior chamber where it is drained in the anterior
irido-corneal angle. The major part, 75-90% of the aqueous humor is filtrated
through the trabecular meshwork (TM) [2]. The aqueous humor then enters the
canal of Schlemm via its inner wall that consists of an endothelial monolayer
[3]. Furthermore, the drainage continues to the collector channels and the
episcleral venous system, where the pressure is approximately 8-10 millimeter
mercury (mmHg) [4].

The remaining aqueous portion is drained via the uveoscleral pathway that passes
the iris root and ciliary body and out through the suprachoroidal space [5]. The
outflow through the TM is pressure-dependent and influenced by both the IOP

2
and the episcleral venous pressure while the uveoscleral pathway is believed to
work independently of the intraocular pressure [6, 7].

The balance between the secretion of aqueous humor and the rate of its outflow
determines the IOP. In the healthy eye, flow of aqueous humor against resistance
generates an average IOP of approximately 15-16 mmHg [8, 9]. Sufficient IOP is
necessary to inflate the eye and sustain the shape and optical properties of the
globe. Reduction of aqueous humor outflow resulting in an elevated IOP is a
central principle of glaucoma pathophysiology [6].

Pathophysiology
The pathogenesis of glaucoma is unknown, but several different theories are
proposed. An elevated IOP may cause mechanical stress and traction at the
lamina cribrosa, the weakest point of the posterior part of the eye where the optic
nerve, composed of the axons of the retinal ganglion cells, exits the eye. This
tension may cause a compression and deformation of the lamina cribrosa with
subsequent mechanical damage to the axons and disruption of axonal transport,
which causes a reduced supply of neurotrophic factors to the retinal ganglion cells
[10, 11]. Another hypothesis argues that the ocular blood supply is disrupted
which causes ischemia and loss of the retinal ganglion cells, suggesting that for
instance a low systemic blood pressure may increase the risk of glaucoma [12, 13].
Some studies argue that in glaucoma that occurs at normal levels of IOP, so called
normal-tension glaucoma, a pathological pressure difference between the IOP
and the intracranial pressure (ICP) at lamina cribrosa due to low ICP may explain
the cause of glaucoma [14, 15]. However, this is a topic of debate with conflicting
results in the literature [16]. Furthermore, additional theories exist.

Epidemiology
The prevalence of glaucoma varies greatly depending on geographic region and
ethnicity [17, 18]. In 2020 it was estimated that 76 million people in the world
suffered from glaucoma. This number is expected to increase to 112 million by
2040, mainly due to increasing populations and longer life-expectancy mainly in
Asia and Africa [17]. The prevalence of OAG in European populations aged 40
years or older, was estimated to be 2.1%. [19, 20] In the Nordic countries, there
are regional differences with a higher prevalence in parts of Finland, Norway,
Iceland and northern Sweden [21-26] compared with Denmark [27] and
compared with an early study from southern Sweden [28]. The number of people
using topical IOP-lowering treatment in the Nordic countries exceeded 0.4
million in 2017 and is likely to increase by 50% by the year 2040 [29]. In a large
population study, the Malmö Eye Survey, the prevalence of open-angle glaucoma
was approximately 5% in 75-year-olds and approximately 2% in the age group 57-
79 years [30].

3
Glaucoma is estimated to be the second most common global cause of blindness
after cataract; hence it is the primary cause of irreversible blindness [31, 32]. A
Swedish study showed that during their lifetime, 42% of patients with open-angle
glaucoma became blind in one eye and 16% became bilaterally blind as a
consequence of glaucoma, despite treatment [33]. The increased prevalence of
glaucoma due to an aging population is likely to demand great professional and
economical resources from the future health care system and to have a large
impact on the quality of life for many patients.

Glaucoma types
Glaucoma is divided into two main types depending on the anatomical conditions
of the affected eye: (1) open-angle glaucoma (OAG) where the anterior chamber
angle between the posterior cornea and anterior iris is open, and (2) angle-closure
glaucoma (ACG), where the anterior chamber angle is closed or obstructed. Open-
angle glaucoma is further divided into primary open-angle glaucoma (POAG) and
secondary glaucoma. Briefly, in POAG there is no detectable cause for the disease
whereas in secondary glaucoma, an underlying cause can be identified. [34].

Primary open-angle glaucoma (POAG)

POAG is the most common type of glaucoma and is characterized as a painless,
chronic progressive optic neuropathy with typical changes to the optic nerve head
and retinal nerve fiber layer leading to a gradual loss of the visual field. The
condition is characterized by an open anterior chamber angle and is not explained
by other underlying ocular or systemic diseases [18, 35]. At least half of the
patients with POAG are not aware of having the disease [18, 36]. Eyes with POAG
may have an elevated IOP, or the IOP may be normal, so called normal-tension
glaucoma (NTG).

Ocular hypertension (OH) displays an elevated IOP, defined by the European

Glaucoma Society (EGS) as an IOP > 21 mmHg, in the absence of damage to the
optic nerve. Eyes with OH have a greater risk of developing glaucoma [37, 38].

Pseudoexfoliation glaucoma
Exfoliation syndrome is a systemic condition where an accumulation of abnormal
extracellular protein material called pseudoexfoliations (PEX) occurs, both in the
eyes and in other organs. The condition has been associated with genetic changes
in the gene coding for the lysyl oxidase-like (LOXL-1) protein, which promotes
the construction of elastin fibers that are important constituents of exfoliations
[39]. PEX is visible in the anterior parts of the eye, typically as a ring-shaped
structure on the anterior lens capsule (Figure 3).

4
 Figure 3. Pseudoexfoliation syndrome. Notice the exfoliation ring on the anterior
lens capsule (arrow). Picture used with kind permission from a patient.

The protein aggregates accumulate in the anterior chamber angle where it is

believed to occlude the trabecular meshwork and results in a decreased outflow
of aqueous humor and an increased IOP [40]. PEX is common in northern
Sweden and affects almost 25% of people at age 66 [23]. The prevalence of
pseudoexfoliations increases with higher age and the risk of developing
glaucoma, i.e., pseudoexfoliation glaucoma (PEXG), is several times higher in
an eye in which PEX is present [23, 41, 42]. PEXG is, in the Nordic countries,
considered a subtype of OAG, while in many other countries it is classified as a
secondary glaucoma. PEXG is often characterized by a high level of IOP,
pronounced IOP fluctuations and rapid glaucoma progression [40, 43].

Secondary glaucoma
Secondary open-angle glaucoma is a heterogenous group of subtypes in which an
identifiable cause for the glaucoma is present. Secondary OAG includes
neovascular glaucoma (NVG), pigmentary glaucoma, post-traumatic glaucoma
and glaucoma that develops after ocular surgery or ocular conditions such as
uveitis, retinal detachment, tumors and intraocular bleeding. Furthermore, it also
covers for example glaucoma related to the use of certain medical drugs and
glaucoma associated with systemic diseases such as inflammation, infections or

5
amyloidosis [38]. Congenital glaucoma is a complex innate condition which will
not be included in the focus of this thesis.

Risk factors for open-angle glaucoma

Increased IOP is associated with most, but not all, cases of glaucoma. The IOP,
however, is the only modifiable risk factor known, and it is important in both the
risk of developing glaucoma, and the progression of the disease. Several studies
have shown that reduction of the IOP both delays the onset of glaucoma and also
slows down the disease progress [37, 44-47].

Furthermore, described risk factors for glaucoma development include a family

history of glaucoma [13], high myopia [48], African ancestry [49],
pseudoexfoliation syndrome in combination with high IOP [42] and thin central
corneal thickness (CCT) [37]. Risk factors for glaucoma progression are older age
[18, 50], increased IOP [45], pseudoexfoliations [51] and hemorrhages at the
margin of the optic disc [18, 52].

Diagnostics and monitoring of glaucoma

Measurement of IOP is an important part of a standard clinical eye examination.
It is used as a risk assessment for the presence or development of glaucoma and
as a tool to evaluate the effect of a glaucoma treatment. Goldmann applanation
tonometry (GAT) [53], is still the gold standard method of measurement,
especially in glaucoma care. In order to perform a GAT measurement, the eye
needs to be anesthetized and fluorescein is applied to the ocular surface. Then an
optical prism is pressed against the cornea in order to applanate a predefined area
(7.35 mm2). The force needed to applanate this area is proportional to the IOP in
the eye. Rebound tonometry (IcareÒ) is another example of a method frequently
used in clinical practice [54]. It does not require anesthetics and the apparatus is
hand-held and easy to use, which makes is suitable for screening purposes and
when measuring IOP in children or people who are difficult to examine in the slit
lamp [55].

Furthermore, the appearance of the optic nerve head is assessed by an

examination, most often through indirect fundoscopy at the slit-lamp. Signs of
glaucoma such as narrowing of the neuroretinal rim leading to cupping (Figure
4), pallor of the optic nerve head, disc hemorrhages and other anatomical signs
of glaucoma are determined. The findings are often confirmed by optical
coherence tomography, an imaging technique based on interferometry that
measures the optic nerve head, retinal nerve fiber layer and the ganglion cell
complex. It can be used as a tool to detect and measure glaucoma progression via
trend analyses of the thickness of the retinal nerve fiber layer [56].

6
Figure 4. Optic nerve head with typical structural glaucomatous changes. Picture used with
kind permission from a patient.

Test of visual fields is a very important examination in glaucoma care since it

assesses the function of the optic nerve (Figure 5). Glaucoma causes a progressive
loss of the visual field, usually beginning as a scotoma in the mid-periphery,
which may go unnoticed for several years. The most central part of the visual field
is often spared until very late stages of the disease. The size and distribution of a
visual field defect can be detected with a visual field test. Standard automated
perimetry (SAP), is a computerized static threshold examination where the
patient attempts to detect white stimuli against a white background. SAP is a

7
sensitive method that detects glaucomatous defects at an early stage and plays a
crucial part in glaucoma diagnostics [57-59].

Figure 5. Visual field of the right eye with an arcuate scotoma, a typical glaucomatous defect.
This visual field defect corresponds to the optic nerve damage in Figure 4. Picture used with kind
permission from a patient.

Finally, the anterior chamber angle can be visualized through gonioscopy, in

order to identify anatomical conditions associated with glaucoma [59]. Angle
landmarks are inspected, and assessments include width of the angle (distance
between the corneal endothelium and the anterior iris), angle pigmentation and
occurrence of blood vessels or synechiae.

8
Glaucoma treatment and compliance
All currently known glaucoma treatments aim to reduce the IOP by decreasing
the production of or facilitating the outflow of aqueous humor. This may be
achieved by topical or systemic IOP-lowering medications, laser treatment or
surgery. Several topical medications inhibit the production of aqueous and these
include beta-blockers, carbonic anhydrase inhibitors and alpha-2 selective
adrenergic agonists. The most powerful IOP lowering drugs available, the
prostaglandin analogues (PGA), increase the uveoscleral outflow. Another way to
increase the outflow is to contract the ciliary muscle and TM, which is achieved
by parasympatichomimetics. Furthermore, dehydration of the vitreous with an
osmotic agent can efficiently reduce the IOP [38].

In open-angle glaucoma, the most common clinical approach is to initiate

glaucoma treatment with an IOP-reducing eye drop, usually a PGA or a ß-blocker,
or by performing LTP. If the reduction of IOP is insufficient or if the glaucoma
damage proceeds despite these first steps, combinations of different classes of
IOP-lowering treatment or additional LTP is tried. The next line of treatment is
glaucoma surgery where the gold standard is trabeculectomy, a filtering surgical
procedure. In recent years the development of various surgical methods has
increased the treatment options [60]. Many of the surgical procedures often
provide a substantial IOP reduction but demand frequent post-operative
examinations and are sometimes associated with complications and re-
treatments. Transscleral cyclophotocoagulation is a laser method that is generally
used in advanced glaucoma cases.

IOP-reducing eye drops are often effective but have the disadvantage of potential
local or systemic side effects caused either by the active substance or by the
included preservatives [61]. For instance, betablockers may cause respiratory
distress, bradycardia, hypotonia, confusion and hallucinations [62, 63].
Glaucoma eye drops are installed once or several times every day which might be
challenging and lead to poor compliance. This has proven to be even more
problematic when a patient is treated with several drops with complicated dose
regimens [64]. Electronic eye drop monitoring revealed 76-86% drop compliance
[65] and real-life compliance is possibly worse since open-angle glaucoma is
relatively asymptomatic and the treatment is lifelong without obvious subjective
improvement [66, 67].

9
Laser treatment in glaucoma

Laser trabeculoplasty
Laser trabeculoplasty (LTP) is a well-established IOP-lowering treatment option
in glaucoma. The laser spot is aimed at the trabecular meshwork in order to
facilitate the outflow of aqueous humor, which will contribute to a reduction of
IOP. LTP is efficient in POAG, and can also be used in PEXG, pigmentary
glaucoma and ocular hypertension (OH) [68-70]. Several studies show that the
effect of LTP is comparable to that of IOP-lowering eye drops [71-73].

LTP can be used as a primary treatment or as an addition to medical therapy. It

is often used early in the disease process when the glaucoma damage is limited.
The use as a first-line treatment is gaining increased popularity due to several
reasons: it is a relatively simple and quick procedure performed in the
ophthalmologist’s office, and it is safe for the patient. Moreover, LTP has the great
advantage of not being reliant upon patients’ adherence. Several studies support
the use of LTP as a primary treatment [68-70]. LTP is also efficient as a
replacement treatment or as a complement when IOP is not sufficiently
controlled by IOP-lowering eye drops [74, 75].

