Lamellar corneal lenticule graft to treat keratolysis after AlphaCor

Transcription

EJO
ISSN 1120-6721
Eur J Ophthalmol 2015; 25 (1): 1-7
DOI: 10.5301/ejo.5000497
ORIGINAL ARTICLE
Lamellar corneal lenticule graft to treat keratolysis after
AlphaCor keratoprosthesis implantation
Louis Hoffart1, Gérard Carles2, Frédéric Matonti3
Ophthalmology Department, Aix-Marseille University - APHM, Hôpital de la Timone, Marseille - France
Pharmacy Department, APHM, Hôpital de la Timone, Marseille - France
3
Ophthalmology Department, Aix-Marseille University - APHM, Hôpital Nord, Marseille - France
1
2
ABSTRACT
Purpose: Clinical assessment of AlphaCor keratoprosthesis and evaluation of surgical method to treat keratolysis
in case of stromal necrosis occurrence.
Methods: This is a noncomparative, retrospective, interventional case series. The medical records of 12 eyes
of 12 patients who underwent consecutive AlphaCor keratoprosthesis implantations were reviewed. Patients
with severe bilateral corneal pathology unsuitable for a conventional corneal graft, a best-corrected visual acuity
(BCVA) from light perception (LP) to 20/200, with no active ocular surface inflammation, controlled intraocular
pressure prior to the surgery, and an unstimulated Schirmer test of >2.5 mm at 5 minutes were included. Postoperative medications included topical dexamethasone, ciprofloxacin, and 2% cyclosporine A. Main outcome
measures included BCVA and complications occurrence.
Results: After a mean follow-up of 25 ± 12.3 months (range 2-38 months), 8 (66.7%) AlphaCor devices were
retained. Postoperative BCVA ranged from LP to 20/63 (mean gain of 2.5 ± 3.1 lines). Seven cases of stromal
melt (58.3%) occurred. Three were reversed to penetrating keratoplasty and 3 had a donor corneal layer fixated over the AlphaCor with satisfactory results (mean follow-up 23 ± 1.6 months). There were no instances
of endophthalmitis, retinal detachment, or glaucoma exacerbation.
Conclusions: AlphaCor showed a low incidence of the classic keratoprosthesis complications but a high occurrence of recipient cornea necrosis. Corneal melts were successfully managed in 3 cases by lamellar corneal lenticule graft, thereby increasing the retention of AlphaCor and maintaining BCVA.
Keywords: Corneal dystrophy, Keratoplasty, Keratoprosthesis
Introduction
Penetrating keratoplasty (PK) is the most common and the
most successful form of tissue transplantation (1). While the
success rate of PK may be more than 90% in the treatment
of corneal disorders such as keratoconus, traumatic corneal
scars, dystrophy, and degeneration (2, 3); it is extremely poor
in patients with ocular surface disorders such as immunologically mediated cicatrizing conjunctivitis, loss of limbal cells
from chemical or thermal burns, or after multiple transplant
rejections (4). For such eyes, which are at too high a risk of
Accepted: May 13, 2014
Published online: September 1, 2014
Corresponding author:
Dr. Louis Hoffart
Service d’Ophtalmologie
Hôpital d’Adultes de la Timone
264 rue Saint Pierre
13385 Marseille cedex 5, France
[email protected]
© 2014 Wichtig Publishing
graft failure after conventional corneal transplantation, keratoprosthesis (KPro) surgery may be indicated.
The first KPro to receive US Food and Drug Administration
(FDA) clearance (in 1992) was the nonintegrated Boston KPro
(5), which is anchored in place by the mechanical pressure
produced by the tight apposition of front and back polymethylmethacrylate collar-button plates sandwiching the peripheral corneal tissue (6). However, this mechanical pressure
also impairs the nutrient supply to the sandwiched corneal
tissue, possibly increasing the risk of corneal necrosis (7). Despite design modifications in the form of holes and the use of
a porous backplate reducing the nutritional challenge to the
sandwiched tissue, alternative ways to allow KPro integration
to the ocular tissues are desirable (8).
With the assumption that porous materials will improve
biologic integration to the host tissue, several materials like
Teflon, Gore-Tex, and Dacron were investigated. However, only
poly (2-hydroxyethyl methacrylate) (PHEMA), a hydrophilic
polymer, was found to significantly promote cell adhesion
and biointegration (9). Additionally, the material was unique
in that the water content could be altered to produce a onepiece device composed of a central transparent optic unified to a peripheral opaque sponge skirt. The two are fused
Keratolysis treatment after AlphaCor keratoprosthesis
2
together with an interconnecting polymer network that prevents leakage, dehiscence, and downgrowth at the interface
(10). AlphaCor, previously known as the Chirila KPro, is the
only US FDA-approved biointegrated KPro that allows biointegration (11) in the form of stromal fibroblast ingrowth and
collagen deposition into the peripheral porous PHEMA skirt
(12). Previous publications have documented the clinical use of
AlphaCor with low risk of the classic triad of KPro complications:
progressive glaucoma, endophthalmitis, or retinal detachment
(13-16). However, there is a need to decrease instances of stromal melts and improve overall retention rates (17).
In this retrospective case review, we evaluated the functional results and tolerance in 12 consecutive patients who
underwent AlphaCor keratoprosthesis implantation at our
center. Related to the high rate of corneal necrosis in our experience, we discuss surgical technique modifications to treat
keratolysis after AlphaCor implantation.
Methods
This retrospective case review included 12 eyes of 12
patients who had undergone consecutive keratoprosthesis
implantations. All surgeries were performed by a single surgeon (L.H.) who has extensive experience in corneal grafting
techniques. Inclusion criteria were severe bilateral corneal
pathology unsuitable for a conventional corneal graft owing to the presence of risk factors for failure (multiple previous graft rejection or extensive corneal neovascularization),
a best-corrected visual acuity from light perception (LP) to
20/200, no active ocular surface inflammation, controlled
intraocular pressure (IOP) prior to the surgery, and an unstimulated Schirmer test of more than 2.5 mm of tear secretion at 5 minutes. Patients with cicatrizing ocular diseases
such as ocular pemphigoid or Stevens-Johnson syndrome
were excluded. All patients were informed appropriately
about the procedure and expected outcomes and signed
appropriate consent statements.
Surgical technique
The implantation of AlphaCor keratoprosthesis was performed by a 2-stage procedure, as described by Hicks et al
(13). The first stage was performed under general anesthesia.
After a superior conjunctival peritomy, a guarded knife was
used to make a superior 180°/300-μm-deep incision in the
sclera 1 mm posterior to the limbus. A crescent-dissecting
blade was used to perform lamellar dissection at the same
depth, thus allowing the creation of a flap of the superior
cornea. Retraction of the superior flap inferiorly allowed the
center of the posterior lamella to be visualized and trephined
with a 3.5-mm disposable skin biopsy punch, entering the anterior chamber. The AlphaCor was then centered in front of
the posterior trephination and the superior lamellar flap was
sutured with interrupted 10/0 nylon sutures. A Gunderson
conjunctival flap was then created and brought over the corneal surface. Postoperative medications included dexamethasone TID for 1 month and cyclosporine 2% TID for the long
term. The second stage of the procedure was performed after
6 months. It involved the removal of the tissues anterior to
the AlphaCor optic under peribulbar anesthesia using a 3-mm
skin biopsy punch. After stage 2, postoperative medication included topical dexamethasone 3 times daily slowly tapered
over 6 weeks along with continued long-term use of topical
ciprofloxacin TID and 2% cyclosporine TID.
In the event of a postoperative stromal melt, eyes were either reversed to a PK or underwent a replacement of the melted corneal tissue with a lamellar corneal lenticule. This “rescue” surgical procedure was used to avoid the reversal of the
AlphaCor: an 8.5-mm corneal trephine was used to trephine
the corneal superficial flap (or the peripheral rim when the procedure was done after stage II) partially up to 200 μm followed
by manual lamellar dissection and removal. A 300-μm 8.7-mmdiameter anterior corneal lamellae from a donor cornea was
prepared using femtosecond laser (520F, Technolas Perfect
Vision, Heidelberg, Germany) and fixated by 16 interrupted
sutures to the recipient’s corneal rim (Video 1, Treatment of
corneal necrosis after AlphaCor implantation by a lamellar donor corneal layer fixated over the keratoprosthesis. Available
online at www.eur-j-ophthalmol.com).
Preoperative examination included medical history,
uncorrected visual acuity and best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, and Schiötz tonometry
(where possible, or else a digital IOP assessment). When observable, a dilated fundus examination was performed and in
case of previous glaucoma, modifications of optic disc were
assessed by comparison of optic nerve numerical pictures, or
conventional B-mode ultrasonography was used for evaluation of retinal disorders. Additionally, optical coherence tomography (3D OCT-1000, Topcon, Tokyo, Japan) was used to
analyze anterior segment anatomy. The follow-up schedule
involved weekly assessments during the first postoperative
month followed by monthly visits.