LTP has two major subtypes, argon laser trabeculoplasty (ALT) and selective laser
trabeculoplasty (SLT). Previously, ALT was more frequently used but during the
last two decades, SLT has gained popularity and is now widely performed. Several
studies show that ALT and SLT reduce IOP with similar efficacy [76-79]. LTP is
often successful leading to a mean IOP reduction of 20-25% in treated eyes [80,
81]. A schematic view of treatment with ALT versus SLT is depicted in Figure 6.

LTP is described as a relatively safe treatment with few complications. A transient

IOP spike post-LTP >5 mmHg has been recorded in approximately 5-30% of
treated eyes [73, 80, 82, 83]. Another described complication is a mild anterior
uveitis following LTP [80], more so in ALT than in SLT [84]. ALT treatment may
cause peripheral anterior synechiae at the site of treatment [85] and promote
cystic macular edema. Further complications of LTP include hyphema, corneal
inflammation and corneal edema [86, 87].

Argon laser trabeculoplasty (ALT)

ALT was first described by Wise and Witter in 1979. Argon continuous-wave laser
(green or blue/green) was originally used but has later been replaced by a diode
laser [88]. In ALT, thermal energy is applied to the trabecular meshwork where
it causes a mechanical damage through shrinkage of collagen fibers.
Furthermore, ALT causes a focal photocoagulative tissue necrosis leading to

10
small areas of fibrosis [88]. This is believed to bring about extension and
widening of adjacent trabecular spaces which in turn enables an increased
outflow through the TM. However, theories suggest several mechanisms of
action, both mechanical -- but also biochemical and cellular [89]. These
mechanisms include stimulation of cell division in the TM and increased turnover
of juxtacanalicular intracellular matrix caused by the laser therapy [90, 91].

The effect of ALT depends on the absorption of the argon laser light by melanin
in the target tissues. Eyes with pseudoexfoliation glaucoma generally have a high
degree of angle pigmentation which makes ALT a suitable option in these eyes
[40, 92]. The TM tissue alterations following ALT due to the thermal damage
renders repeated treatment of the same area less effective [93].

Figure 6. Schematic illustration of laser trabeculoplasty. Gonioscopic view of the anterior

chamber angle illustrating the approximate difference in laser spot size (50 µm versus 400 µm)
between argon laser trabeculoplasty (ALT) and selective laser trabeculoplasty (SLT).
Illustration by Erika Rasmuson.

Selective Laser Trabeculoplasty (SLT)

SLT was developed secondary to the introduction of selective phototermolysis,
the dermatological method where thermal radiation is targeted to certain cells
within a tissue [94]. The SLT as an IOP-lowering treatment was first launched in
1998 [95]. It comprises a Q-switched, short pulsed, frequency-doubled Nd:YAG
(532 nm) laser that, like ALT, targets the cells of the trabecular meshwork.

11
However, SLT selectively influences intracellular melanin granules in the TM
cells leaving adjacent non-pigmented structures unaffected [94]. The very short
pulse duration of SLT (3 nanoseconds) is shorter than the time for the heat
generated by melanin to flow into the surrounding tissue. Additionally, the total
energy delivered in SLT is significantly lower than in ALT [96]. Taken together,
this leads to no or minimal collateral thermal damage to the trabecular meshwork
and re-treatment of previously treated areas may be successful [93, 97].

The exact mechanism of IOP reduction by SLT is not fully understood [98]. As
with ALT, different theories have been proposed. Findings in rabbit eyes suggest
that SLT leads to liberation of free oxygen radicals that in turn cause an
inflammatory cascade [99]. Studies show that the number of monocytes and
macrophages in the TM increases substantially after SLT, and this increase may
play a role in lowering IOP by remodeling the extracellular matrix [93, 100]. SLT
is also believed to stimulate cell division in the anterior trabecular meshwork,
providing pluripotent cells that migrate and repopulate the treated sites over the
following weeks. The clinical evaluation of the effect of SLT is usually measurable
after weeks which would correlate well with the cellular theory [101].

Transscleral cyclophotocoagulation
Transscleral cyclophotocoagulation (TCP) is a treatment alternative that is most
often used in eyes with severe glaucoma damage and poor visual potential. It may
be an option if invasive glaucoma surgery has failed or when a patient, due to, for
instance other diseases, is not a suitable candidate for surgery. TCP is also used
to relieve pain, if present, in blind eyes with high IOP. TCP was first introduced
in the early 1970s [102]. Previously, a ruby laser or Nd-YAG laser was used, but
these were later replaced by a semiconductor diode laser. The TCP diode laser
most commonly used has a wavelength of 810 nm that permits good penetration
of the sclera and selective absorption by the pigmented tissues (melanin) of the
ciliary body [103, 104]. The laser energy is delivered via a quartz fiber with a
round tip, the “G-probe”, designed to enhance transmission through the sclera by
indentation (Figure 7). The energy causes a partial destruction of the secretory
epithelium of the ciliary body This destruction leads to a reduction in the
production of aqueous humor which in turn lowers the IOP.

12
 Figure 7. Transscleral cyclophotocoagulation. The image illustrates the transfer of laser
energy by the G-probe through the sclera to the underlying ciliary body.
Illustration by Erika Rasmuson.

Many studies report efficacy outcomes evaluating TCP, [105-110]. However, the
definitions of success vary between the studies, which makes comparisons of
TCP results challenging. TCP is predominantly used in eyes with severe
glaucoma damage and low visual potential. However, there are studies
suggesting that TCP may be used as a primary treatment in eyes with good
vision [107, 111-113]. Regarding the effect, some studies argue that the total laser
energy delivered is positively associated with the IOP-lowering effect [108, 114],
while other studies show no obvious correlation between energy and effect [107,
115, 116].

One of the most feared complications of TCP is a conditioned called phthisis

bulbi. The word originates from the Greek word phthiein which translates to
“shrinkage” or “to waste away” and it represents a state of shrinkage, atrophy and
loss of function of the affected eye [117]. Other known side-effects of TCP are
persistent hypotony, deterioration of visual acuity (VA), intraocular hemorrhage,
atonic pupil, lens subluxation and prolonged intraocular inflammation [103, 107,
118-120]. IOP spikes after TCP have been reported [121, 122]. It has been
suggested that the risk of developing phthisis and hypotony is related to the

13
energy applied at a single treatment [109]. If the total energy of TCP is below 80
Joule (J) the risk of severe complications is low [118].

At the Department of Ophthalmology, Umeå University Hospital, Umeå, Sweden,

TCP has been performed for many years. A protocol using relatively low energy is
used and one quadrant of the sclera and underlying ciliary body is left untreated
to limit the damage and hence avoid severe complications.

The Glaucoma Intensive Treatment Study (GITS)

GITS is a prospective, randomized clinical trial including newly diagnosed
glaucoma patients in Malmö and Umeå [123]. The general aim of the study was
to compare the standard regime of successively increased glaucoma therapy with
an immediate multi-treatment regimen. The visual field progression, IOP, quality
of life, side effects and compliance were evaluated in order to find differences
between the groups during a 5-year follow-up period. In GITS, patients with
newly diagnosed, untreated POAG or PEXG in at least one eye were eligible.
Included patients were randomized to receive either monotherapy according to
glaucoma guidelines [59], (a stepwise treatment initiated with a single eye drop
followed by additional therapy if necessary) or multi-therapy consisting of
intensive treatment including eyedrops with drugs from three different classes
plus 360° LTP. In this thesis, all subjects in studies III and IV belonged to the
GITS multitherapy group.

Need for further laser treatment research?

Although there are many publications that have reported results on TCP, the vast
majority are retrospective studies with small study populations and variations in
the definition of success, glaucoma types and energy protocols. These variations
make comparisons and generalizations of conclusions difficult. Little is known
about the short-term complications. Furthermore, the long-term complications
are varying. Regarding LTP, previous studies mostly included eyes with relatively
high IOP levels, but the knowledge of the additional effect of LTP in multi-treated
eyes with low IOP levels is limited.

14
Hypotheses and aims
The overall purpose of this thesis was to increase the knowledge regarding laser
treatments in glaucoma. The general aims were to study the efficacy and safety of
two of the most common types of laser treatments, namely laser trabeculoplasty
(LTP) and transscleral cyclophotocoagulation (TCP) -- both in a short- and long-
term perspective.

Based on our clinical experience, we hypothesized that TCP would be safe and
effective when performed with a medium-energy protocol. Furthermore, we
wanted to investigate potential IOP fluctuations during the first 24 hours
following TCP where our hypothesis was that we would identify IOP spikes.

Given the increased clinical interest in LTP, we sought to study if LTP had an
additional IOP lowering effect when performed in newly diagnosed eyes already
treated with several IOP-lowering substances. We hypothesized that LTP would
have an additional IOP-lowering effect in these eyes.

The specific aims of the thesis were:

• To evaluate the long-term efficacy and safety of TCP during two years in
glaucoma patients treated at our clinic, using a medium energy protocol.

• To evaluate and map the short-term IOP changes during the first 24
hours after TCP treatment.

• To examine whether LTP may effectively reduce the IOP in multi-treated

eyes with low IOP levels in the short-term and long-term perspective.

15
Materials and Methods
Subjects
In study I, all subjects were glaucoma patients from the northern region of
Sweden, an area comprising approximately 50% of the country area, but only
about 10% of the inhabitants. All patients were treated at the Department of
Ophthalmology, University Hospital of Umeå, Sweden. The patients were either
local or referred from another eye clinic in northern Sweden (from the main
hospitals of Sunderby Hospital in the north to Sundsvall Hospital in the south,
Figure 8). In all cases, the clinical assessment suggested that the patient required
a TCP, and the referral for the treatment was made by the patient`s treating
physician. In study I, a retrospective analysis was made of the medical records
from all 300 patients who were treated with TCP at our clinic between January
2010 and December 2014.

Figure 8. Main referral centres for studies I and II. The regional hospitals in Northern
Sweden from which glaucoma patients were referred to the University hospital of Umeå.
Image adapted from Wikimedia Commons.

16
In study II, glaucoma patients in our clinic destined for TCP or patients that
were referred to our clinic for TCP treatment from the other northern Sweden
eye clinics were asked for participation. Fifty-eight patients were included from
April 2016 to June 2022.

All subjects in studies III and IV were participants in the Glaucoma Intensive
Treatment Study (GITS) and belonged to the group that was randomized to
receive multitherapy. The group was comprised of patients with newly diagnosed
untreated POAG or PEXG in at least one eye and aged 40-78 years. There was no
upper or lower limit for untreated IOP. The group included 152 eyes (initially 155
but three eyes withdrew directly after inclusion and before receiving LTP).
Further information regarding subjects and study design has been previously
provided [123].

All patients included in studies I-IV had a diagnosis of open-angle glaucoma. In

study I and II, all types and stages of glaucoma were included and in studies III
and IV the patients were newly diagnosed with open-angle glaucoma (POAG or
PEXG).

IOP measurements
Goldmann Applanation Tonometry (GAT) was used in all studies (I-IV). In study
I, most of the measurements were performed with GAT. Due to the lack of patient
compliance some measurements were performed with rebound tonometry
(IcareÒ). In study II, the IOP was measured with both GAT and rebound
tonometry. The mean value of three GAT measurements was used for analysis.
The rebound tonometry values were used as an objective control. In the other
studies (I, III and IV), the IOP was based on a single measurement at each time
point.

In study I, measurements of IOP were recorded at baseline, and postoperatively

at one week, 1, 3, 6, 12 and 24 months. Since this was a retrospective analysis of
medical records, a time point as close as possible to the scheduled time point was
chosen. In study II, IOP was measured before TCP and after 1, 2, 4, 6 and 24
hours. In studies III and IV, IOP was measured before LTP, at four time points
during the first year and then twice every year up to 36 months, followed by
annual measurements up to 60 months. Extra measurements were made when
needed, for instance after a change in therapy.

17
Laser treatments

Transscleral cyclophotocoagulation
In study I, TCP was performed under subtenonal, peribulbar or generalized
anaesthesia using the Oculight Sx semiconductor diode 810-nm laser and the
contact G-probe (Iris Medical Instruments, CA, USA). In most cases power was
steadily increased from 1800 mW to 2500 mW, however, the energy range could
vary between at lowest 800 mW and up to 2700 mW. Each application had a
duration of 2000 ms (2 seconds). In case of an audible “pop”, the energy was
reduced by 200 mW and the procedure continued. Typically, 18 applications were
distributed in a non-overlapping fashion over 270 degrees of the circumference.
Usually, the superior nasal quadrant was left untreated to limit the damage to the
ciliary body and hence avoid hypotony. The total energy delivery during a
standard procedure was 84 J. After TCP the eyes were treated with topical
steroids for at least three weeks. If a sufficient IOP reduction was achieved by
TCP, the number of topical glaucoma medications was reduced after assessment
by the treating ophthalmologist. Oral acetazolamide was usually discontinued
directly after TCP and in a few cases re-introduced when considered as
unavoidable. Re-treatment with TCP or other glaucoma surgery was performed
during the 2-year follow-up when the postoperative IOP reduction was assessed
as unsatisfactory by the treating physician. The TCP treatment in study II was
performed as described above, except for the fact that all procedures were
performed in subtenonal anaesthesia, by the same surgeon and that oral
acetazolamide was discontinued at least 24 hours prior to treatment.