Visual acuity was scored on Early Treatment Diabetic Retinopathy Study chart as the total number of letters read correctly
and expressed as a logarithm of the minimum angle of resolution (logMAR) units. Patients who failed to read any letters were
tested using counting fingers (CF), hand movements (HM), and
LP. For visual acuity less than CF 2 feet, the following arbitrary
logMAR values were used: CF in front of the eye = logMAR 2.2;
HM = logMAR 2.3; LP = logMAR 2.5; and no LP = logMAR 3.
Results
The mean age of the patients at implantation was 58.8 ± 19.6
years (range 15-85 years). The mean follow-up duration after
stage I was 25 ± 12.3 months (range 2-38 months, n = 12 eyes).
Eleven cases (91.7%) had completed the second stage involving
the opening of the tissues anterior to the AlphaCor optic.
Preoperative status of the cases is described in Table I.
Patients typically had complex ocular histories with multiple pathologies; the commonest primary corneal diagnoses
were chemical injuries (3 cases), herpes simplex virus keratitis (2 cases), and atopic keratoconjunctivitis (2 cases). Ten
patients (83.3%) had a history of one or more failed donor
corneal grafts prior to keratoprosthesis implantation with
a mean number of prior grafts of 2.3 ± 2.3 (range 0-9 previous grafts). Two cases had not received a donor corneal
graft owing to a judgment that failure would be inevitable.
Eleven patients showed a massive superficial and deep corneal neovascularization prior to implantation, with mean
4
15
20
P
Quadrants with
neovessels
Schirmer I, mm
IOP, mm Hg
Lens status
Glaucoma
P
20
15
4
1
HM
Viral
keratitis
85/F
2
Dorzolamide,
timolol,
apraclonidine
Glaucoma
P
15
15
4
2
LP
Inflammatory
corneal
perforation
60/M
3
Phaco scleral
buckling
Dorzolamide,
timolol,
brimodine
Dorzolamide,
timolol,
brimodine
RD,
glaucoma
P
20
15
0
1
LP
PBK
66/M
5
Phaco
trabe
Glaucoma
P
15
<10
4
9
LP
Chemical
burn
70/F
4
Phaco
A
18
10
4
2
LP
Chemical
burn
64/M
6
P
18
15
4
0
CF 2’
Atopic
keratoconjunctivitis
15/M
7
Phaco
trabe
Glaucoma
A
20
15
4
2
LP
Aniridia
58/M
8
Phaco
P
15
15
4
4
LP
Keratoconus
72/F
9
A
18
10
4
3
LP
Bacterial
keratitis
35/F
10
Phaco
P
15
10
4
2
LP
Viral
keratitis
73/M
11
Phaco
P
18
10
3
4
HM
Trauma
71/M
12
A = aphakic; BCVA = best-corrected visual acuity; CF = counting fingers; HM = hand movement; IOP = intraocular pressure; LP = light perception; P = phakic; Phaco = phacoemulsification; RD = retinal detachment; Trabe = trabeculectomy; PBK = Phakic Bullous Keratopathy.
Associated
treatment
Previous
surgery
Limbal
autograft
0
Prior corneal
grafts
Associate
ocular
pathologies
HM
Chemical
burn
Initial
ocular
pathology
BCVA
38/M
Age/sex
1
Patient number
TABLE I - Clinical results of implantation of the alphacor keratoprosthesis: patients’ preoperative condition
Hoffart et al
3
2 Lamellar
corneal grafts
Lamellar
corneal graft
Necrosis 1 mo
after stage 2
Reversal with
Surgical
corneal
membrane
allograft
removal
Reversal with
corneal
allograft
RPM
Necrosis 2
mo after
stage 2
Necrosis 6 mo
after stage 2
Reversal with
corneal
allograft
Additional
surgery
Necrosis 2 mo
after stage 1
and extrusion
Necrosis 8 mo
after stage 2
Postoperative
complication
BCVA = best-corrected visual acuity; CF = counting fingers; HM = hand movement; LP = light perception; NA = not applicable; RPM = retroprosthetic membrane.
Lamellar
corneal graft
Necrosis 4
mo after
stage 1 RPM
Necrosis
2 wk after
stage 2
CF
CF
CF
HM
LP
HM
20/63
20/200
20/200
Postoperative
BCVA
HM
LP
HM
HM
LP
LP
LP
LP
LP
CF
LP
HM
Preoperative
BCVA
HM
LP
LP
21
21
23
28
28
31
25
1
8
Follow-up
after step 2, mo
NA
31
31
27
28
29
34
34
37
38
7
14
Follow-up
after step 1, mo
2
38
38
11
10
9
8
7
6
5
4
3
2
1
Patient number
TABLE II - Clinical results of implantation of the alphacor keratoprosthesis: postoperative results, complications, and additional procedures at the last follow-up
12
4
number of quadrants of corneal deep vessels being 3.5 ± 1.2
(range 0-4 quadrants). Concurrent glaucoma was present
in 5 cases; however, IOP was controlled preoperatively
with medications and/or trabeculectomy. The preoperative
BCVA ranged from LP to CF at 2 feet.
Postoperative outcome at the last follow-up time is
summarized in Table II. Eight of the 12 (66.7%) AlphaCor devices were retained at the end of the follow-up period. The
mean gain of BCVA was 2.5 ± 3.1 lines of visual acuity (range
from 0 lines to +11 lines; no eyes lost any lines of visual acuity). Five patients (41.6%) remained free of any complication,
requiring no additional surgery. Two cases (16.6%) developed retroprosthetic membrane formation. While one case
was easily managed by Nd:YAG laser, the thicker case needed
further surgical removal. There were no instances of surface
infection, endophthalmitis, postoperative inducement of glaucoma, or retinal detachment. No eye required subsequent
eyelid alteration surgery. Corneal necrosis was noted to be
the commonest complication, observed in 7 (58.3%) eyes, 6
of which were associated with preexisting risk factors, e.g.,
a history of chemical burn (2 cases), ocular surface inflammation (2 cases), and herpes simplex keratitis (2 cases), and
1 case showed no predisposing factor. Kaplan-Meier survival
curve and cumulative incidence curves demonstrate device retention and melt onset (Figs. 1 and 2). The mean time to melt
onset was 7.4 ± 3.9 months after stage I (n = 2 eyes) and
3.3 ± 3.1 months after stage II surgery (n = 5 eyes). The initial
3 episodes of keratolysis were reversed to penetrating keratoplasty. One case of stromal necrosis was associated with spontaneous fibrovascular closure of the posterior trephination;
the keratolysis in this case led to keratoprosthesis extrusion
followed by spontaneous re-closure of cornea. However, in the
subsequent 3 cases (patients 7, 11, and 12), a lamellar donor
corneal layer was fixated over the AlphaCor to the recipient
corneal rim (Figs. 3 and 4) and was found to have an improvement of visual acuity from preoperative levels having a postoperative BCVA at last follow-up ranging from CF to 20/63. In
these patients, one case of recurrence of corneal necrosis was
observed at 3 postoperative months and needed a replacement of the corneal lenticule. No other instance of corneal necrosis was observed in these patients, with a mean follow-up of
23 ± 1.6 months (range 21-25 months).
Discussion
Patient selection is critical to minimize the incidence of
anatomical complications (15). The highest retention rates
after AlphaCor implantations were observed in cases of
multiple failed grafts without previous chemical burns, herpes simplex virus keratitis, persistent ocular surface inflammation, or severe dry eye (18). Patients with no prior graft
procedures could also benefit from AlphaCor implantation
based on corneal condition, especially in case of massive corneal neovascularization. Some special patient requirements
should be also considered for AlphaCor implantation, such as
close proximity to surgeon practice due to the extended clinical follow-up and a nonsmoking environment due to optic
discoloration possibility (19).
Notwithstanding the outcomes of AlphaCor in limiting
the risk of sight-threatening complications, corneal necrosis
Hoffart et al
Fig. 1 - Clinical results of the AlphaCor keratoprosthesis: KaplanMeier curve of device retention.
5
Fig. 2 - Clinical results of the AlphaCor keratoprosthesis: cumulative
incidence curve of stromal melts.
Fig. 3 - Keratolysis treatment by corneal lamellar
graft after implantation
of the AlphaCor keratoprosthesis. (A) Preoperative slit-lamp picture
(case 7). (B) Clinical presentation 1 month after
stage II surgery. (C) Upper superficial corneal
flap necrosis with skirt
exposure. (D) Clinical
presentation 1 week after lamellar keratoplasty
procedure to avoid keratoprosthesis extrusion.