Laser trabeculoplasty
The eyes included in studies III and IV were treated with laser trabeculoplasty
one week after the initiation of IOP-lowering eye drops. The treatment consisted
of 360° SLT or ALT, according to the operator’s choice or availability of laser
equipment. SLT was performed with an Ellex Tango laser instrument (Ellex Inc.,
Adelaide, SA, Australia) with static settings except for the energy level, which was
adjusted according to the degree of angle pigmentation and the formation of
“champagne” bubbles. In Umeå, ALT was performed using a diode laser Iris
Oculight GL Green 532 Laser (IRIDEX Corporation, Mountain View, CA, USA)
with the spot size set at 50 µm. In Malmö, ALT was performed with a Zeiss
VISULAS 532 v. 1.53 (Carl Zeiss Meditec AG, Jena, Germany) with a spot size set
at 50 µm. Both lasers had a duration setting of 0.1 second.

18
Visual acuity
In study I, VA was measured using the Snellen
Decimal LogMAR
chart, as decimal acuity. This is the most used
method to measure the VA in the clinical 0.001 3
setting. Data were collected from medical 0.01 2
records. The decimal acuity values were 0.1 1
converted (Table 1) into the equivalent in 0.2 0.70
logMAR (logarithm of the minimum angle of 0.3 0.52
resolution) in order to permit statistical 0.4 0.40
analyses [124]. A high logMAR value 0.5 0.30
corresponds to a low VA, and vice versa. In cases 0.6 0.22
of poorer visual acuity, VA was reported as
0.7 0.16
counting fingers, hand movements, light
0.8 0.10
perception, perception or amaurosis. Light
perception with and without projection and 0.9 0.05
absence of light perception were excluded from 1.0 0.00
the analyses as generally recommended [124]. 1.2 -0.08
In study I, the eyes were divided into groups 1.4 -0.15
according to baseline VA: better VA (Snellen VA
³ 0.1) and poorer VA (Snellen VA < 0.1). In Table 1. Conversion from
studies II-IV, the VA was tested with the Early decimal visual acuity to the
Treatment Diabetic Retinopathy Study logMAR equivalent.
(ETDRS) -charts at four meters distance and the
logMAR value was determined.

19
Statistical methods
In studies I-IV, data were presented as means and standard deviations (SD).
Paired-samples T-test was used to detect and compare differences in the
parameters between baseline and examinations during the follow-up period.
Independent-samples T-test or one-way ANOVA (analysis of variance) was used
to detect and compare differences between groups. In study III, a multivariate
analysis was performed to identify factors associated with IOP reduction
including pre-LTP IOP, age, gender, LTP type and occurrence of exfoliation
syndrome. A p-value <0.05 was considered statistically significant.

In studies I and II, only one eye per patient was analyzed. In case of bilateral
treatment, the right eye was chosen (study I). Depending on eligibility, some
patients had both their eyes included in studies III and IV. Generalized Estimated
Equations (GEE) was used to correct p-values for this combination of one or two
eyes per patient. Data analyses were performed using SPSS Statistics Version
24.0 (study I), 26.0 (study III) and 28.0 (studies II and IV) (SPSS Inc, Chicago
Illinois, USA).

Definitions of treatment success and failure

In study I, eyes that required glaucoma surgery (other than additional TCP)
during follow-up were defined as failures (and were accounted for in the
calculation of the success rate).

In study I, treatment success was defined as an IOP ³6 mmHg and £18 mmHg,
with or without glaucoma medications and re-treatments with TCP at the two-
year follow-up. An upper and lower limit of IOP was included in the definition in
order to exclude cases of hypotony, as recommended in the guidelines on
designing glaucoma trials by the World Glaucoma Association. Those guidelines
state that definitions of IOP success should include an upper and lower limit,
include more than one upper limit, or a combination of an upper limit and a
percentage reduction [125].

In studies III and IV addition of glaucoma drops, additional LTP or glaucoma

surgery were considered therapy failures.

Study drop-out
In study I, 53 out of 300 eyes (18%) did not complete the entire follow-up of the
two-year study period for various reasons. The major causes were death (n = 22),
termination of follow-up due to blindness (n = 6) or other diseases hindering
further examinations (n = 7). Ten patients had required other glaucoma surgery

20
than TCP, and these eyes were excluded from the analysis. Further details
regarding missing data are described in paper I.

In study II, all patients completed the one-day study. In studies III and IV, with
a study-period of up to five years, two patients (three eyes) chose to withdraw
directly after the randomization. Additionally, three patients (three eyes) passed
away during follow-up. All other participants (n = 149) remained in the study
during the follow-up period.

Ethical considerations
The studies included in this thesis were reviewed and approved by the Regional
Ethical Review Board at Umeå University (studies I and II) and the Regional
Ethical Review Board at Lund University (studies III and IV). Furthermore, the
Glaucoma Intensive Treatment Study (GITS) was approved by the Swedish
Medical Product Agency and registered in EudraCT (studies III and IV). All
studies adhered to the tenets of the Declaration of Helsinki [126].

Consent
In studies II-IV written informed consent was collected from all participants prior
to inclusion. Consent was obtained after the patients had received oral and
written study information and were given the opportunity to ask questions. In
study I, the ethical approval did not require individual informed consent due to
the material being retrospective and based on a large number of patients who
lived spread out over a large geographical area. Furthermore, many treatments
were performed several years earlier, and patients had passed away during follow
up. Taken together, these reasons made the collection of individual informed
consent difficult if not impossible.

Risk of harm
The risk of harm by participating in the studies included in this thesis must be
very small. The subjects’ participation in studies I and II did not change their
intended treatment or glaucoma prognosis since the glaucoma care and
treatment decisions were made by their treating physicians (not a member of the
research group). The measurements of IOP or visual acuity (studies I-IV) are
routine ophthalmological examination procedures and were not associated with
any physical or psychological harm for the patients. However, in study II the
patients were subjected to repeated IOP measurements which may have been
strenuous. There is a slightly increased risk of corneal erosions after repeated IOP
measurements. Some patients were in pain postoperatively and may have found
the measurement procedures exhausting. However, the advantage of support

21
from a physician and the feeling of being taken care of may have outweighed the
disadvantages of the discomfort.

In studies III-IV all patients had received three IOP-reducing medical substances
from the start and LTP treatment one week later. This type of initial multitherapy
is not the conventional approach to start glaucoma therapy, but the GITS study
was designed to compare initial multitherapy to the common regimen of stepwise
increased treatment. Thus, some of these patients probably received more
extensive treatment than necessary with a subsequent possible increase in side-
effects and adverse events. To minimize potential adverse events the patients
were encouraged to take immediate contact if problems arose. In addition, they
were carefully monitored in accordance with the study protocol. In case of side
effects, a change of treatment or other arrangements were made at the discretion
of the treating physician and in collaboration with the patient. The results of all
studies were presented at a group level and the data were handled securely to
ensure the protection of sensitive personal information.

22
Results
Transscleral cyclophotocoagulation
Three-hundred patients were treated with TCP at the University Hospital of
Umeå between January 2010 and December 2014 (study I). A total of 366 TCP
treatments were performed during the time period since several patients had
more than one treatment. In study II, 58 patients received TCP between April
2016 and June 2022. Two eyes were treated twice, the second treatment was not
included in the analyses. Patient characteristics, types of glaucoma and previous
glaucoma surgeries for both studies I and II are presented in Table 2.

Patient characteristics Study I Study II

Age (years) 72 (± 17) 75 (± 9)
Female % (n) 48 (145) 36 (21)
No of glaucoma medications 3.1 (± 1.0) 3.5 (± 1.1)
Oral acetazolamide (%) 30 (n = 90) -
Baseline IOP (mmHg) 29.3 (± 11) 26.2 (± 8.9)
Eyes with decimal VA 0.1-1.0 44% (n=131) 41% (n=24)

Glaucoma types % (n) Study I Study II

POAG 15 (46) 14 (8)
PEXG 40 (120) 43 (25)
NVG 22 (65) 26 (15)
OSG 19 (58) 17 (10)
Unknown 4 (11) -

Previous glaucoma surgery Study I Study II

% (n)
None 74 (222) 52 (30)
Trabeculectomy 17 (51) 16 (9)
Deep sclerectomy 3.7 (11) 5 (3)
TCP 6.0 (18) 28 (16)
Shunt / tube 2.7 (8) 10 (6)
Cyclokryoablation 0.7 (2) -

Table 2. Patient characteristics in eyes treated with TCP. Data are presented as mean ± standard
deviation unless otherwise stated.
No = number, IOP = intraocular pressure, VA = visual acuity, POAG = primary open-angle
glaucoma, PEXG = pseudoexfoliation glaucoma, NVG = neovascular glaucoma, OSG = other
secondary glaucoma, TCP = transscleral cyclophotocoagulation.

23
IOP – first 24 hours after TCP
The mean IOP and the mean IOP change in all 58 eyes in study II are shown in
Table 3a. Table 3b shows the mean IOP at the different time points organized by
glaucoma type. The mean IOP at the different time points in all eyes and in eyes
divided by glaucoma type are plotted in Figure 9.

IOP IOP change

Mean SD n Range Mean SD p
Baseline 26.2 8.9 58 12 - 49
1h 23.1 8.9 58 10 - 47 - 3.0 7.5 0.003
2h 22.3 7.3 58 9 - 44 - 3.9 6.9 <0.001
4h 23.9 9.0 58 7 - 49 -2.2 10.1 0.099
6h 25.8 9.0 58 9 - 49 -0.4 10.9 0.792
24 h 18.0 7.6 58 7 - 40 -8.1 7.8 <0.001

Table 3a. Intraocular pressure (mmHg) change during the first 24 hours after TCP.

POAG PEXG
IOP change SD n p IOP change SD n p
1h - 6.2 7.8 8 0.059 -0.8 6.8 25 0.558
2h - 4.4 9.6 8 0.234 -1.7 5.2 25 0.121
4h - 4.7 11.9 8 0.303 +2.5 8.5 25 0.160
6h -5.4 11.9 8 0.241 +5.1 9.7 25 0.015
24 h -9.0 10.2 8 0.04 -6.1 7.3 25 <0.001

NVG OSG
IOP change SD n p IOP change SD n p
1h - 3.6 9.6 15 0.171 -5.2 6.8 10 0.001
2h - 5.7 8.3 15 0.019 -6.2 5.2 10 0.003
4h - 6.5 10.5 15 0.03 -5.6 8.5 10 0.058
6h -4.2 11.1 15 0.163 -4.3 9.7 10 0.103
24 h -9.9 8.2 15 <0.001 -9.8 7.3 10 <0.001

Table 3b. Intraocular pressure change after TCP in different glaucoma types.
IOP = intraocular pressure, POAG = primary open-angle glaucoma, PEXG = pseudoexfoliation
glaucoma, NVG = neovascular glaucoma, OSG= other secondary glaucoma, SD = standard
deviation, n = number of eyes, p = p-value

24
 Fig. 9. Intraocular pressure (IOP) development during the first 24 hours after transscleral
cyclophotocoagulation.
The mean IOP at different time points presented according to the glaucoma type. The orange
line represents primary open-angle glaucoma (POAG), the red line pseudoexfoliation glaucoma
(PEXG), the yellow line neovascular glaucoma (NVG) and the green line other secondary
glaucoma (OSG).

Occurrence of IOP spikes

During the first 24 hours, five of the studied eyes (9%) displayed an IOP elevation
of ³20 mmHg (range 20.4 – 28.6). Of these, four eyes had a diagnosis of PEXG,
and one eye had NVG. Eleven eyes (19%) experienced an IOP elevation of ³10
mmHg compared with baseline at some examination point during the first 24
hours. Most of these eyes had PEXG (n = 7), the others had NVG (n = 2), POAG
(n = 1) and OSG (n = 1). Twenty-three eyes had an IOP elevation ³5 mmHg (40%)
and twenty-five (43%) had an IOP elevation of ³3 mmHg at least at one time point
during the 24-hour follow-up.

IOP – 2-year retrospective follow-up after TCP

Mean IOP at baseline was 29.3 (±11.0) mmHg (n = 297). After TCP, the IOP was
reduced by a mean of 11.5 (±12.0) mmHg at one year (n = 258, p < 0.001) and
12.6 (±12.0) mmHg at two years (n = 245, p < 0.001). If the effect of only one TCP
treatment per eye was analyzed (excluding re-treatments with TCP), the IOP was

25
reduced by a mean of 10.7 (±11.3) mmHg at one year (n = 214, p < 0.001) and 11.8
(±11.5) mmHg at two years (n = 195, p < 0.001), respectively.

The number of topical glaucoma medications was reduced from approximately

three before the laser to two at the 24-month follow-up. Thirty percent (n = 90)
of the patients were treated with oral acetazolamide prior to TCP treatment and
this number was reduced to 5.3% (n = 13) at two years. The mean IOP values and
the mean number of glaucoma medications at baseline and during follow-up are
presented in Figure 10. Two of the three study subjects lacked IOP data at baseline
but presented IOP measurements at the 2-year follow-up. This explains the
difference in number of subjects between the paired analysis and the total
number of observations at the 2-year follow-up (n = 245 and n = 247,
respectively).

Figure 10. Development of IOP and need of topical IOP-lowering substances following
transscleral cyclophotocoagulation. Values of IOP and number of topical IOP-lowering
substances (drops) are expressed as means at the different time points. Error bars denote
standard deviation. Eyes that required glaucoma surgery during the follow-up period (n = 10)
were thereafter excluded from the analysis.
IOP = intraocular pressure, mo = months.

26
Global success, defined as an IOP ³6 mmHg and £18 mmHg, with or without
glaucoma medications and re-treatments with TCP, was 64 % at two years (n =
257), achieved by a mean of 1.2 treatments. The 10 eyes that had required other
glaucoma surgery than TCP were regarded as failures and considered in the
calculation of the success rate. Table 4 shows the number of patients who
achieved “success” at different upper limits of IOP at 12 and 24 months. The
global success rates varied between different glaucoma types; 76% in POAG (n =
38), 71% in PEXG (n = 106), 62% in OSG (n = 52) and 46% in NVG (n = 54) with
the definition (³6 - £ 18) at 24 months. Nineteen percent of the patients (n = 58)
required one or more re-treatments during the two-year follow-up.

IOP (mmHg) 12 mo. % (n) 24 mo. % (n)

³6 to £15 42 (113) 48 (124)
³6 to £18 60 (162) 64 (164)
³6 to £21 69 (185) 72 (186)

Table 4. Success rates after TCP treatment. The proportion of eyes achieving success defined
by different IOP limits.
IOP = intraocular pressure, n = number of eyes, mo. = months

Visual acuity after TCP, short- and long-term evaluation

In the 24-hour evaluation (study II), the mean VA at baseline was 0.64 (±0.3)
logMAR just before the TCP treatment and 0.66 (±0.4) logMAR at the 24-hour
examination (p = 0.87). This calculation was based on the 24 patients (41%)
where the VA could be measured with the ETDRS chart. The remaining 34 eyes
had a baseline VA of counting fingers (n = 11), hand movements (n = 13), light
perception (n = 4) or were amaurotic (n = 6). When excluding the six blind eyes,
the VA in this group was unchanged in 75% (n = 21) of the eyes, reduced in 11%
(n = 3) and improved in 14% (n = 4).

In the two-year follow-up of TCP (study I), the VA in the group of eyes with better
VA, was significantly reduced from 0.55 (±0.3) logMAR (n = 131) to 1.1 (±0.9)
logMAR at the 2-year follow-up (n = 76). In four eyes, VA was reduced to light
perception or less due to retinal detachment (n = 1) and uncontrolled glaucoma
(n = 3). At two years, 55% (n = 44) had a VA loss of ³ two lines on the Snellen
chart. In this group there were two cases of persistent corneal edema that was
first described at the one-week follow-up examination and one patient suffered
from a central venous occlusion, which led to a decline in VA. In many cases the
cause of VA decline was not commented on or further explained in the medical
records. The changes in VA during follow-up were equal in the different glaucoma

27
types. In the group with poorer VA (n = 83) the result was unchanged or improved
in 56% (n = 49) and decreased in 41% (n = 34).

Complications of TCP
There was no case of phthisis bulbi or persistent hypotony in any of our studied
patients.

In study II, apart from the fact that 40% of the eyes experienced post-operative
IOP spikes of 5 mmHg or higher, no other complications were described during
the first 24 hours.

In study I, five eyes with severe glaucoma damage prior to TCP displayed a late-
onset hypotony that appeared after more than a year after the laser treatment.
Other complications were dislocated intraocular lenses (n = 3), transient
postoperative macular edema (n = 3), persistent corneal erosions (n = 6, where
two required amnion transplantation and one developed a fungal keratitis),
corneal edema (n = 6) and perioperative scleral burn (n = 1).

28
Laser trabeculoplasty
In studies III and IV, 155 eyes (124 patients) were randomized to receive
multitherapy. Two patients (three eyes) withdrew directly after randomization
and did not receive LTP. Therefore, 152 eyes of 122 patients were treated with
LTP. During follow-up three patients passed away (three eyes), leaving a total of
119 patients (149 eyes; 98%) that completed 60 months of follow-up.

The baseline characteristics of the multitherapy group are shown in Table 5.

n (%) Mean SD Range

Age (years) - 68.7 5.8 52 - 78

IOP before medical treatment (mmHg) - 25.3 7.9 12 - 49

IOP before LTP (mmHg) - 14.0 3.5 6 - 25

CCT (µm) - 547 33 464 - 640

Female 55 (45) - - -

Exfoliation syndrome 38 (25) - - -

ALT, energy (mW) 27 (18) 638 201 380 - 900

SLT, energy (mJ) 125 (82) 66 20 29 - 130

Table 5. Baseline- and treatment characteristics of the 152 eyes treated with LTP.
IOP = intraocular pressure, LTP = lasertrabeculoplasty, CCT = central corneal thickness,
ALT = argon laser trabeculoplasty, SLT = selective laser trabeculoplasty, SD = standard
deviation, n = number of eyes

IOP change after LTP

The mean IOP in the multi-treated group before the initiation of medical
treatment was 25.3 mmHg. One week after medication was started, but before
LTP, the IOP was 14.0 (±3.5) mmHg (n = 152). The IOP change after LTP in all
eyes is shown in Table 6.

29
 IOP change (mmHg)

Follow-up (months) Mean SD n p

1 -1.2 3.0 152 <0.001

3 -1.1 3.2 152 <0.001

6 -0.7 3.3 151 0.02

12 +0.1 3.8 150 0.68

24 +0.2 3.3 150 0.51

36 +0.3 3.3 150 0.32

48 +0.1 3.2 149 0.87

60 +0.9 4.6 149 0.02

Table 6. Intraocular pressure changes in all eyes after LTP.

LTP = laser trabeculoplasty, IOP = intraocular pressure, SD = standard deviation,
n = number of eyes, p = p-value

The relationship between the IOP change at 12 months and the IOP before LTP
can be seen in Figure 11. The slope of the line was -0.6, hence, for every mmHg
higher pre-LTP IOP, the IOP was reduced by an additional 0.6 mmHg after LTP.
According to the scatter plot, a pre-LTP IOP <15 mmHg represents a point at
which no IOP reduction was shown.

30
 Figure 11. Association between pre-LTP IOP and IOP change at 12 months.
A pre-LTP value lower than 15 mmHg corresponds to no change of IOP following LTP. Square
size represents the number of cases (Scale).
IOP = intraocular pressure, LTP = laser trabeculoplasty.

In study III, factors associated with a greater IOP reduction 12 months after LTP
were examined in a multivariate analysis. This showed that pre-LTP IOP was
significantly associated with IOP reduction. Older age, male gender and ALT
treatment were also significantly associated with a greater IOP reduction.
Presence of exfoliation syndrome was significantly associated with less IOP
reduction following LTP.

Since the results from study III suggested that LTP caused no or minimal effect
in eyes with pre-LTP IOP <15 mmHg, LTP was further analyzed after separating
the eyes into groups based on the IOP level before LTP (studies III and IV). The
IOP reduction was considerably greater at all time points in the group with pre-
LTP IOP ³15 compared with the group with pre-LTP IOP <15 mmHg (Table 7).

31
 Follow-up IOP <15 mmHg IOP ³15 mm Hg
(months)
Mean SD n p Mean SD n p

Pre-LTP IOP 11.9 2.0 96 17.6 2.5 56

1 - 0.3 2.7 96 0.27 - 2.6 3.1 56 <0.001

3 0.0 2.8 96 1.0 - 3.0 3.1 56 <0.001

6 + 0.3 2.7 95 0.26 - 2.6 3.4 56 <0.001

12 + 1.5 3.2 94 <0.001 - 2.1 3.8 56 <0.001

24 +1.5 2.8 94 <0.001 -1.9 3.0 56 <0.001

36 +1.5 2.7 94 <0.001 -1.7 3.2 56 <0.001

48 +1.0 2.9 94 0.002 -1.6 3.1 55 <0.001

60 +2.2 4.3 94 <0.001 -1.2 4.3 55 0.05

Table 7. Intraocular pressure changes after LTP, all eyes subdivided into groups with lower IOP (<15
mmHg) or higher IOP (³15 mmHg) before LTP.
IOP = intraocular pressure, POAG = primary open-angle glaucoma, PEXG = pseudoexfoliation
glaucoma, SD = standard deviation, n = number of eyes, p = p-value

During the follow-up period, some eyes required enhanced IOP-lowering

therapy: additional IOP-lowering drops, re-treatment with LTP or glaucoma
surgery (Figure 12).

32
 Figure 12. Flow-chart of included eyes in studies III and IV. During analysis, participants eyes
were grouped as having IOP <15 mmHg or ³15 mmHg. Eyes lost to follow-up and eyes that
required an increase of glaucoma treatment are shown.
*These five eyes also received other additional IOP-lowering therapy.
IOP = intraocular pressure, LTP = laser trabeculoplasty, SLT = selective laser trabeculoplasty,
ALT = argon laser trabeculoplasty.

Eighteen eyes, equally divided between the groups with pre-LTP <15 and ³15
mmHg, that required additional therapy were considered treatment failures.
Further IOP analysis was performed in which these eyes were excluded from the
analysis after the treatment had been increased. The IOP change is shown in
Table 8 and the mean IOP at the different time points of follow-up is shown in
Figure 13.

33
 Follow-up IOP <15 mmHg IOP ³15 mmHg
(months)
Mean SD n p Mean SD n p

Pre-LTP IOP 11.9 2.0 96 17.6 2.5 56

1 - 0.3 2.7 96 0.27 - 2.6 3.1 56 <0.001

3 0.0 2.8 96 1.0 - 2.9 2.9 55 <0.001

6 + 0.4 2.7 95 0.23 - 2.4 3.2 55 <0.001

12 + 1.5 3.2 94 <0.001 - 1.9 3.4 55 <0.001

24 +1.5 2.8 92 <0.001 -1.8 2.8 53 <0.001

36 +1.5 2.7 89 <0.001 -1.7 2.9 50 <0.001

48 +1.1 2.8 87 0.002 -1.7 2.8 48 <0.001

60 +2.2 3.1 85 <0.001 -0.7 4.3 46 0.32

Table 8. Intraocular pressure changes after LTP, where eyes are excluded from the analysis after
enhancement of IOP-lowering treatment.
IOP = intraocular pressure, POAG = primary open-angle glaucoma, PEXG = pseudoexfoliation
glaucoma, SD = standard deviation, n = number of eyes, p = p-value

34
 Figure 13. Mean IOP at different time points after LTP. The solid blue line represents the eyes
with pre-LTP IOP <15 mmHg and the dotted green line represents the eyes with pre-LTP IOP
³15 mmHg. Error bars show standard deviation. Eyes that received additional treatment were
thereafter excluded from the analysis.
IOP = intraocular pressure, LTP = laser trabeculoplasty, n = number of eyes

Complications after LTP

The results from study III confirmed that LTP is a safe procedure. Mild anterior
chamber inflammation was found in two subjects (3 eyes) 4 – 5 days after SLT.
The inflammation resolved after treatment with topical steroids (dexamethasone
x 3 for one week). Mild discomfort and light sensitivity were reported by three
additional patients post-LTP, but the symptoms did not cause the patients to seek
medical care. One eye developed a hyphema after ALT, this was resorbed without
intervention after five days. One eye had a flare-up of a herpes zoster-infection 3
days post-ALT, this eye had not been receiving corticosteroids post-LTP.

35
Discussion and clinical implications
Efficacy of TCP
In our study of 300 northern Sweden glaucoma patients, we found an overall
considerable IOP reduction after TCP treatment. The success rate in our study
group was 64% at two years achieved by an average of 1.2 treatments. We defined
success as an IOP ³6 mmHg and £18 mmHg with or without glaucoma
medications and re-treatments with TCP. Previous studies comparing the efficacy
of TCP show highly variable success rates, likely due to the discrepancies
regarding the definition of success, types of glaucoma included, energy settings,
length of follow-up and re-treatment rates [106, 127-129]. Some studies had a
definition of success similar to our study, with a lower and upper IOP limit (often
between 5 or 6 and 21), in order to exclude cases of hypotony. In these studies,
success rates varied between 54% and 80% with 1.16–1.86 treatment per eye [106,
127-129]. Since the intended target pressure in severe glaucoma is usually low, we
chose to use definitions with lower set upper limits of IOP (³6 mmHg and £15 or
18 mmHg, respectively). If we would have selected the limit between 6 and 21
mmHg as many of the other studies, the success rate was 72%, achieved by a mean
of 1.2 treatments. Thus, our results were in line with the other studies in this
aspect. Some studies report higher success rates but with a definition of success
that include an upper IOP boundary but not a lower boundary. Hence, this also
allows eyes with potential post-laser hypotony in the reported success rate [108,
130-132]. An exception is a study of 49 eyes with a high proportion of POAG,
lower-energy treatment settings (57.6 J per treatment) and a success rate of
almost 80% achieved by 1.7 TCP treatments [113].

Our study group included the largest number of PEXG evaluated after TCP
treatment (n = 120). The effect of TCP was overall good in the PEXG group with
a success rate of 71% at two years. It has been suggested that the accumulation of
exfoliation material on the zonules may decrease the laser uptake in endoscopic
cyclophotocoagulation [133] and such an interference may also be possible in
TCP. Very few studies have focused on TCP treatment in eyes with PEXG. One
study suggests a lower success rate (25% at one year) in 24 eyes with PEXG [112].
In contrast, a study evaluating 16 eyes with PEXG showed that 81% of the eyes
achieved a post-laser IOP between 8 – 21 mmHg, when using a 670 nm diode TCP
[110]. In our study group, the effect of TCP in eyes with PEXG was considerable
and our results support the use of TCP in this category of patients.