6
Fig. 4 - Keratolysis treatment by
corneal lamellar graft after implantation of the AlphaCor keratoprosthesis: slit-lamp photograph (left)
and optical coherence tomography
image (right) where superficial corneal flap was replaced with donor
corneal tissue after corneal necrosis
2 weeks following stage 2 AlphaCor
surgery (case 11).
was observed in approximately 58% of cases during the
25 ± 12.3 months of follow-up and occurred mainly in patients with ocular surface inflammation, dryness, or previous
herpetic keratitis and usually started by epithelial ulceration
quickly followed by a stromal necrosis that could extend to
the keratoprosthesis. However, there was no correlation of
keratolysis incidence with the number of previous allografts.
The rate of corneal melts in our study is substantially more
than the reasonable 11.4% reported by Hicks et al (13);
however, it corroborates the 60% incidence reported by
Jirásková et al (20). This could be related to use of topical medroxyprogesterone 1% in the Hicks and Crawford study (21).
Jirásková et al used dexamethasone 0.1% as a long-term immunosuppressant and we added cyclosporine A 2% because
of its dual benefit of reducing ocular surface inflammation
and preventing graft rejection. Although we did not have
a control group, review of the published literature reveals
that compared with medroxyprogesterone 1% (13), topical
cyclosporine A 2% showed low efficacy in stromal necrosis
prophylaxis. Even in the presence of a high incidence of keratolysis, our retention rate of 66.7% at 25 ± 12.3 months of
follow-up is similar to the Hicks et al 80% at 1 year and 62% at
2 years (13). This is because we could effectively manage the
cases of even extensive corneal necrosis with an innovative
yet simple procedure. In the 3 cases of stromal melt and skirt
exposure, we covered the keratoprosthesis by a donor corneal layer after removal of the patient’s superficial corneal flap.
This method prevented the removal of the keratoprosthesis
and restored the visual acuity, in all 3 eyes, to a level no less
than that reached earlier, after stage II procedure. After the
procedure, the superficial donor corneal layer showed only
slight epithelial edema with reasonable clarity of the stroma
in front of the AlphaCor device, as previously observed by
Ngakeng et al (16). In case of donor graft necrosis, replacement of the corneal lenticule could be easily managed.
It is important to note that 5 out of 7 cases of corneal
necrosis had presented after stage II; specifically, the mean
time to onset of melting after stage II was 3.3 ± 3.1 months
in these 5 eyes. In the 3 patients managed with the rescue
procedure with a mean follow-up of 23 ± 1.6 months, one
case of recurrence of keratolysis was observed and needed a replacement of the corneal lenticule. We hypothesize
that avoiding exposure of the optic may not only decrease
the incidence of corneal melts but also ease the postoperative maintenance. Because visual acuity after this
procedure was no less than that achieved earlier after
stage II, a modified single-stage implantation, where superficial corneal flap is replaced with a donor corneal tissue at
the time of AlphaCor implantation, should be investigated by
further studies. This modification of the former method may
expedite visual rehabilitation, decrease instances of corneal
necrosis, and further reduce the already low risk of intraocular complications.
Future studies may be directed to evaluate the efficacy
and safety of the new procedure described here. The only
obvious drawback of such a single-stage procedure is from
a logistics viewpoint; i.e., it would necessitate the presence of donor corneal tissue, which is not needed in the
currently described 2-stage implantation technique. Clinical experience with AlphaCor is limited but evolving. Our
study substantiates the findings of the previous publications that AlphaCor showed a low incidence of the classic
triad of keratoprosthesis complications. Additionally, lamellar corneal lenticule fixation over the AlphaCor successfully
managed corneal melts, thereby increasing the retention of
AlphaCor and maintaining BCVA.
Acknowledgment
The authors thank Raman Bedi, MD, for critical review of the manuscript, and IrisARC–Analytics, Research & Consulting (Chandigarh,
India), for editing assistance.
Disclosures
Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with
this submission.
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EJO
ISSN 1120-6721
Eur J Ophthalmol 2015; 25 (1): 8-13
DOI: 10.5301/ejo.5000498
ORIGINAL ARTICLE
Effectiveness of transscleral cyclophotocoagulation
as adjuvant therapy for refractory glaucoma in
keratoprosthesis patients
Dajiang Wang, Jifeng Yu, Lei Tian, Liqiang Wang, Yifei Huang
Department of Ophthalmology, Chinese PLA General Hospital, Beijing - China
ABSTRACT
Purpose: To evaluate the efficacy and safety of diode laser transscleral cyclophotocoagulation (DLTSC) as an adjuvant therapy to treat refractory glaucoma diagnosed before or after Moscow Eye Microsurgery Complex (MICOF)
keratoprosthesis surgery.
Methods: Fifteen patients underwent unilateral DLTSC to treat refractory glaucoma diagnosed before or after undergoing MICOF keratoprosthesis surgery. The cause for keratoprosthesis was alkali burn in 8 patients (53.33%);
thermal burn, sulfuric acid burn, and Steven-Johnson syndrome in 2 patients (13.33%) each; and ocular cicatricial
pemphigoid in 1 patient (6.67%). Best-corrected visual acuity (BCVA), intraocular pressure (IOP), any medications, and adverse events were recorded before DLTSC and on postoperative day 7; months 1, 3, and 6; and every
6 months afterwards.
Results: The patients were followed up for an average of 13.15 ± 9.35 months. The IOP was significantly less at
postoperative months 6, 12, 24, and 36. There were no changes in BCVA after DLTSC. No significant changes in
medication to treat ocular hypertension were prescribed.
Conclusions: Diode laser transscleral cyclophotocoagulation is an effective treatment option for refractory
glaucoma and can be used as a therapy adjuvant to keratoprosthesis. Long-term effects require further clinical
observation.
Keywords: Diode laser transscleral cyclophotocoagulation, Glaucoma, MICOF keratoprosthesis
Introduction
Keratoplasty is a highly successful primary therapeutic
option for conditions such as corneal endothelial decompensation, keratoconus, corneal dystrophy, and cornea degenerative diseases (1). However, its use is limited in severe corneal
damage, such as that caused by chemical or thermal burns
and related corneal scar and vascularization; eyelid or conjunctival sac function abnormalities, including complete occlusion of symblepharon, Stevens-Johnson syndrome (SJS), and
ocular cicatricial pemphigoid (OCP); as well as in multiple corneal graft failure associated with severe vascularization (1, 2).
Keratoprosthesis is a surgical process to restore vision
by replacing the damaged or diseased cornea with an artificial cornea-like device (keratoprosthesis) (3). Although
Published online: July 4, 2014
Dajiang Wang
Department of Ophthalmology
Chinese PLA General Hospital
Beijing 100853, China
[email protected]
keratoprosthesis has significantly improved in recent years,
achieving best-corrected visual acuity (BCVA) and preventing various postoperative surgical complications remain
challenges. Moscow Eye Microsurgery Complex (MICOF)
keratoprosthesis has been widely used in Russia, Ukraine,
and other countries from the former Soviet Union, eastern
Europe, and Asia. In China, more than 100 patients have undergone MICOF keratoprosthesis since 2000, with the longest follow-up period of more than 10 years (3). Moscow
Eye Microsurgery Complex keratoprosthesis significantly
improves postoperative BCVA, and provides a treatment option for patients with corneal blindness. However, similar to
other types of keratoprosthesis, the complexity of the operation and the variety of postoperative complications are
major challenges for clinical application.
The development of glaucoma, a common complication
after MICOF keratoprosthesis, can irreversibly damage visual
function. The incidence of postoperative glaucoma is very
high in patients with a cornea severely damaged due to disease, injury, or infection, or in patients who had glaucoma
before MICOF keratoprosthesis. Currently, there are several
therapeutic options for keratoprosthesis-associated glaucoma, including medication to decrease intraocular pressure
(IOP), glaucoma valve implantation, and cyclodestructive operation (4, 5). In addition, diode laser transscleral cyclophoto© 2014 Wichtig Publishing
Wang et al
9
coagulation (DLTSC) has been widely used to treat refractory
glaucoma, in which aqueous humor secretion is lowered by
destroying the ciliary body pigmented epithelium and nonpigmented epithelium (6). Transscleral cyclophotocoagulation is also effective for IOP control after other types of
keratoprostheses.
The objective of the current study was to evaluate the
efficacy and safety of transscleral cyclophotocoagulation to
treat refractory glaucoma in patients who underwent or were
scheduled for MICOF keratoprosthesis.