Approximately one in five eyes (19%) needed re-treatments during follow-up. The
amount of energy level delivered in a single TCP session has been suggested to

36
affect both the treatment success rate and the need for re-treatment [106, 108,
114, 134]. In enucleated human or cadaver eyes, it has been shown that a certain
energy level per delivered pulse is needed (2.25–4.5 J) for sufficient destruction
of the ciliary body. [135-137], Given the retrospective nature of our study our
energy protocol varied but most often the energy delivery was 80-90 Joule per
treatment. Re-treatment rates in previous studies vary between none up to 60%
[118]. Studies with a higher number of re-treatments all had a milder energy
protocol (44-56 J per treatment session) [109, 127, 138], low complication rates
and relatively high success rates (74-88%). However, studies with lower re-
treatment rates were found to have varied levels of delivered energy (48-116J),
complications and success rates (64-92%) [115, 131, 139]. In our study, both the
level of energy and the overall success rate were in the middle part of the spectrum
with a relatively low rate of re-treatments and complications.

The patients were able to reduce their number of topical glaucoma drops with a
mean of one substance during follow-up. This could be of clinical importance
since a complicated regime of eye drops might lead to a decreased quality of life
and to a reduced adherence to the treatment. Most of the patients who were
treated with oral acetazolamide before TCP could discontinue their treatment
during follow-up.

Safety of TCP
In accordance with our hypothesis, there were no severe complications following
the performed TCP treatments. There was no case of phthisis bulbi described in
the medical records during the follow-up period. Phthisis bulbi is the most feared
complication and one of the major reasons that TCP is generally reserved for eyes
with advanced glaucoma damage.

The energy delivered in a single treatment session is theoretically associated with

complications, where a higher energy would cause more complications [109]
Reported numbers of hypotony cases vary between 0% and 25% and phtisis
between 0% and 9.9% [108, 140, 141]. A review by Ishida et al. proposed that a
protocol with a mean energy delivery of 80J or less tends to have very low
complication rates, whereas a higher mean energy delivery has a higher
occurrence of both phthisis and hypotony [118]. An exception to this is a diagnosis
of neovascular glaucoma, which is reported to be a potential risk factor of
hypotony regardless of delivered energy [129, 140]. The absence of hypotony and
phthisis in our material might be due to our use of a treatment protocol with
relatively low energy, and that a quarter of the ciliary body circumference was left
untreated. Also, a smaller proportion -- only one in five patients, had a diagnosis
of NVG in our study group.

37
A few of the studied eyes (n = 5) developed a state of hypotony a year or more
following TCP. In the medical records there was no description of a shallow
anterior chamber, choroidal detachment or other anatomical signs of hypotony.
These five eyes were severely impaired by glaucoma before the TCP and most of
them were amaurotic (four amaurotic eyes, one with a VA of counting fingers). A
small proportion of the eyes (4%) suffered from complications of TCP that
affected the cornea (edema, erosions, keratitis), 1% displayed macular edema and
1% experienced IOL dislocation. Similar rates of these complications have been
previously described in the literature [120, 142].

In the short-term evaluation of TCP (study II), 40% had an IOP spike of 5 mmHg
or higher, and a considerable number of eyes, almost one in five eyes, experienced
an IOP spike of 10 mmHg or higher during the first 24 hours. Furthermore,
almost one in ten eyes had a peak of 20 mmHg or higher. A diagnosis of PEXG
was over-represented in the eyes that had the highest IOP spikes. A few studies
have examined the short-term IOP fluctuations after TCP [121, 122, 143]. Uppal
et al examined the occurrence of IOP spikes in 53 eyes after TCP. They found that
34% had an elevation ³3 mmHg and 17% had an elevation of ³10 mmHg during
the first three hours. In our study, the mean IOP was highest after 6 hours post-
TCP. It is not known how the IOP developed during the hours after the 6-hour
examination but by 24 hours the level was normalized in most cases. The
prospective study by Uppal et al. included only two cases of PEXG (4%) compared
with 43% in our material. The frequency of IOP spikes was slightly higher in our
study which may be explained by the higher proportion of PEXG. Furthermore,
we saw the highest elevation of IOP six hours post-TCP, a time point that was not
included in the study by Uppal et al. In a retrospective study of 116 eyes 11%
experienced an IOP spike (defined as IOP ³5 mmHg) one hour after TCP [122],
with a trend towards higher occurrence of spikes in eyes with NVG and after re-
treatment with TCP. As in our results and the study of Uppal et al., no predictive
factors (including age, gender, total energy delivered, number of pops) were
found. Razeghinejad et al. studied ten eyes in sedated glaucoma patients and
showed a significant IOP increase in almost all eyes just after TCP [143]. No
details regarding the glaucoma type were provided. IOP measurements in that
study were made with Tono-pen, compared to measurements with GAT in the
current study.

It is not fully understood why some eyes develop IOP spikes after laser treatment.
One theory is that the necrosis and disruption of the ciliary processes caused by
TCP may create air bubbles (typically heard as “pop” sounds) that increase the
intraocular volume. This expansion would then cause a sudden rise in IOP that
the impaired TM cannot properly handle [143]. Furthermore, ultrasound
performed after TCP demonstrated debris arising from the ciliary body which
may cause a temporary block of the trabecular meshwork leading to an acute IOP

38
spike [144]. It is possible that this effect may be enhanced by a sudden liberation
of exfoliative material that would explain our results with IOP spikes in PEXG
eyes. Mild inflammation and trabeculitis has also been shown histologically in
enucleated eyes post-TCP, and this may also contribute to an impaired aqueous
outflow and subsequent rise in IOP [135]. The kind of post-laser IOP elevation
seen in the current study is alarming, since the raised IOP may significantly
accelerate the injury in already impaired eyes.

TCP – effect on visual acuity

The visual acuity was significantly reduced during follow-up, both in the eyes with
better vision prior to treatment and in the eyes with lower vision (study I). In
some cases, the reason behind the deterioration was evident, such as a vascular
event, amotio retinae or corneal opacification. In most cases, however, it was not
possible to retrieve the underlying reason from the medical records. Often the
medical records gave the appearance that glaucoma progression had taken place,
but it was not clearly stated. It is not possible to state that the decline in visual
acuity was unrelated to the TCP treatment, and it is also difficult to state the
opposite. Other possible causes could be cataract maturation or increase of age-
related macular degeneration, two common co-morbidities in this category of
patients. 55% of the eyes lost ³2 lines on the Snellen chart (0% – 55% reported in
previous studies with duration of follow-up between 9–66 months). Glaucoma
progression is often reported as the main underlying reason [113, 132]. The
corresponding VA loss in eyes one year after trabeculectomy or tube surgery has
been reported as 33% and 32%, respectively [145]. A few studies argue that TCP
might be a suitable option for eyes with good visual acuity [113, 132]. From our
results it was not possible to draw this conclusion, and further prospective studies
are needed to establish the impact that TCP has on visual acuity.

In study two, the visual acuity after 24 h was unchanged, which suggests that the
decline in visual acuity does not occur in the early phase after TCP. It is, however,
not possible to know that there was no progression of glaucoma damage caused
by the IOP spikes since visual field testing was not performed.

TCP - place in glaucoma management

Our results confirmed that TCP has a considerable IOP-reducing effect, between
11 and 12 mmHg after 1 and 2 years respectively. The method also has other
advantages, not least in the current group of patients with severe glaucoma
damage, high age and other diseases. In this category of patients, the ability to
attend to frequent examinations associated with other types of glaucoma surgery
is often limited, and this has been further stressed after the recent Covid-19
pandemic [146]. The IOP reducing power of TCP is undoubtedly impressive, and

39
it is in line with other types of glaucoma surgery. The possibility to reduce the
number of eye drops may also be very valuable for the patient, both in terms of
general quality of life but also for the health of the ocular surface. However, TCP
is not free from complications. It poses a challenge to assess whether some of the
long-term manifestations found in our study, for instance the visual acuity
decline, were caused by the treatment or the actual glaucoma. The large
proportion of eyes responding with IOP spikes post-laser are a cause of concern
and should be considered when developing treatment guidelines. The common
discontinuation of oral acetazolamide just prior to TCP should be re-evaluated
and perhaps postponed until after 24 hours post-TCP, since the great majority of
the studied eyes had a normalized IOP at that time point. This should especially
be considered in eyes with PEXG where the risk of an IOP spike is particularly
high. Another option could be to measure the IOP 4-6 hours post-laser in order
to detect an upcoming spike. This would, however, require additional medical
resources since the patients are usually discharged just after TCP.

Efficacy of LTP
When all included eyes that received LTP after initial multi-treatment were
analyzed together, LTP caused a small transient effect that had faded completely
at the 12-month control (study III). This modest effect is probably explained by
the relatively low level of IOP before laser treatment (14 mmHg), since a higher
IOP before LTP has previously been shown to provide a greater IOP reduction
after laser [74, 75, 81, 147-149] However, our results showed that, in our
population, eyes with a pre-LTP IOP of ³15 mmHg had a significantly greater
IOP reduction than the eyes with pre-LTP IOP <15 mmHg. The eyes with the
higher pre-LTP IOP displayed an IOP reduction of approximately 2 mmHg that
was maintained up to four years of follow-up. A study in multi-treated eyes with
low IOP levels reports an IOP reduction of 1.3 mmHg sustained over 6 months
following SLT [74]. The main difference compared with the current study is the
duration of topical treatment prior to laser treatment. In our study group the eyes
were treated with IOP-lowering drops for one week while Pillunat et al. included
patients that were treated for several years [74].

The group of eyes with an IOP <15 mmHg before LTP did not experience any IOP
reduction after LTP on a group level. Instead, the IOP successively increased in
this group during follow-up. The IOP in eyes with untreated PEXG was showed
an increase over time, most likely due to accumulation of exfoliative material in
the TM. This mechanism is also most likely present in treated eyes with PEXG,
which may have contributed to the general IOP increase in our study group.
Furthermore, the treatment with glaucoma drops was reduced during follow-up
in 12% of these eyes which may have contributed to the increase in IOP.

40
The effect of LTP was highly associated with the pre-LTP IOP, and for every
mmHg higher IOP before laser, the IOP was reduced by an additional 0.6 mmHg
after treatment. Similar reductions have been previously shown, both in the Early
Manifest Glaucoma Trial (EMGT) and Laser in Glaucoma and Ocular
Hypertension Trial (LiGHT) studies [68, 81]. In an eye with a relatively low IOP
the possibility to further reduce the IOP is limited. This is most likely due to a
“floor effect” i.e., when a treatment affects the trabecular meshwork (TM) and
Schlemm’s canal, the IOP cannot be reduced to a level lower than that of the
episcleral venous pressure. Hence, a higher-pressure gradient may promote the
outflow through the TM after LTP. [74, 150].

In our study group we showed that pre-LTP IOP, older age, male gender and ALT
treatment (versus SLT) were all associated with a greater IOP reduction after
LTP. Presence of exfoliation syndrome was associated with less IOP reduction at
12 months. The results were unexpected since eyes with PEXG often have highly
pigmented trabecular meshwork and some studies propose a greater effect of SLT
in eyes with a higher amount of angle pigmentation which causes a greater
absorption of laser energy [151-153]. A possible explanation for our outcome
could be the circumstance that the eyes in our study had already achieved a
considerable IOP reduction due to multi-treatment. Eyes with PEXG usually
present with higher IOP levels than POAG [154], and, given the positive
association of a high pre-LTP IOP on the treatment effect, may partly explain the
greater effect of LTP in PEXG seen in other studies. Furthermore, we found that
the IOP was significantly higher in eyes with PEXG than in POAG at the 60-
month follow-up. The effect of LTP in eyes with PEXG tend to fade over time,
possibly due to the continuation of accumulation of exfoliative material, which
may explain the increase in IOP in this group [155, 156].

Safety of LTP
There were no severe side-effects associated with the LTP treatment. In study III,
we saw that a small percentage of the eyes (2-4%) reacted with a mild and
transient anterior chamber inflammation after LTP. However, almost one in four
eyes received prophylactic topical steroids after LTP, which may have masked
cases of inflammation. One theory suggests that topical steroid treatment after
SLT might affect the treatment effect because of the inhibition of the
inflammatory response with, for instance the attraction of monocytes and
macrophages likely being related to the IOP reduction of SLT. However, this is
not clarified and there are studies showing the same IOP reduction with or
without post-SLT steroid treatment [157] After ALT, there was also one case of
transient hyphema. This has been previously reported after both ALT and SLT
[86, 158, 159].

41
LTP in glaucoma care
Eyes with an IOP of 15 mmHg and higher prior to LTP showed an IOP reduction
of approximately 2 mmHg that was maintained up to four years of follow-up. This
may not appear to be an impressive effect, but in eyes that already have a
relatively low IOP prior to treatment, an additional reduction of this magnitude
might be of sufficient value. The consequence of our findings may for some
patients postpone or even decrease the need for glaucoma surgery, which is
associated with more severe complications. In the clinical setting, a glaucoma
patient may often have multiple drops and still display glaucoma progression
despite of relatively modest IOP levels. In these cases, given the beneficial safety
profile of LTP, our results can support a clinical decision to perform LTP
treatment. If the IOP pre-laser is then under 15 mmHg, the chances of LTP
success are limited and other treatment options such as surgery should be
considered in cases of uncontrolled glaucoma progression.

Study population and patient selection

In studies I and II, the included eyes had a relatively high mean IOP level before
the TCP treatment (29.3 and 26.2 mmHg, respectively). This might be due to the
high proportion of PEXG (approximately 40 % in each study) and NVG (22-26%)
which both often display high IOP levels [40, 160]. In both studies I and II, many
of the patients have advanced glaucoma, several IOP-lowering drops and low VA.
One in four patients had previous glaucoma surgery (study I). Thirty percent of
the patients were treated with oral acetazolamide (study I), which is a common
pre-operative routine in order to prevent any further glaucoma damage while
awaiting the laser procedure. Taken together, the study groups of both studies I
and II consisted of generally fragile eyes with refractory glaucoma, which matches
well with the clinical situation.