Materials and Methods
Patients
Fifteen patients (13 male and 2 female, mean age 37.6 ±
12.28 years) underwent keratoprosthesis for cornea that was
severely damaged with alkali burn (n = 8, 53.33%), thermal
or sulfuric acid burn, SJS (n = 2 each, 13.33%), or OCP (n = 1,
6.67%). These patients underwent unilateral DLTSC as a
treatment for refractory glaucoma, diagnosed before or after
keratoprosthesis. Eight patients were diagnosed with glaucoma before keratoprosthesis replacement, and 7 patients
developed secondary glaucoma after keratoprosthesis replacement. The primary outcome measure was IOP; the secondary outcome measure was BCVA. The use of antiglaucoma
medications and the type and number of preoperative or postoperative complications were recorded. The data were retrospectively and noncomparatively reviewed.
All 15 patients had undergone MICOF keratoprosthesis
for severely damaged cornea. None of these patients had undergone any surgical treatment for refractory glaucoma such
as glaucoma valve implantation and trabeculoplasty.
Preoperative assessment
All patients underwent a comprehensive ophthalmic examination including BCVA measurement, IOP by palpation
method, routine ocular photographing, electroretinography,
visual evoked potential, and ultrasound biomicroscopy to
reveal corneal thickness and ocular structures. Ultrasonic inspection helped in visual function prognosis.
Glaucoma diagnosis criterion
Glaucoma diagnosis was based on the tactile assessment
of IOP performed independently by 2 physicians. The IOP was
characterized as low tension (<10 mm Hg), normal tension
(10-21 mm Hg), or high tension (>21 mm Hg).
MICOF keratoprosthesis surgical treatment
The MICOF keratoprosthesis consisted of 2 stages. During stage 1, a deep lamellar pocket (6 × 8 mm) was made in
the central region of the cornea and a titanium frame with a
polymethylmethacrylate core was implanted into the pocket.
A healthy conjunctiva, if available, was used to completely
cover the corneal surface; however, in most cases, a buccal
mucosal graft was sutured over the corneal and scleral surfaces. Stage 2 was performed 3 months after stage 1. During
Fig. 1 - An eye with acid burn was treated with artificial cornea
transplantation and auricular cartilage fixation. The patient developed high intraocular pressure and then received diode laser transscleral cyclophotocoagulation.
stage 2, pars plana irrigation was established, and a 2.5-mm
diameter of corneal tissue overlying the center of the frame
was removed by trephining. The polymethylmethacrylate
core was unscrewed, and the underlying corneal tissue was
removed (2.2 mm in diameter). The nucleus of the lens was
crushed and removed through the central hole in the cornea,
and a polymethylmethacrylate optical stem was screwed
onto the central frame, after which the residual cortex, iris,
and anterior vitreous were removed by standard pars plana
vitrectomy. When required, autograft auricular cartilage was
supplied to maintain the health of the supporting optic tissue
(Fig. 1). All keratoprosthesis surgeries were performed by a
single experienced corneal surgeon (YF.H.).
Diode laser transscleral cyclophotocoagulation
All transscleral cyclophotocoagulation operations were
performed under retrobulbar anesthesia by a single experienced glaucoma surgeon (DJ.W.). Anesthesia was achieved
using 4 to 5 mL of 2% lidocaine solution. A diode laser (Iris
Medical Instruments, Mountain View, California, USA) was
transsclerally targeted at the ciliary body using a hand-held
fiber optic G-probe (Iris Medical Instruments). When the corneal limbus was not visible due to damaged condition of the
eye surface, ultrasound biomicroscopy was used to clear the
position of ciliary body. If structure and position of the ciliary body were normal, a caliper would be used to measure 6
mm from the center of the keratoprosthesis, and the optical
probe was placed accordingly. A total of 20 to 40 spots delivered cyclophotocoagulation of 270 degrees at a power of
2000 mw and a duration of 2 seconds.
Postoperative follow-up
The follow-up examinations were carried out on pos
toperative day 7; months 1, 3, and 6; and every 6 months
afterwards, or more often according to the condition of the
DLTSC-glaucoma-MICOF keratoprosthesis
10
TABLE I - Patient characteristics and intraocular pressure before and after diode laser transscleral cyclophotocoagulation
Patient
Prior diagnosis
Sex
Age, y
Follow-up
period
IOP before
laser
IOP at last follow-up
examination
Change in medications
before and after DLTSC
1
Alkali burn
Male
22
1
High
Normal
-2
2
Alkali burn
Male
19
24
High
Normal
-2
3
Acid burn
Male
35
12
High
Normal
-3
4
Alkali burn
Male
47
24
High
High
-1
5
SJS
Female
55
24
High
Normal
-1
6
Thermal burn
Male
34
24
High
Normal
0
7
Alkali burn
Male
33
24
High
Normal
-2
8
Thermal burn
Male
40
24
High
Normal
-1
9
OCP
Female
65
6
High
Normal
-1
10
Alkali burn
Male
26
3
High
Normal
-2
11
Acid burn
Male
28
24
High
Normal
-3
12
Alkali burn
Male
41
6
High
Normal
-3
13
SJS
Male
47
3
High
Normal
-2
14
Alkali burn
Male
37
12
High
Normal
-2
15
Alkali burn
Male
35
24
High
Normal
-2
Mean
37.6
13.15
SD
12.28
9.35
DLTSC = diode laser transscleral cyclophotocoagulation; IOP = intraocular pressure; OCP = ocular cicatricial pemphigoid; SJS = Stevens-Johnson syndrome.
patient. The mean follow-up period was 13.15 ± 9.35 (range
1-24) months. Ten patients completed 1-year follow-up examinations, and 8 patients completed 2-year follow-up examinations. The examinations included BCVA, IOP, number
of medications, and any adverse effects. All preoperative
IOP-lowering medications were continued postoperation.
Additionally, in order to reduce the postoperative inflammation, prednisolone acetate 1% eyedrops QID were used for
2 weeks. The postoperative inflammation reaction, such as
eye pain, conjunctival hyperemia, and vitreous inflammatory
cells, was closely observed for 2 weeks, and adverse effects
were recorded.
Statistical analysis
Data are expressed as mean ± SD. The IOP data are expressed as low, normal, or high. The IOP data were analyzed
using a 2 × 3 contingency Table test to compare IOP before
and after DLTSC. Wilcoxon signed-rank test for nonparametric
data was used for the comparison and analysis of BCVA and
number of medications. A p value <0.05 was considered statistically significant.
Results
Diode laser transscleral cyclophotocoagulation was performed unilaterally on 15 patients with refractory glaucoma
and no complications before, during, or after keratoprosthesis. The preoperative diagnosis and other detailed information are shown in Table I. The patients had not undergone
any other surgical glaucoma treatment except for DLTSC. Preoperative and postoperative IOP were measured by palpation
(Fig. 2). There was a significant difference between preoperative and postoperative IOP (p = 0.006, n = 15). Figure 2 shows
that there was a decrease in the number of patients with high
IOP at 1 week after DLTSC. The IOP improvement continued
until postoperative month 24. The DLTSC was repeated in
6 patients, in which 1 patient had multiple DLTSC. In addition,
repeated DLTSC was performed for patients with unchanged
IOP but progressive visual field loss.
The BCVA at final follow-up examination ranged from
light perception to 20/30. Improved vision was defined as
≥1 Snellen line gain or change from light perception to perception of hand movements, and worsened vision was defined as Snellen falloff ≥1 line. Stable vision was defined as
the same Snellen line or the same visual perception before
and after DLTSC. According to these criteria, there were
7 eyes with an improved or unchanged BCVA at the last visit;
of these, 5 eyes had a BCVA ≥20/60. There were 8 eyes with
worsened BCVA. When all patients were analyzed, no change
was observed.
There was a significant medication usage fall after DLTSC
treatment for all 15 patients. Twelve patients had 3 medications and 2 patients had 4 medications at pre-DLTSC stage.
Wang et al
Fig. 2 - Intraocular pressure before and after transscleral cyclophotocoagulation.
Fig. 3 - Number of medications before and after diode laser transscleral cyclophotocoagulation.
At final follow-up, 2 patients had 1 medication, 4 patients had
2, 1 patient had 3, and 1 patient discontinued. The number of
antiglaucoma medications slightly increased over time, and a
mean of 1.2 medications at postoperative month 6 after operation increased to a mean of 1.6 medications at postoperative month 24, compared with the mean of 3.1 medications
at preoperation (Fig. 3). Despite anti glaucoma medication
and DLTSC treatment, progressive vision loss was observed
in 8 eyes. There were no obvious complications found after
operation, including no ocular hypotony (IOP ≤5 mm Hg),
eyeball atrophy, and no appearance or position alteration of
MICOF keratoprostheses after DLTSC.
Discussion
The MICOF keratoprosthesis was designed at the Eye
Surgery Center of Russia. It is similar to osteo-odonto kera© 2014 Wichtig Publishing
11
toprosthesis and Boston-type II keratoprosthesis in terms of
structure and functionality. These 3 procedures are commonly used for ocular diseases such as corneal scar tissue lesions,
corneal neovascularization nebula, severe dry eye due to
SJS or OCP, extremely few or no tear secretion, and severe
chemical burn. Moscow Eye Microsurgery Complex keratoprosthesis patients often include those excluded from Boston
keratoprosthesis implants, severe symblepharon, and conjunctival sac narrowing.
Gradual narrowing of the anterior chamber angle may be
the major cause of glaucoma after keratoprosthesis surgery
(7). The diagnosis of glaucoma after MICOF keratoprosthesis
surgery is similar to that of conventional glaucoma, except
for one feature that depends on alteration of IOP, the optic
disc cupping ratio, and early-stage visual field alteration. The
anterior ocular segment structure of MICOF keratoprosthesis
patients is significantly different from that of normal eyes, because of severe injury to the conjunctival sac, surgical resection of the iris and lens, and the characteristics of the MICOF
keratoprosthesis. The optical zone diameter of the MICOF
keratoprosthesis mirror column is only 2.5 mm, which makes
examination of the fundus and optic disc difficult, especially
in patients with vitreous opacity.
There are a variety of diagnostic methods available for
glaucoma. The glaucomatous optic image analyzer allows
identification of alterations in the visual field, which is critical for early-stage glaucoma diagnosis (8, 9). However, this
method may not be appropriate for MICOF keratoprosthesis
patients as the small optical zone diameter of the MICOF
keratoprosthesis may prohibit examination with the glaucomatous optic image analyzer. In addition, the optical zone diameter of the MICOF keratoprosthesis may lead to a defect
of the patient’s peripheral visual field. This makes it difficult
to ascertain the relative contribution of glaucoma to the final
visual state of many eyes studied. To overcome this limitation, the postoperative BCVA of the keratoprosthesis can be
significantly increased; however, the perception sensitivity of
the patient is usually not high enough to accommodate this,
and dynamic vision cannot be measured for some patients.
Therefore, inspection of the visual field with the glaucomatous optic image analyzer is usually reserved for patients with
appropriate BCVA.
Glaucoma diagnosis based on the tactile assessment of
IOP was used in the current study. Intraocular pressure measurements by palpation are considered the most accurate,
as the traditional noncontact and contact electronic and mechanical devices cannot detect alterations of IOP, which can
vary significantly (3). For patients with decreased visual acuity of unknown origin, IOP alteration should be considered after excluding alteration of diopter, vitreous opacity or sterile
vitritis (ultrasound could be used for differential diagnosis),
and fiber membrane hyperplasia on the posterior and anterior surfaces of the mirror column.
The current study indicated that increased IOP refractory to medications in patients with keratoprosthesis
could be managed successfully by DLTSC. Mean IOP in patients with refractory glaucoma was significantly reduced
post DLTSC to levels that appear to be superior to those
reported in other studies, albeit with a different type of
study population and surgical protocols. Semchyshyn et al
DLTSC-glaucoma-MICOF keratoprosthesis
12
(10) reported that DLTSC after aqueous shunt placement
could decrease IOP by approximately 60%. The IOP of 20%
of patients was restored to normal by a single treatment,
whereas other patients required medication to reduce intraocular hypertension, and some patients needed repeat
DLTSC, possibly due to anterior or posterior displacement
of the borders of the ciliary body that occurred before or
after keratoprosthesis surgery (11, 12). The exact anatomic
region of the cornea is difficult to identify during aqueous
shunt placement due to severe injury and the high rate of
postoperative fibrosis when lip mucosa or ear cartilage are
used as the tube implants (13). However, glaucoma shunt
surgery has demonstrated significant therapeutic effect in
patients with pharmaceutically uncontrolled glaucoma and
keratoprostheses (5, 14, 15).
A report of Boston keratoprosthesis surgery in 141 eyes
showed that glaucoma developed in 21 eyes (15%), of which
11 eyes underwent shunt surgery with few satisfactory effects (16). The failure of the surgery was likely due to the
increased resistance to aqueous flow across the capsular
wall and scar formation around the shunt plate (17). In contrast, uncontrolled glaucoma that developed following osteo-odonto keratoprosthesis was successfully treated with
DLTSC to decrease IOP (18). In the current study, most patients’ eyes were chemically burned and had severely damaged anatomical structure of the eye surface. Therefore,
we chose DLTSC instead of a glaucoma shunt because the
condition of the conjunctiva made a shunt unsuitable. Diode
laser transscleral cyclophotocoagulation was performed for
7 eyes (46.7%), and BCVA was improved or remained stable, which was consistent with the other published results
(18-20). The glaucoma in our study was refractory, but there
was a significant difference regarding the number of medications before and after DLTSC.
There were several limitations to our study. First, it was
a retrospective and noncomparative clinical trial. The sample size was small, and the mean follow-up duration was
short. Second, and the major limitation of our study, was
the IOP assessment method in patients who underwent
keratoprosthesis placement. This is an inherent challenge
because palpation was the only way to estimate IOP. However, consistent estimation of IOP was achieved by 2 independent physicians for all patients. In additional support of
this methodology, there are studies indicating that IOP can
be accurately assessed by palpation by experienced physicians (21, 22).
Conclusion
The occurrence of glaucoma after keratoprosthesis surgery has been recognized by both patients and clinicians,
especially for patients with scar-forming conditions such as
chemical burns, SJS, and OCP. In the current study, we showed
that DLTSC has beneficial effects in controlling IOP in patients
with severe ocular surface damage, and that DLTSC could be
considered as adjuvant therapy for MICOF keratoprosthesis
patients with refractory glaucoma. Among the 15 eyes that
underwent DLTSC, IOP of 3 eyes (20%) was restored to normal
and remained stable without medication, whereas 12 eyes
(80%) were still in need of medication. Our findings indicate
that accurate localization of the ciliary body may improve the
efficacy of DLTSC, yet further exploration and a comparison
with cyclocryosurgery is needed for evaluation of long-term
efficacy.
Acknowledgment
The authors thank Dr. Bing Chen and Qinghua Yang for technical
assistance.
Disclosures
Financial support: Supported by National Sciences Fund of China
(No. 81170830) and Postdoctoral Fund of China (201104781).
Conflict of interest: None of the authors has conflict of interest
with this submission.
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Oculoplastic technique of connecting a glaucoma valve shunt
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EJO
ISSN 1120-6721
Eur J Ophthalmol 2015; 25 (1): 14-17
DOI: 10.5301/ejo.5000494
ORIGINAL ARTICLE
Correlation of intraocular pressure with central corneal
thickness in premature and full-term newborns
Eyyup Karahan1, Mehmet Ozgur Zengin2, Ibrahim Tuncer1, Neslihan Zengin3
.
Department of Ophthalmology, Alfagoz Eye Center,
Izmir - Turkey
.
2
Department of Ophthalmology, Izmir University, Izmir - Turkey
.
3
Department of Pediatrics, Dr. Behçet Uz Children’s Hospital, Izmir - Turkey
1
ABSTRACT
Purpose: To evaluate the relation of central corneal thickness (CCT) and intraocular pressure (IOP) in preterm and
full-term newborns.
Methods: The study included preterm infants who were admitted to the neonatal intensive care unit. A group of
consecutive full-term newborns served as control group. Linear and multiple regression analysis were carried out
to assess the association of IOP with sex, gestational/postconceptional age, birthweight, mean oxygenation time,
stages of retinopathy of prematurity (ROP), and CCT. Linear and multiple regression analysis were also carried
out to assess the association of CCT with sex, gestational/postconceptional age, birthweight, mean oxygenation
time, and stages of ROP.
Results: Mean IOP was 17.5 ± 2.1 mm Hg in premature newborns and 16.3 ± 1.9 mm Hg in full-term newborns
(p = 0.001). Mean CCT was 576.5 ± 16.8 µm in premature newborns and 562.7 ± 18.5 mm in full-term newborns
(p = 0.000). Intraocular pressure was not correlated with CCT in preterm infants. Intraocular pressure was moderately correlated with CCT in full-term infants. Sex, postconceptional age at birth and at measurement, age after
birth at measurement, birthweight, mean oxygenation time, and stage of ROP were not related to IOP. Central
corneal thickness was not correlated with any parameter.
Conclusions: Our results showed that the CCT does not affect IOP significantly in preterm infants. More prospective studies are needed for determining the effect of CCT and other ocular and systemic factors on IOP in preterm
infants.