The large proportion of pseudoexfoliation glaucoma in our study material is of

particular interest since it is a glaucoma category not highly represented in laser
treatment studies. PEXG is more abundant in northern Scandinavia than in most
other parts of the world [23] and since our study was carried out in northern
Sweden, the prevalence of PEXG is high.

In studies III and IV, the study group was comprised of eyes with newly diagnosed
POAG or PEXG. The degree of glaucoma in the eyes was, as intended, mild to
moderate, since a Visual Field Index ³65% was a requirement for inclusion. This
fact makes the study group in studies III and IV quite different from the patients
in studies I and II, where the grade of glaucoma was far more severe. Compared
with studies I and II, these patients were a few years younger (mean age 69 years
compared with 72 and 75 in studies I and II, respectively), this is probably

42
explained by the fact that these patients were recently diagnosed with glaucoma.
The IOP before initiation of drops was 25 which is slightly lower than in studies I
and II, most likely since NVG, that tend to have high IOP levels, were only
included in the latter studies.

Strengths and limitations

The studies presented within this thesis have different strengths and limitations.
Study I is a retrospective analysis which is associated with some limitations. The
lack of an untreated control group makes it difficult to know how the IOP would
develop if the eyes were left untreated. A control group would have been
particularly valuable in the analysis of the VA where it is probable that the decline
in VA was influenced by factors other than the treatment itself. Furthermore,
approximately one in five eyes were lost to follow-up due to various reasons. The
interpretation of the postoperative examinations also sometimes posed a major
challenge. The VA examination, for instance, was often left out or not fully
described, and thereby not possible to translate into an analyzable unit.
Furthermore, the IOP measurements were a mixture of GAT and rebound
tonometry (IcareÒ). The subjects in studies III and IV were part of a randomized
study, however the GITS was not originally designed to analyze the effect of LTP,
hence there was not a control group to adjust for potential confounders.

The major strengths of study I were the large study population, and the high
proportion of PEXG included, which is unique. This provided new knowledge in
this category of glaucoma patients which is valuable since PEXG is often
aggressive and difficult to treat. All patients that were treated between 2010 and
2014 were included so there was no selection bias. The study provides real-life
data which may be of clinical value since it reflects a realistic situation and the
challenges it poses. The follow-up time of 2 years is relevant from a clinical
perspective since glaucoma is a chronic disease, and a shorter follow-up may be
misguiding. In study II the main strength is the prospective design and fixed
protocol.

Studies III and IV have the advantage of a prospective design including a

relatively large study group with newly diagnosed glaucoma. There was a
standardized protocol regarding LTP treatments and examinations during
follow-up. All levels of IOP were included which prevented regression to the
mean. There was a substantial follow-up time of five years and an excellent level
of participation throughout the study period (98%).

43
Conclusions

• TCP has a high IOP reducing efficacy in various types of glaucoma,

including PEXG.

• A high proportion of the treated eyes suffer from IOP spikes during the
first 24 hours after TCP, which needs to be taken into consideration in
clinical practice.

• No serious persistent complications were seen after TCP. A decline in VA

was concerning but difficult to explain.

• The effect of LTP is dependent on the IOP before the treatment, a higher
pre-LTP IOP causes a larger IOP reduction post-laser.

• If the IOP is lower than 15 mmHg the chances of LTP success are highly
limited.

44
Acknowledgements
Gauti Jóhannesson, huvudhandledare. Tack för allt stöd genom hela
doktorandtiden, alla roliga och intressanta diskussioner (på ibland oväntade
platser!), alla spännande möten, alla nya snabbkommandon i macbooken, alla
timmar vi vridit och vänt på formuleringar till peken, all choklad. Tack för att du
alltid tagit dig tid att lyssna och peppa oavsett vart på jordklotet du befunnit dig.
Din aldrig sinande positivitet och vänlighet är en stor källa till inspiration.

Christina Lindén, bihandledare och forskningsmamma. Ditt stöd har varit

ovärderligt genom åren, både vetenskapligt och personligt, tack för allt. Ditt sätt
att alltid vara elegantast på alla möten trots att du har den minsta packningen är
också en stor källa till beundran.

Björn Lundberg, bihandledare. Tack för givande diskussioner kring metoder

och artikelskrivning, goda råd kring statistik och allmän trevlighet.

Stort tack till GITS-kollegorna i Malmö, Boel Bengtsson och Anders Heijl
för att ni delat med er av ert stora kunnande och för klok feedback vid
artikelskrivandet. Tack till Sabina Andersson-Geimer och Johan Aspberg
för gott samarbete. Stort tack även till Catarina Villalba för tålamod och
administrativ hjälp och Jonnhy Ring för hjälp med figurer till
publikationerna.

Ingela Persson, ett stort tack för hjälpen vid rekryteringen av

cyklodiodpatienterna. Utan dig, ingen 24 h-studie. Tack även till Shahed
Shahali som också hoppat in och hjälpt till. Ni är ett dream team!

Ett enormt tack till alla glaukompatienter som deltagit i mina laserstudier.
Er medverkan har gjort forskningen möjlig och jag hoppas kunna återgälda er
på något vis genom att öka kunskapen om glaukombehandling.

Ett varmt tack vill jag rikta till Fatima Pedrosa-Domellöf, Anders
Behndig, Berit Byström och Patrik Danielson för att ni delar med er av
ert kunnande och skapar ett varmt, roligt och forskningsvänligt klimat helt utan
vassa armbågar. Tack Eva Mönestam för diskussioner och goda råd kring
logMAR beräkningar och annat. Tack också till mina nuvarande (och fd)
doktorandkollegor Anneli Fredriksson, Ania Cikowska-Filipek, Andreas
Viberg, Martin Kristiansen och Sofie Elving för alla intressanta
diskussioner och skratt.

45
Tack till fantastiska Sofia Berg, Marita Sparrman-Ivarsson, Jenny
Sandström och Jenny Lundmark för ert engagemang och hårda arbete i
glaukomforskningens tjänst.

Stort tack även till Lyn Pascual för all hjälp med logistik och praktisk support
vid TCP-behandlingarna i 24 h-studien.

Tack till alla kollegor och personal på ögonkliniken. Jag känner mig lyckligt
lottad att vara en del av ögongänget där stämningen är outstanding oavsett om
det är daglig styrning eller jubilarfest. Karin Kallur, tack för alla fikan,
onsdagsgympa och för att du är min eviga rumskompis. Tack hela ”ST-gänget”
(nuvarande och mer eller mindre gamla) för fredags-9:an och roliga AW. Tack
till Brita Olsson och Tommy Persson för klok och varm ledning av kliniken
och Monika E Johansson för all hjälp kring schemafrågor.

Tack till min älskade mamma Sigbritt, lillasyster Rebecka och lillebror
Fredrik. Tack för allt roligt vi gjort tillsammans, alla resor, jular, middagar,
stughäng, svammel och prat om allt mellan himmel och jord. Ni har gett mig
den bästa grunden att stå på. Tack även till min fina svåger Thorsten och
svägerska Kristin samt mina underbara syskonbarn Emil, Edith, Stig och
Tage.

Tack till min saknade pappa Torgny för allt stöd och kärlek. Jag försöker gå i
dina stora fotspår när det gäller forskning och mycket annat och jag tror att du
skulle ha gillat min bok.

Tack även till farmor Marianne och faster Åsa som varit stora förebilder både
vetenskapligt och på många andra plan. Och tack kusinerna för alla fina
sommarminnen.

Stort tack till svärmor Britt, svärfar Christer och svärmormor Gerda. Att få
bli del av er familj har bjudit på så mycket glädje och roliga projekt genom åren.
Ni är underbara.

Tack även till kära svägerskan Maja, svåger Ingvar och barnen för alla roliga
stunder tillsammans, ni är guld värda och vi är så glada att ni flyttat till Umeå!

Tack till den andra, lite mindre högljudda, halvan av ”Cirkus Tallvägen”;
Ingela, Per, Elsa och Agnes. Ni förgyller vår vardag och helg med allt från
pooldrinkar och skidåkning till fredagstacos och promenader till återvinningen.
Vi är så glada att ha er. Tack även för hjälp med kappan och disputationfesten!

46
Tack alla goda vänner, gamla och nya. Sofia, för din vänskap ända sedan vi var
lågstadietjejer som älskade hästar. Anna för lång vänskap och Stina för att du
förgyllde min tid på läkarprogrammet. Nasim för allt kul vi haft på medicinsk
kemi. Greys-gänget för allt prat, fika och eventuellt lite Greys anatomy i
bakgrunden.

Mina fina ungar, Iris, Love, Ejvind och Ester. Livet blir aldrig tråkigt med er
och ni gör mig lycklig vareviga dag. Älskar er till månen.

Johan min Johan. Make tillika co-pilot i vårt stundtals (oftast) rätt kaosartade
om än kärleksfulla hem. Tack för att du vandrar genom livet med mig och att du
alltid får mig att känna att allt är möjligt. Älskar dig så.

47
References

1. Brubaker, R.F., Flow of aqueous humor in humans [The Friedenwald

Lecture]. Invest Ophthalmol Vis Sci, 1991. 32: p. 3145-3166.

2. Grant, W.M., Further studies on facility of flow through the trabecular

meshwork. AMA Arch Ophthalmol, 1958. 60(4 Part 1): p. 523-33.

3. Ethier, C.R., The inner wall of Schlemm's canal. Exp Eye Res, 2002.
74(2): p. 161-72.

4. Phelps, C.D. and M.F. Armaly, Measurement of episcleral venous

pressure. Am J Ophthalmol, 1978. 85(1): p. 35-42.

5. Bill, A., Uveoscleral drainage of aqueous humor: physiology and

pharmacology. Prog Clin Biol Res, 1989. 312: p. 417-27.

6. Goel, M., et al., Aqueous humor dynamics: a review. Open Ophthalmol

J, 2010. 4: p. 52-9.

7. Brubaker, R.F., Measurement of uveoscleral outflow in humans. J

Glaucoma, 2001. 10(5 Suppl 1): p. S45-8.

8. Leydhecker, W., K. Akiyama, and H.G. Neumann, [Intraocular pressure

in normal human eyes]. Klin Monbl Augenheilkd Augenarztl Fortbild,
1958. 133(5): p. 662-70.

9. David, R., et al., Epidemiology of intraocular pressure in a population

screened for glaucoma. Br J Ophthalmol, 1987. 71(10): p. 766-71.

10. Fechtner, R.D. and R.N. Weinreb, Mechanisms of optic nerve damage in
primary open angle glaucoma. Surv Ophthalmol, 1994. 39(1): p. 23-42.

11. Burgoyne, C.F., et al., The optic nerve head as a biomechanical

structure: a new paradigm for understanding the role of IOP-related
stress and strain in the pathophysiology of glaucomatous optic nerve
head damage. Prog Retin Eye Res, 2005. 24(1): p. 39-73.

12. Osborne, N.N., et al., A hypothesis to explain ganglion cell death caused
by vascular insults at the optic nerve head: possible implication for the
treatment of glaucoma. Br J Ophthalmol, 2001. 85(10): p. 1252-9.

13. Leske, M.C., et al., Risk factors for incident open-angle glaucoma: the
Barbados Eye Studies. Ophthalmology, 2008. 115(1): p. 85-93.

48
14. Ren, R., et al., Cerebrospinal fluid pressure in glaucoma: a prospective
study. Ophthalmology, 2010. 117(2): p. 259-66.

15. Berdahl, J.P., R.R. Allingham, and D.H. Johnson, Cerebrospinal fluid
pressure is decreased in primary open-angle glaucoma. Ophthalmology,
2008. 115(5): p. 763-8.

16. Lindén, C., et al., Normal-Tension Glaucoma Has Normal Intracranial

Pressure: A Prospective Study of Intracranial Pressure and Intraocular
Pressure in Different Body Positions. Ophthalmology, 2018. 125(3): p.
361-368.

17. Tham, Y.C., et al., Global prevalence of glaucoma and projections of

glaucoma burden through 2040: a systematic review and meta-analysis.
Ophthalmology, 2014. 121(11): p. 2081-90.

18. Leske, M.C., Open-angle glaucoma -- an epidemiologic overview.

Ophthalmic Epidemiol, 2007. 14(4): p. 166-72.

19. Kapetanakis, V.V., et al., Global variations and time trends in the
prevalence of primary open angle glaucoma (POAG): a systematic
review and meta-analysis. Br J Ophthalmol, 2016. 100(1): p. 86-93.

20. Rudnicka, A.R., et al., Variations in primary open-angle glaucoma

prevalence by age, gender, and race: a Bayesian meta-analysis. Invest
Ophthalmol Vis Sci, 2006. 47(10): p. 4254-61.

21. Ringvold, A., et al., The middle-Norway eye-screening study. II.

Prevalence of simple and capsular glaucoma. Acta Ophthalmol
(Copenh), 1991. 69(3): p. 273-80.

22. Hirvelä, H. and L. Laatikainen, Visual acuity in a population aged 70

years or older; prevalence and causes of visual impairment. Acta
Ophthalmol Scand, 1995. 73(2): p. 99-104.

23. Aström, S., H. Stenlund, and C. Lindén, Incidence and prevalence of

pseudoexfoliations and open-angle glaucoma in northern Sweden: II.
Results after 21 years of follow-up. Acta Ophthalmol Scand, 2007.
85(8): p. 832-7.

24. Ekström, C., Prevalence of open-angle glaucoma in central Sweden. The

Tierp Glaucoma Survey. Acta Ophthalmol Scand, 1996. 74(2): p. 107-12.

25. Jonasson, F., et al., Prevalence of open-angle glaucoma in Iceland:

Reykjavik Eye Study. Eye (Lond), 2003. 17(6): p. 747-53.

26. Karvonen, E., et al., Prevalence of glaucoma in the Northern Finland

Birth Cohort Eye Study. Acta Ophthalmol, 2019. 97(2): p. 200-207.

49
27. Kolko, M., et al., The Prevalence and Incidence of Glaucoma in
Denmark in a Fifteen Year Period: A Nationwide Study. PLoS One,
2015. 10(7): p. e0132048.

28. Bengtsson, B., The prevalence of glaucoma. Br J Ophthalmol, 1981.

65(1): p. 46-9.

29. Bro, T., K. Wickström, and C. Lindén, The future is old - Patients with
topical ocular hypotensive treatment in the Nordic region between
2008 and 2017 with projections for 2040. Acta Ophthalmol, 2021.
99(8): p. e1442-e1448.

30. SBU rapport: Öppenvinkelglaukom (grön starr). Diagnostik,

uppföljning och behandling, 2008. Statens beredning för medicinsk
utvärdering.

31. Quigley, H.A., Glaucoma. Lancet, 2011. 377(9774): p. 1367-77.

32. Quigley, H.A. and A.T. Broman, The number of people with glaucoma
worldwide in 2010 and 2020. Br J Ophthalmol, 2006. 90(3): p. 262-7.

33. Peters, D., B. Bengtsson, and A. Heijl, Lifetime risk of blindness in

open-angle glaucoma. Am J Ophthalmol, 2013. 156(4): p. 724-30.

34. Khaw, P.T., P. Shah, and A.R. Elkington, Glaucoma--1: diagnosis. Bmj,
2004. 328(7431): p. 97-9.

35. Foster, P.J., et al., The definition and classification of glaucoma in

prevalence surveys. Br J Ophthalmol, 2002. 86(2): p. 238-42.

36. Grødum, K., A. Heijl, and B. Bengtsson, A comparison of glaucoma

patients identified through mass screening and in routine clinical
practice. Acta Ophthalmol Scand, 2002. 80(6): p. 627-31.

37. Kass, M.A., et al., The Ocular Hypertension Treatment Study: a

randomized trial determines that topical ocular hypotensive medication
delays or prevents the onset of primary open-angle glaucoma. Arch
Ophthalmol, 2002. 120(6): p. 701-13; discussion 829-30.

38. European Glaucoma Society, Terminology and Guidelines for

Glaucoma. 2020. 5th edition.

39. Thorleifsson, G., et al., Common sequence variants in the LOXL1 gene
confer susceptibility to exfoliation glaucoma. Science, 2007. 317(5843):
p. 1397-400.

50
40. Holló, G., A. Katsanos, and A.G. Konstas, Management of exfoliative
glaucoma: challenges and solutions. Clin Ophthalmol, 2015. 9: p. 907-
19.

41. Grødum, K., A. Heijl, and B. Bengtsson, Risk of glaucoma in ocular

hypertension with and without pseudoexfoliation. Ophthalmology,
2005. 112(3): p. 386-90.

42. Ekström, C. and A. Alm, Pseudoexfoliation as a risk factor for prevalent

open-angle glaucoma. Acta Ophthalmol, 2008. 86(7): p. 741-6.

43. Heijl, A., et al., Natural history of open-angle glaucoma.

Ophthalmology, 2009. 116(12): p. 2271-6.

44. Leske, M.C., et al., Risk factors for open-angle glaucoma. The Barbados
Eye Study. Arch Ophthalmol, 1995. 113(7): p. 918-24.

45. Heijl, A., et al., Reduction of intraocular pressure and glaucoma

progression: results from the Early Manifest Glaucoma Trial. Arch
Ophthalmol, 2002. 120(10): p. 1268-79.

46. Nemesure, B., et al., Incident open-angle glaucoma and intraocular

pressure. Ophthalmology, 2007. 114(10): p. 1810-5.

47. Miglior, S., et al., Results of the European Glaucoma Prevention Study.
Ophthalmology, 2005. 112(3): p. 366-75.

48. Grødum, K., A. Heijl, and B. Bengtsson, Refractive error and glaucoma.
Acta Ophthalmol Scand, 2001. 79(6): p. 560-6.

49. Tielsch, J.M., et al., Racial variations in the prevalence of primary open-
angle glaucoma. The Baltimore Eye Survey. Jama, 1991. 266(3): p. 369-
74.

50. Chauhan, B.C., et al., Canadian Glaucoma Study: 2. risk factors for the
progression of open-angle glaucoma. Arch Ophthalmol, 2008. 126(8):
p. 1030-6.

51. Leske, M.C., et al., Factors for glaucoma progression and the effect of
treatment: the early manifest glaucoma trial. Arch Ophthalmol, 2003.
121(1): p. 48-56.

52. Bengtsson, B., et al., Disc hemorrhages and treatment in the early
manifest glaucoma trial. Ophthalmology, 2008. 115(11): p. 2044-8.

53. Goldmann, H., [A new applanation tonometer]. Bull Mem Soc Fr

Ophtalmol, 1954. 67: p. 474-7; discussion, 477-8.

51
54. Kontiola, A., A new electromechanical method for measuring
intraocular pressure. Doc Ophthalmol, 1996. 93(3): p. 265-76.

55. Fernandes, P., et al., Comparison of the ICare rebound tonometer with
the Goldmann tonometer in a normal population. Ophthalmic Physiol
Opt, 2005. 25(5): p. 436-40.

56. Sung, K.R., et al., Progression detection capability of macular thickness

in advanced glaucomatous eyes. Ophthalmology, 2012. 119(2): p. 308-
13.

57. Heijl, A., Automatic perimetry in glaucoma visual field screening. A

clinical study. Albrecht Von Graefes Arch Klin Exp Ophthalmol, 1976.
200(1): p. 21-37.

58. Johnson, C.A., J.L. Keltner, and F.G. Balestrery, Suprathreshold static
perimetry in glaucoma and other optic nerve disease. Ophthalmology,
1979. 86(7): p. 1278-86.

59. Heijl, A., et al., The Glaucoma Guidelines of the Swedish

Ophthalmological Society. Acta Ophthalmol Suppl (Oxf ), 2012(251): p.
1-40.

60. McAlinden, C., Selective laser trabeculoplasty (SLT) vs other treatment

modalities for glaucoma: systematic review. Eye (Lond), 2014. 28(3): p.
249-58.

61. Baudouin, C., Detrimental effect of preservatives in eyedrops:

implications for the treatment of glaucoma. Acta Ophthalmol, 2008.
86(7): p. 716-26.

62. Munroe, W.P., J.P. Rindone, and R.M. Kershner, Systemic side effects
associated with the ophthalmic administration of timolol. Drug Intell
Clin Pharm, 1985. 19(2): p. 85-9.

63. Inoue, K., Managing adverse effects of glaucoma medications. Clin

Ophthalmol, 2014. 8: p. 903-13.

64. Robin, A.L., et al., Adherence in glaucoma: objective measurements of

once-daily and adjunctive medication use. Am J Ophthalmol, 2007.
144(4): p. 533-40.

65. Schwartz, G.F. and H.A. Quigley, Adherence and persistence with
glaucoma therapy. Surv Ophthalmol, 2008. 53 Suppl1: p. S57-68.

66. Hoevenaars, J.G., et al., Will improvement of knowledge lead to

improvement of compliance with glaucoma medication? Acta
Ophthalmol, 2008. 86(8): p. 849-55.

52
67. Sleath, B., et al., Patient-reported behavior and problems in using
glaucoma medications. Ophthalmology, 2006. 113(3): p. 431-6.

68. Gazzard, G., et al., Selective laser trabeculoplasty versus eye drops for
first-line treatment of ocular hypertension and glaucoma (LiGHT): a
multicentre randomised controlled trial. Lancet, 2019. 393(10180): p.
1505-1516.

69. Tuulonen, A., et al., Laser trabeculoplasty versus medication treatment

as primary therapy for glaucoma. Acta Ophthalmol (Copenh), 1989.
67(3): p. 275-80.

70. Bergeå, B., L. Bodin, and B. Svedbergh, Primary argon laser

trabeculoplasty vs pilocarpine. II: Long-term effects on intraocular
pressure and facility of outflow. Study design and additional therapy.
Acta Ophthalmol (Copenh), 1994. 72(2): p. 145-54.

71. Nagar, M., E. Luhishi, and N. Shah, Intraocular pressure control and
fluctuation: the effect of treatment with selective laser trabeculoplasty.
Br J Ophthalmol, 2009. 93(4): p. 497-501.

72. Katz, L.J., et al., Selective laser trabeculoplasty versus medical therapy
as initial treatment of glaucoma: a prospective, randomized trial. J
Glaucoma, 2012. 21(7): p. 460-8.

73. Lai, J.S., et al., Five-year follow up of selective laser trabeculoplasty in

Chinese eyes. Clin Exp Ophthalmol, 2004. 32(4): p. 368-72.

74. Pillunat, K.R., et al., Preoperative intraocular pressure as a predictor of

selective laser trabeculoplasty efficacy. Acta Ophthalmol, 2016. 94(7): p.
692-696.

75. Khawaja, A.P., et al., Real-World Outcomes of Selective Laser

Trabeculoplasty in the United Kingdom. Ophthalmology, 2020. 127(6):
p. 748-757.

76. Damji, K.F., et al., Selective laser trabeculoplasty v argon laser

trabeculoplasty: a prospective randomised clinical trial. Br J
Ophthalmol, 1999. 83(6): p. 718-22.

77. Damji, K.F., et al., Selective laser trabeculoplasty versus argon laser
trabeculoplasty: results from a 1-year randomised clinical trial. Br J
Ophthalmol, 2006. 90(12): p. 1490-4.

78. Hutnik, C., et al., Selective Laser Trabeculoplasty versus Argon Laser
Trabeculoplasty in Glaucoma Patients Treated Previously with 360
degrees Selective Laser Trabeculoplasty: A Randomized, Single-Blind,
Equivalence Clinical Trial. Ophthalmology, 2019. 126(2): p. 223-232.

53
79. Russo, V., et al., Selective laser trabeculoplasty versus argon laser
trabeculoplasty in patients with uncontrolled open-angle glaucoma. Eur
J Ophthalmol, 2009. 19(3): p. 429-34.

80. Nagar, M., et al., A randomised, prospective study comparing selective

laser trabeculoplasty with latanoprost for the control of intraocular
pressure in ocular hypertension and open angle glaucoma. Br J
Ophthalmol, 2005. 89(11): p. 1413-7.

81. Heijl, A., et al., Effects of argon laser trabeculoplasty in the Early
Manifest Glaucoma Trial. Am J Ophthalmol, 2011. 152(5): p. 842-8.

82. Bovell, A.M., et al., Long term effects on the lowering of intraocular
pressure: selective laser or argon laser trabeculoplasty? Can J
Ophthalmol, 2011. 46(5): p. 408-13.

83. Feldman, R.M., et al., Long-term efficacy of repeat argon laser

trabeculoplasty. Ophthalmology, 1991. 98(7): p. 1061-5.

84. Martinez-de-la-Casa, J.M., et al., Selective vs argon laser

trabeculoplasty: hypotensive efficacy, anterior chamber inflammation,
and postoperative pain. Eye (Lond), 2004. 18(5): p. 498-502.

85. Rouhiainen, H.J., M.E. Teräsvirta, and E.J. Tuovinen, Peripheral

anterior synechiae formation after trabeculoplasty. Arch Ophthalmol,
1988. 106(2): p. 189-91.

86. Rhee, D.J., O. Krad, and L.R. Pasquale, Hyphema following selective
laser trabeculoplasty. Ophthalmic Surg Lasers Imaging, 2009. 40(5): p.
493-4.

87. Knickelbein, J.E., et al., Acute corneal edema with subsequent thinning
and hyperopic shift following selective laser trabeculoplasty. J Cataract
Refract Surg, 2014. 40(10): p. 1731-5.

88. Wise, J.B. and S.L. Witter, Argon laser therapy for open-angle
glaucoma. A pilot study. Arch Ophthalmol, 1979. 97(2): p. 319-22.

89. Van Buskirk, E.M., et al., Argon laser trabeculoplasty. Studies of

mechanism of action. Ophthalmology, 1984. 91(9): p. 1005-10.

90. Bylsma, S.S., et al., Trabecular cell division after argon laser
trabeculoplasty. Arch Ophthalmol, 1988. 106(4): p. 544-7.

91. Bradley, J.M., et al., Mediation of laser trabeculoplasty-induced matrix

metalloproteinase expression by IL-1beta and TNFalpha. Invest
Ophthalmol Vis Sci, 2000. 41(2): p. 422-30.

54
92. Bergeå, B., Some factors affecting the intraocular pressure reduction
after argon laser trabeculoplasty in open-angle glaucoma. Acta
Ophthalmol (Copenh), 1984. 62(5): p. 696-704.

93. Kramer, T.R. and R.J. Noecker, Comparison of the morphologic

changes after selective laser trabeculoplasty and argon laser
trabeculoplasty in human eye bank eyes. Ophthalmology, 2001. 108(4):
p. 773-9.

94. Latina, M.A. and C. Park, Selective targeting of trabecular meshwork

cells: in vitro studies of pulsed and CW laser interactions. Exp Eye Res,
1995. 60(4): p. 359-71.