Keywords: Central corneal thickness, Intraocular pressure, Prematurity, Retinopathy of prematurity
Introduction
Low birthweight and gestational age are related to some
morbidity and mortality during the newborn period. Preterm
and low birthweight infants are frequently exposed to high
concentrations of oxygen and are at risk for development of
retinopathy of prematurity (ROP) (1-3). Retinopathy of prematurity, a neovascular disease of the retina found in very
premature infants, can result in lifelong visual limitations.
Regular screening for ROP is necessary for these vulnerable,
high-risk infants after birth. Intraocular pressure (IOP) and
Published online: June 1, 2014
Eyyup Karahan, MD
Alfagoz Eye Center
Mithatpasa Cad. No: 247/A
35330, Balcova
Izmir, Turkey
[email protected]
corneal thickness can be easily measured by a handheld instrument during routine ophthalmic examination. The first
studies detailing the IOP in this population were published
in the 1950s by Dolcet (4) and Brockhurst (5), who found
mean IOPs of 35 mm Hg and 24.5 mm Hg, respectively; both
values were considered much higher than those expected
for normal adults. In more recent studies by McKibbin et al
(6) and Axer-Siegel et al (7), the mean IOPs ranged between
15.5 and 16.3 mm Hg. Although recent studies revealed
lower IOP measurements compared with studies in the
1950s, they also showed that IOP decreases as the postconceptional age (PCA) increases in preterm infants. A previous
longitudinal study revealed IOP of 16.9 mm Hg and 14.6 mm
Hg at 26.1 and 46.4 postconceptional weeks, respectively.
A decrease in IOP after birth has been suggested by others
(8). Compared with full-term newborns, premature newborns have greater central corneal thickness (CCT) (9-13),
which decreases progressively (10-13). It can be postulated
that the well-known increasing effect of CCT on IOP is valid
in preterm infants. However, there is very little information
about the relation of CCT and IOP in preterm infants. There
are few studies investigating the effects of some parameters such as gestational/postconceptional age, birthweight,
Karahan et al
15
mean oxygenation time, stages of ROP, bronchopulmonary
dysplasia, and CCT on IOP (14, 15).
The aim of this study was to evaluate the relation of CCT and
IOP in preterm and full-term newborns and the difference between premature and full-term newborns regarding IOP and CCT.
Methods
The study included preterm infants (gestational age
<37 weeks) who were admitted to the neonatal intensive care
unit. A group of consecutive full-term newborns (gestational
age ≥37 weeks) served as control group. The IOP and CCT were
measured for both the study and control subjects. Exclusion
criteria were ocular or systemic malformations, genetic anomalies, and stage III or IV intraventricular hemorrhage. The gestational age of each infant was determined based on obstetric
history and early obstetric ultrasound and confirmed by clinical
examination of the newborn infant. The postconceptional age
was calculated by adding the postnatal age of the infant at the
time of ophthalmic examination to the gestational age. Premature newborns examined during a screening visit for ROP
performed within the first month of life, from January 2013 to
June 2013, were included in this study. Patients with a major
organ dysfunction or a syndrome or with factors possibly affecting IOP also were excluded. Oxygen was administered with
intermittent positive pressure ventilation (Infant Star; Infrasonics Inc., San Diego, California, USA).
The study was performed in accordance with the tenets of the Declaration of Helsinki. Informed consent was
obtained from the parents after the aim and the risks of the
study had been fully explained. The study was approved by
our institutional review board (TAEK-004).
Ophthalmologic examination included biomicroscopy by
hand-held slit-lamp, corneal diameter determination, and
ophthalmoscopy by binocular indirect ophthalmoscope in mydriasis. All IOP measurements were obtained with the infant
lying supine and, when necessary, in the incubator. After the
application of 0.5% proparacaine (0.5% Alcaine; Alcon, Puur,
Belgium) in both eyes, a neonatal Barraquer eyelid speculum
was placed on the eye. Three sequential IOP measurements,
with 5% confidence for each eye, were made using a previously calibrated tonometer (Tonopen XLTM, Mentor O & O
Inc., Santa Barbara, California, USA). The IOP measurement
recorded for each evaluation was the mean value of these 3
measurements. Intraocular pressure was measured before the
dilation of pupils and indirect ophthalmic examination for ROP
when the infant was quiet and still to avoid a Valsalva-like effect. None of the patients received sedative drugs or muscle
relaxants before or during the eye examination. All IOP measurements were recorded by the same individual (M.O.Z.).
Central corneal thickness was determined with a portable
pachymeter, AccupachVI (Accutome Inc., Malvern, Pennsylvania, USA). In each eye, 3 measurements were taken, and
the mean of the measurements was used in the analysis.
Both eyes of all infants were measured by the same operator,
all during the same hours (between 3 PM and 5 PM). The first
examined eye was chosen for the analysis.
Mean values of IOP and CCT were compared regarding
ROP stage with the use of a one-way analysis of variance
test; the IOP and CCT values of premature and full-term newborns were compared with t test. Linear and multiple regression analysis were carried out to assess the association of
IOP with sex, gestational/postconceptional age, birthweight,
mean oxygenation time, stages of ROP, and CCT. Linear and
multiple regression analysis were carried out to assess the association of CCT with sex, gestational/postconceptional age,
birthweight, mean oxygenation time, and stages of ROP. A
p value <0.05 was considered statistically significant.
Results
A total of 63 premature (38 male) and 55 full-term (35
male) white newborns were included in the study. Table I
shows the patient demographics. The mean age at measurement was 32.7 ± 1.7 and 39.8 ± 0.9 weeks, respectively (mean
age after birth, 3 ± 1 and 1 ± 1 weeks, respectively). Thirtyeight of 63 preterm infants had no sign of ROP, 15 had stage
1 or 2 ROP, and 10 had stage 3 ROP. Thirty of 63 premature
newborns never needed oxygenation, 11 were oxygenated
for 1 to 7 days, 20 were oxygenated for 8 to 28 days, and 2
were oxygenated for more than 28 days. Mean IOP was 17.5 ±
2.1 mm Hg (range 13-22 mm Hg) in premature newborns and
16.3 ± 1.9 mm Hg (range 13-21 mm Hg) in full-term newborns
(p = 0.001). Mean CCT was 576.5 ± 16.8 μm (range 545-616
μm) in premature newborns and 562.7 ± 18.5 µm (range 533611 μm) in full-term newborns (p = 0.000). A subanalysis of
premature newborns was carried out based on ROP and oxygenation. Mean IOP in premature newborns without ROP was
17.3 ± 1.9 mm Hg (range 13-22 mm Hg), and it was 17.8 ±
2.3 mm Hg (range 13-21 mm Hg) in premature newborns with
TABLE I - Characteristics of premature and full-term newborns
Premature newborns (n = 63),
mean ± SD (range)
Full-term newborns (n = 55),
mean ± SD (range)
p Value
PCA age at birth, wk
28.5 ± 2.1 (24-33)
38.8 ± 0.9 (37-41)
0.000a
PCA at measurements, wk
32.7 ± 1.7 (29-37)
39.8 ± 0.9 (38-42)
0.000a
1290 ± 312 (610-2250)
3408 ± 334 (2870-4100)
0.000a
17.5 ± 2.1 (13-22)
16.3 ± 1.9 (13-21)
0.001a
576.5 ± 16.4 (545-616)
562.7 ± 18.4 (533-611)
0.000a
Birthweight, g
IOP, mm Hg
CCT, µm
CCT = central corneal thickness; IOP = intraocular pressure; PCA = postconceptional age.
a
Significant.
Correlation of IOP with CCT in newborns
16
ROP (p = 0.550). Mean CCT in premature newborns without
ROP was 575.5 ± 14.3 μm (range 547-642 μm), and it was
578.3 ± 19.3 μm (range 545-616 μm) in premature newborns
with ROP (p = 0.214). Mean IOP in premature newborns
who never needed oxygenation was 16.8 ± 1.9 mm Hg (range
13-21 mm Hg); it was 17.9 ± 2.0 mm Hg (range 12-22 mm Hg) in
those who needed oxygenation (p = 0.061). Mean CCT in premature newborns who never needed oxygenation was 575.0 ±
11.8 μm (range 554-592 μm); it was 577.3 ± 18.2 μm (range
545-616 μm) in those who needed oxygenation (p = 0.598).
Linear variation analysis revealed that IOP was not correlated
with CCT in preterm infants (r = 0.029, p = 0.846), whereas
IOP was moderately correlated with CCT in full-term infants
(r = 0.486, p = 0.001). Subanalyses of premature infants for
correlation of IOP and CCT were also performed. The IOP and
CCT were not correlated in premature infants without ROP
(r = 0.067, p = 0.687) and with ROP (r = 0.065, p = 0.759). The
IOP and CCT were also not correlated in premature infants
who never needed oxygenation (r = 0.356, p = 0.124) or needed oxygenation (r = 0.177, p = 0.255). Sex, postconceptional
age at birth and at measurement, age after birth at measurement, birthweight, mean oxygenation time, stage of ROP,
and presence or not of bronchopulmonary dysplasia were not
related to IOP. Univariate analysis showed that CCT was not
correlated with any parameter. Multivariate analysis showed
that neither IOP nor CCT was related to any parameter.
Discussion
Measurement of IOP is a key assessment for diagnosis
and treatment of glaucoma. Intraocular pressure levels in
preterm infants are thought to be different from those in
adults and full-term newborns. To date, relatively few studies
have reported IOP in preterm infants (14-20). Two previous
studies in the 1950s suggested a range between an average
of 24.5 mm Hg and 35.0 mm Hg (4, 5). In later clinical trials,
IOP levels ranged between 10.1 (±2.0) and 13.3 (±2.9) mm Hg
depending on postnatal/postconceptional age (8); 15.7 (±2.3)
and 16.3 (±3.7) mm Hg in 2 separate control groups (7); 15.5
(13.5-18.2) mm Hg (19); and 18.6 mm Hg (±2.3) (20).
All the studies mentioned above were cross-sectional
studies. Few longitudinal studies have suggested that premature newborns have greater IOP compared with full-term
newborns (8, 14, 21). In 1999, Ricci (8) evaluated the IOP of
20 preterm infants in a longitudinal study with 5 visits and
concluded that the mean IOP following birth decreased progressively. In 2008, Ng et al (14) reported that IOP decreases
as PCA increases in preterm infants. Ng et al found an IOP reduction of 0.11 mm Hg for each 1-week increase in PCA. Ng et
al found a median IOP of 16.9 (14.5-19.3) to 14.6 (12.2-17.1)
at 26.1 and 46.4 weeks of postconceptional age. Lindenmeyer et al (21) found a 0.29-mm Hg decrease per week as the
PCA increased. The mean IOP was decreased from 16.3 mm
Hg (10.52-22.16) at 26.3 weeks to 13.1 mm Hg (7.28-18.929
at 37.6 weeks of PCA. Our results were consistent with previous studies. In our study, mean IOP was 17.5 ± 2.2 mm Hg in
premature newborns and 16.2 ± 1.8 mm Hg in full-term newborns. The exact mechanism giving rise to a decline in IOP
with increasing maturity is not fully understood. Whether this
phenomenon represents a programmed maturation process
related to an increase in dimension of ocular structures or
under the influence of complex neuroendocrine control requires further investigation.
The negative correlation of IOP with PCA may be related
to CCT. Some studies have reported that premature newborns have greater CCT compared with full-term newborns
(9-13), which decreases progressively (10-13). In the present
study, mean CCT in preterm infants was 576.5 ± 16.8 µm, and
mean CCT was 562.7 ± 18.5 µm in full-term infants.
Although it is well-known that CCT and IOP have a correlation, there is little information about the correlation of
CCT and IOP in preterm and full-term newborns. Uva et al
(15) evaluated the IOP and CCT in premature and full-term
newborns. Multivariate analysis indicated that the main factor affecting IOP was CCT and they concluded that the IOP
measurements in premature newborns were slightly greater than in full-term newborns because of increased CCT.
However, in their study, full-term and preterm infants were
analyzed together, so a conclusion about the effect of CCT in
premature newborns is not possible. In our study, the effect
of CCT on IOP was separately evaluated in preterm and fullterm infants. Linear regression analyses revealed that CCT did
not affect IOP in preterm infants, but in full-term infants, CCT
was a significant factor affecting the IOP. Our results did not
support the hypothesis that the negative correlation of IOP
and PCA is related to CCT in preterm infants. Some other ocular and systemic factors affect IOP rather than CCT in preterm
infants. However, in our study, none of the factors we investigated was related to IOP or CCT.
This study has several limitations. The distribution of participants did not reflect a normal population because the
sample size was small. Measurements were performed by
use of the smallest wire lid speculum with the subjects under
topical anesthesia. Intraocular pressure could have increased
because of the reaction of the awake infant to ophthalmic
examination. The use of an eyelid speculum in anesthetized
children has been found to increase IOP by an average of
4 mm Hg (7). Low scleral rigidity in preterm infants may increase this effect. However, all measurements were performed
by the same investigator with a standardized technique.
In conclusion, to our knowledge, this is the first study
showing that the CCT does not affect IOP significantly in
preterm infants. More prospective studies are needed for
determining the effect of CCT and other ocular and systemic
factors on IOP.
Disclosures
Conflict of interest: None of the authors has conflict of interest
with this submission.
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14. Ng PC, Tam BS, Lee CH, et al. A longitudinal study to establish
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Corneal diameter, axial length, and intraocular pressure in premature infants. Ophthalmology. 1992;99:1296-300.
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Intraocular pressure, pulse amplitude and pulsatile ocular
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EJO
ISSN 1120-6721
Eur J Ophthalmol 2015; 25 (1): 18-26
DOI: 10.5301/ejo.5000506
ORIGINAL ARTICLE
Meta-analysis of randomized controlled trials comparing
latanoprost with other glaucoma medications in chronic
angle-closure glaucoma
Jingjing Li1,2*, Xiaoti Lin3,4*, Minbin Yu1
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou - People’s Republic of China
Department of Ophthalmology, Xiangyang Central Hospital, Teaching Hospital of Medical College of Hubei University of Arts and Science,
Xiangyang, Hubei Province - People’s Republic of China
3
Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou - People’s Republic of China
4
Department of Surgery, Fujian Provincial Tumor Hospital, Teaching Hospital of Fujian Medical University, Fuzhou - People’s Republic of China
1
2
*These authors contributed equally to this manuscript
ABSTRACT
Purpose: To evaluate the efficacy and safety of latanoprost compared with other glaucoma medications in the
treatment of chronic angle-closure glaucoma (CACG) and to provide the basis for clinical medication.
Methods: Major literature databases were searched for randomized controlled trials (RCT) involving latanoprost
among patients with CACG. Primary outcome measures were absolute changes in intraocular pressure (IOP) and
incidence of ocular adverse events. Statistical analyses included the calculation of standardized mean difference
(SMD) and relative risk (RR). The statistical analysis was performed using STATA version 12.0 software.
Results: Ten RCT involving 1096 patients were included in this meta-analysis. Analysis showed that latanoprost
was not significantly different from other glaucoma medications in reducing IOP (SMD = 0.29, 95% confidence
interval [CI] –0.02 to 0.59, p=0.069). Further subgroup analysis revealed that latanoprost was superior compared
with timolol (SMD = 0.64, 95% CI 0.46 to 0.82, p<0.001) and marginally inferior to travoprost and bimatoprost
(SMD = –0.19, 95% CI –0.35 to –0.02, p = 0.026). As for conjunctival hyperemia, latanoprost caused a higher
proportion than timolol (RR = 2.36, 95% CI 1.27 to 4.37, p = 0.007). However, latanoprost was associated with
lower incidence of conjunctival hyperemia (RR = 0.42, 95% CI 0.30 to 0.59, p<0.001), and with fewer occurrence
of other ocular side effects (excluding conjunctival hyperemia) than travoprost and bimatoprost (RR = 0.61, 95%
CI 0.48 to 0.78, p<0.001).
Conclusions: Travoprost and bimatoprost are superior in IOP control than latanoprost, but latanoprost is better
tolerated in patients with CACG.
Keywords: Angle-closure glaucoma, Intraocular pressure, Latanoprost, Meta-analysis, Prostaglandin analogue,
Timolol
Introduction
Data from population-based epidemiologic studies reveal
that 60 million people worldwide are affected and 8.4 million become bilaterally blind because of glaucoma, with 87%
Accepted: June 17, 2014
Published online: July 8, 2014
Minbin Yu, MD/PhD
State Key Laboratory of Ophthalmology
Zhongshan Ophthalmic Center
Sun Yat-sen University
Guangzhou, 510060
People’s Republic of China
[email protected]
of those with primary angle-closure glaucoma (PACG) residing in Asia (1, 2). Pupillary block is the most common mechanism of PACG, so laser peripheral iridotomy (LPI) or surgical
peripheral iridectomy (PI) have been accepted as first-line
treatment (3). Sharmini et al (4) evaluated a 5-year follow-up
of patients with chronic angle-closure glaucoma (CACG) in East
Asia, and concluded that mean intraocular pressure (IOP) was a
clinically important risk factor in patients with CACG. However,
residual glaucoma is common in many patients whose IOP control was not satisfied after LPI. Therefore, patients with residual
glaucoma need additional medical therapies.