95. Latina, M.A., et al., Q-switched 532-nm Nd:YAG laser trabeculoplasty

(selective laser trabeculoplasty): a multicenter, pilot, clinical study.
Ophthalmology, 1998. 105(11): p. 2082-8; discussion 2089-90.

96. De Keyser, M., et al., Where does selective laser trabeculoplasty stand
now? A review. Eye Vis (Lond), 2016. 3: p. 10.

97. Avery, N., et al., Repeatability of primary selective laser trabeculoplasty

in patients with primary open-angle glaucoma. Int Ophthalmol, 2013.
33(5): p. 501-6.

98. Gupta, M., et al., Morphologic and Cellular Changes Induced by

Selective Laser Trabeculoplasty. Clin Ophthalmol, 2022. 16: p. 1383-90.

99. Guzey, M., et al., Increase of free oxygen radicals in aqueous humour
induced by selective Nd:YAG laser trabeculoplasty in the rabbit. Eur J
Ophthalmol, 2001. 11(1): p. 47-52.

100. Alvarado, J.A., et al., Monocyte modulation of aqueous outflow and

recruitment to the trabecular meshwork following selective laser
trabeculoplasty. Arch Ophthalmol, 2010. 128(6): p. 731-7.

101. Leahy, K.E. and A.J. White, Selective laser trabeculoplasty: current
perspectives. Clin Ophthalmol, 2015. 9: p. 833-41.

102. Beckman, H., et al., Transscleral ruby laser irradiation of the ciliary
body in the treatment of intractable glaucoma. Trans Am Acad
Ophthalmol Otolaryngol, 1972. 76(2): p. 423-36.

103. Pastor, S.A., et al., Cyclophotocoagulation: a report by the American

Academy of Ophthalmology. Ophthalmology, 2001. 108(11): p. 2130-8.

104. Hennis, H.L., et al., Transscleral cyclophotocoagulation using a

semiconductor diode laser in cadaver eyes. Ophthalmic Surg, 1991.
22(5): p. 274-8.

55
105. Brancato, R., et al., Contact transscleral cyclophotocoagulation with
diode laser in refractory glaucoma. Eur J Ophthalmol, 1995. 5(1): p. 32-
9.

106. Murphy, C.C., et al., A two centre study of the dose-response relation for
transscleral diode laser cyclophotocoagulation in refractory glaucoma.
Br J Ophthalmol, 2003. 87(10): p. 1252-7.

107. Egbert, P.R., et al., Diode laser transscleral cyclophotocoagulation as a

primary surgical treatment for primary open-angle glaucoma. Arch
Ophthalmol, 2001. 119(3): p. 345-50.

108. Hauber, F.A. and W.J. Scherer, Influence of total energy delivery on
success rate after contact diode laser transscleral
cyclophotocoagulation: a retrospective case review and meta-analysis. J
Glaucoma, 2002. 11(4): p. 329-33.

109. Vernon, S.A., et al., Diode laser cycloablation in adult glaucoma: long-
term results of a standard protocol and review of current literature. Clin
Exp Ophthalmol, 2006. 34(5): p. 411-20.

110. Raivio, V.E., et al., Cyclophotocoagulation with the transscleral contact

red 670-nm diode laser in the treatment of glaucoma. Acta Ophthalmol,
2008. 86(5): p. 558-64.

111. Kramp, K., H.P. Vick, and R. Guthoff, Transscleral diode laser contact
cyclophotocoagulation in the treatment of different glaucomas, also as
primary surgery. Graefes Arch Clin Exp Ophthalmol, 2002. 240(9): p.
698-703.

112. Grueb, M., et al., Transscleral diode laser cyclophotocoagulation as

primary and secondary surgical treatment in primary open-angle and
pseudoexfoliatve glaucoma. Long-term clinical outcomes. Graefes Arch
Clin Exp Ophthalmol, 2006. 244(10): p. 1293-9.

113. Rotchford, A.P., et al., Transscleral diode laser cycloablation in patients

with good vision. Br J Ophthalmol, 2010. 94(9): p. 1180-3.

114. Noureddin, B.N., et al., Diode laser transcleral cyclophotocoagulation

for refractory glaucoma: a 1 year follow-up of patients treated using an
aggressive protocol. Eye (Lond), 2006. 20(3): p. 329-35.

115. Mistlberger, A., et al., Diode laser transscleral cyclophotocoagulation for

refractory glaucoma. J Glaucoma, 2001. 10(4): p. 288-93.

116. Frezzotti, P., et al., Longterm follow-up of diode laser transscleral

cyclophotocoagulation in the treatment of refractory glaucoma. Acta
Ophthalmol, 2010. 88(1): p. 150-5.

56
117. Tripathy, K., et al., Phtisis Bulbi – a Clinicopathological Perspective.
Semin Ophthalmol, 2018. 33(6): p. 788-803.

118. Ishida, K., Update on results and complications of

cyclophotocoagulation. Curr Opin Ophthalmol, 2013. 24(2): p. 102-10.

119. Schuman, J.S., et al., Contact transscleral Nd:YAG laser

cyclophotocoagulation. Midterm results. Ophthalmology, 1992. 99(7):
p. 1089-94; discussion 1095.

120. Rao, V.J. and M. Dayan, Lens subluxation following contact transscleral
cyclodiode. Arch Ophthalmol, 2002. 120(10): p. 1393-4.

121. Uppal, S., et al., Short-term effect of diode laser cyclophotocoagulation

on intraocular pressure: a prospective study. Clin Exp Ophthalmol,
2015. 43(9): p. 796-802.

122. Contreras, I., et al., [IOP spikes following contact transscleral diode
laser cyclophotocoagulation]. Arch Soc Esp Oftalmol, 2004. 79(3): p.
105-9.

123. Bengtsson, B., et al., The Glaucoma Intensive Treatment Study (GITS),
a randomized clinical trial: design, methodology and baseline data. Acta
Ophthalmol, 2018. 96(6): p. 557-566.

124. Holladay, J.T., Proper method for calculating average visual acuity. J
Refract Surg, 1997. 13(4): p. 388-91.

125. Sharaawy TM, S.M.G.F., World glaucoma association guidelines on

desgn and reporting of glaucoma surgical trials. 2009, Kugler
publications. p. 83.

126. World Medical Association Declaration of Helsinki: ethical principles

for medical research involving human subjects. Jama, 2013. 310(20): p.
2191-4.

127. Schlote, T., et al., Efficacy and safety of contact transscleral diode laser
cyclophotocoagulation for advanced glaucoma. J Glaucoma, 2001.
10(4): p. 294-301.

128. Kaushik, S., et al., Lower energy levels adequate for effective transcleral
diode laser cyclophotocoagulation in Asian eyes with refractory
glaucoma. Eye (Lond), 2008. 22(3): p. 398-405.

129. Ramli, N., et al., Risk factors for hypotony after transscleral diode
cyclophotocoagulation. J Glaucoma, 2012. 21(3): p. 169-73.

130. Gupta, V. and H.C. Agarwal, Contact trans-scleral diode laser

cyclophotocoagulation treatment for refractory glaucomas in the Indian

57
 population. Indian J Ophthalmol, 2000. 48(4): p. 295-300.

131. Lai, J.S., et al., Diode laser transscleral cyclophotocoagulation as

primary surgical treatment for medically uncontrolled chronic angle
closure glaucoma: long-term clinical outcomes. J Glaucoma, 2005.
14(2): p. 114-9.

132. Ghosh, S., et al., Efficacy of transscleral diode laser

cyclophotocoagulation in patients with good visual acuity. Eur J
Ophthalmol, 2014. 24(3): p. 375-81.

133. Francis, B.A., et al., Endoscopic ophthalmic surgery of the anterior

segment. Surv Ophthalmol, 2014. 59(2): p. 217-31.

134. Tzamalis, A., D.T. Pham, and C. Wirbelauer, Diode laser

cyclophotocoagulation versus cyclocryotherapy in the treatment of
refractory glaucoma. Eur J Ophthalmol, 2011. 21(5): p. 589-96.

135. McKelvie, P.A. and M.J. Walland, Pathology of cyclodiode laser: a series
of nine enucleated eyes. Br J Ophthalmol, 2002. 86(4): p. 381-6.

136. Schuman, J.S., et al., Energy levels and probe placement in contact
transscleral semiconductor diode laser cyclophotocoagulation in human
cadaver eyes. Arch Ophthalmol, 1991. 109(11): p. 1534-8.

137. Stroman, G.A., et al., Contact versus noncontact diode laser transscleral
cyclophotocoagulation in cadaver eyes. Ophthalmic Surg Lasers, 1996.
27(1): p. 60-5.

138. Pucci, V., et al., Long-term follow-up after transscleral diode laser
photocoagulation in refractory glaucoma. Ophthalmologica, 2003.
217(4): p. 279-83.

139. Yildirim, N., et al., A comparative study between diode laser

cyclophotocoagulation and the Ahmed glaucoma valve implant in
neovascular glaucoma: a long-term follow-up. J Glaucoma, 2009. 18(3):
p. 192-6.

140. Nabili, S. and C.M. Kirkness, Trans-scleral diode laser cyclophoto-

coagulation in the treatment of diabetic neovascular glaucoma. Eye
(Lond), 2004. 18(4): p. 352-6.

141. Iliev, M.E. and S. Gerber, Long-term outcome of trans-scleral diode

laser cyclophotocoagulation in refractory glaucoma. Br J Ophthalmol,
2007. 91(12): p. 1631-5.

142. Sheheitli, H., et al., Treatment Outcomes of Primary Transscleral

Cyclophotocoagulation. Ophthalmol Glaucoma, 2021. 4(5): p. 472-481.

58
143. Razeghinejad, M.R., A. Hamid, and M.H. Nowroozzadeh, Immediate
IOP elevation after transscleral cyclophotocoagulation. Eye (Lond),
2017. 31(8): p. 1249-1250.

144. Sii, F., P. Shah, and G.A. Lee, Minimising blinding complications of
cyclodiode laser in high risk and only eyes. Eye (Lond), 2007. 21(3): p.
440-1.

145. Gedde, S.J., et al., Treatment outcomes in the tube versus

trabeculectomy study after one year of follow-up. Am J Ophthalmol,
2007. 143(1): p. 9-22.

146. Holland, L.J., J.F. Kirwan, and K.J. Mercieca, Effect of COVID-19
pandemic on glaucoma surgical practices in the UK. Br J Ophthalmol,
2022. 106(10): p. 1406-1410.

147. Garg, A., et al., Primary Selective Laser Trabeculoplasty for Open-Angle
Glaucoma and Ocular Hypertension: Clinical Outcomes, Predictors of
Success, and Safety from the Laser in Glaucoma and Ocular
Hypertension Trial. Ophthalmology, 2019. 126(9): p. 1238-1248.

148. Hodge, W.G., et al., Baseline IOP predicts selective laser trabeculoplasty
success at 1 year post-treatment: results from a randomised clinical
trial. Br J Ophthalmol, 2005. 89(9): p. 1157-60.

149. Mao, A.J., et al., Development of a prediction rule to estimate the

probability of acceptable intraocular pressure reduction after selective
laser trabeculoplasty in open-angle glaucoma and ocular hypertension.
J Glaucoma, 2008. 17(6): p. 449-54.

150. Hirabayashi, M., V. Ponnusamy, and J. An, Predictive Factors for

Outcomes of Selective Laser Trabeculoplasty. Sci Rep, 2020. 10(1): p.
9428.

151. Zaninetti, M., et al., Two-year outcomes of selective laser

trabeculoplasty in oper-angle glaucoma and ocular hypertension. J Fr
Ophthalmol, 2008. 31(10): p. 981-6.

152. Kara, N., et al., Comparison of the efficacy and safety of selective laser
trabeculoplasty in cases with primary open-angle glaucoma and
pseudoexfoliation glaucoma. Kaohsiung J Med Sci, 2013. 29(9): p. 500-
4.

153. Wasyluk, J., et al., The hypotensive effect of selective laser

trabeculoplasty depending on iridocorneal angle pigmentation in
primary open angle glaucoma patients. Arch Med Sci, 2014. 10(2): p.
306-8.

59
154. Hyman, L., et al., Natural history of intraocular pressure in the early
manifest glaucoma trial: A 6-year follow-up. Arch Ophthalmol, 2010.
128(5): p. 601-7.

155. Threlkeld, A.B., et al., Comparative study of the efficacy of argon laser
trabeculoplasty for exfoliation and primary open-angle glaucoma. J
Glaucoma, 1996. 5(5): p. 311-6.

156. Higginbotham, E.J. and T.M. Richardson, Response of exfoliation

glaucoma to laser trabeculoplasty. Br J Ophthalmol, 1986. 70(11): p.
837-9.

157. Realini, T., J. Charlton, and M. Hettlinger, The impact of anti-

inflammatory therapy on intraocular pressure reduction following
selective laser trabeculoplasty. Ophthalmic Surg Lasers Imaging, 2010.
41(1): p. 100-3.

158. Shihadeh, W.A., R. Ritch, and J.M. Liebmann, Hyphema occurring

during selective laser trabeculoplasty. Ophthalmic Surg Lasers Imaging,
2006. 37(5): p. 432-3.

159. Kitazawa, Y., et al., [The technic of argon laser trabeculoplasty and its
results]. Klin Monbl Augenheilkd, 1984. 184(4): p. 274-7.

160. Senthil, S., et al., Neovascular glaucoma - A review. Indian J

Ophthalmol, 2021. 69(3): p. 525-534.

60