The prostaglandin analogs, such as latanoprost, travoprost,
and bimatoprost, have been demonstrated to be effective,
well-tolerated ocular hypotensive medications in cases of primary open-angle glaucoma (POAG) or ocular hypertension (5).
β-blockers represented by timolol and pilocarpine nitrate as
the classic drugs were commonly used for the medical therapy
Li et al
of residual glaucoma. In the last decade, several studies have
shown that prostaglandin analogs were effective in PACG (6-17).
One previous meta-analysis that assessed these new medications as monotherapy in CACG reported that the prostaglandin
analogs were the most effective for IOP control, and timolol was
equally effective (18). However, an additional 3 subsequent primary studies on this topic were published after the meta-analysis
was reported during the past few years, and the conclusion was
controversial (6, 10, 13). Most recently, a meta-analysis by the
same author revealed that latanoprost was significantly superior
in lowering IOP compared with timolol in cases with CACG (19).
Furthermore, Li and Dickersin (20) indicated that the previous
meta-analysis had pooled data incorrectly, and the variance used
was wrong. Given the inconsistency of the published articles and
the insufficient statistical power of primary trials, our purposes
were to update the evidence on this topic, evaluate these new
drugs in the treatment of CACG, and provide the basis for clinical
medication.
Methods
Search strategy
We attempted to follow the quality of reporting of
meta-analyses (QUOROM) guidelines to conduct the present meta-analysis (21). Reports of randomized controlled
trials (RCTs) comparing latanoprost, travoprost, bimatoprost, and timolol were identified through a systematic
search. Two authors (J.L. and X.L.) independently searched
Medline via PubMed, EMBASE, ISI Web of Science, the Chinese Biomedicine Database, Scopus, and Cochrane Controlled
Trials Register database up to March 25, 2014. Search terms
included latanoprost, travoprost, bimatoprost, and angle-closure glaucoma. The commercial name of the medication and
the Medical Subject Heading were also searched. In addition,
the authors performed a manual search of the reference lists
of retrieved papers and review articles. No restrictions of language and publication year were imposed.
Inclusion and exclusion criteria
Studies were included if they met the following criteria:
(1) study design: RCTs; (2) population: patients with CACG
after the PI continued to experience elevated IOP levels. All
recruited patients had occludable angles, with peripheral anterior synechiae (PAS), and optic nerve head and visual field
defect corresponded with the diagnosis of glaucoma; (3) intervention: latanoprost vs other glaucoma drugs; (4) outcome
variables: at least one of the interested outcome variables
discussed later was included. We excluded the abstracts from
conferences without raw data for retrieval, duplicate publications, and reviews.
Data extraction
Two authors (J.L. and X.L.) evaluated the quality of the citations independently and reconciled at a scheduled meeting.
A standard data collection form was used when data extraction was performed. The following information was extracted
from each study: author name, publication year, study design
19
(double-blind, single-blind, parallel or crossover), location of
the study, length of follow-up, number of participants, mean
age, sex, IOP value from baseline to endpoint, and adverse
events. The primary outcome measurements were reduction in IOP level and ocular adverse events over treatment
visits.
Quality assessment
We performed quality assessment of trials with Jadad
scoring system for RCTs (22). The Jadad scale evaluates
method for randomization, double blinding (participant
masking and researcher masking), withdrawals, and dropouts. Total scores ranged from 0 to 5 (highest level). Allocation concealment and generation of random numbers were
also considered. We categorized concealment allocation
as adequate, inadequate, or unclear (23). Discrepancies
in ratings were solved by discussion between 2 authors (J.L.
and X.L.).
Outcome measures
All included studies measured IOP values at follow-up.
The absolute (mm Hg) mean IOP reduction from baseline to
endpoint to evaluate the efficacy was used. This contained
the participants having their IOP levels measured repeatedly
during treatment visits. In order to make good use of as much
of the IOP data as possible in the study objectively, we used
mean diurnal curve during the follow-up visits in the analysis
(20, 24, 25).
For tolerability, we analyzed the ocular adverse events
according to the following subgroups: conjunctival hyperemia, discomfort (itching, eye irritation, eye pain), blurred vision, keratopathy, foreign body sensation.
Statistical analysis
All statistical analyses were performed using STATA
version 12.0 (StataCorp LP, College Station, Texas, USA) and
SPSS 13.0 (SPSS Inc., Chicago, Illinois, USA) statistical packages. For continuous outcomes, we quantified with standardized mean difference (SMD). Dichotomous outcomes
from individual studies were collected to compute relative
risk (RR) with their 95% confidence intervals (CI). Heterogeneity of effective size across studies was tested by using
Q statistic, which considered to be significant if p<0.10. A
quantitative measure of inconsistency across studies, the I2
statistic was calculated (I2≥50% indicating a substantial level
of heterogeneity). If there was heterogeneity within studies
statistically, random-effect model was reported; otherwise,
the fixed-effect model was used for pooling the data. Potential publication bias was evaluated by Begg rank correlation test and Egger linear regression test (26, 27). Fail-safe
N was estimated to explore the file-drawer problem, which
may produce an effected on the study result (28, 29). It indicated the number of unpublished research having a zero
effect that needed to be contained in this meta-analysis to
nullify the significant effect. Additionally, we conducted a
sensitivity analysis excluding studies of poorer quality (Jadad
scores <3). Quantitative variables were measured as mean ±
Latanoprost vs other glaucoma medications in CACG
20
SD, and discrete variables were expressed as proportions (%).
Relationships between categorical variables were detected
by the chi-square test (Fisher correction in case any expected value <5). A p value <0.05 was thought to be statistically
significant, except where otherwise specified. All p values
reported are 2-sided.
Results
Overview
A total of 184 potential relevant abstracts were identified.
We excluded the majority after the first screening according to
abstracts or titles. Moreover, 3 articles were ineligible because
they came from the same trial (30-32). An additional 2 studies
were not accepted because the intervention was not latanoprost (10, 11). Finally, 10 trials reporting on 1096 individuals
were involved in this analysis (6-9, 12-17) (Fig. 1). Two crossover
studies were eligible; both had washout periods (7, 13). Five trials were performed according to the intention-to-treat principle
(9, 13-16), and 5 trials conducted per protocol analysis (6-8, 12,
17). These trials were reported between 2000 and 2013. Four
studies were conducted in China (6, 9, 12, 16), 2 in Singapore
(13, 17), 1 in Japan (8), 1 in India (7), and 2 in several countries
or districts (14, 15). Length of follow-up ranged from 2 weeks
to 3 months. The range of average ages was 58 to 74 years. The
percentage of withdrawals within the studies varied from 6%
to 16%. Details of every study, such as study design, patient
characteristics, intervention, and Jadad score, are presented
in Table I.
Efficacy analysis
The combined result expressed as absolute change in mm
Hg showed that there was no significant difference between
Fig. 1 - Flow diagram for the randomized controlled trials (RCTs)
included in the meta- analysis.
latanoprost and other glaucoma medications in reducing IOP
(SMD = 0.29, 95% CI –0.02 to 0.59, p = 0.069) (Fig. 2) (6-9,
12-17). Significant heterogeneity was present there (χ2 =
50.83, p<0.001, I2 = 82.3%). No evidence of publication bias
was found by using Begg rank correlation test (p = 0.474) and
Egger linear regression test (p = 0.311). The Begg funnel plot
did not indicate any substantial asymmetry.
According to different drug species, we performed subgroup analyses. No heterogeneity was observed (χ2 = 4.87,
p = 0.301, I2 = 17.9%). In general, compared with timolol, latanoprost demonstrated a superior IOP-lowering effect in stratification analysis (6, 7, 12, 15, 17) (SMD = 0.64,
95% CI 0.46 to 0.82, p<0.001) (Fig. 3). The result of fail-safe
N value was robust at 74. In addition, there was a higher
TABLE I - Baseline characteristics of the 10 studies
Study
Design
Comparison
Duration, wk
No. of
patients
Sex,
% M/F
Jadad
score
Industryfunded
Multicenter
Aung et al 2000 (17)
DB, P
LAT vs TIM
2
32
50/50
5
No
Yes
Chew et al 2004 (15)
DB, P
LAT vs TIM
12
275
25/75
5
Yes
Yes
Sihota et al 2004 (7)
SB, C
LAT vs TIM
12
30
60/40
2
No
No
Kong et al 2005 (12)
SB, P
LAT vs TIM
8
49
29/71
3
No
No
Zhao et al 2013 (6)
OL, P
LAT vs TIM
8
141
67/33
3
Yes
Yes
Sakai et al 2005 (8)
OL, P
LAT vs TIM, DORZ
12
36
39/61
2
No
No
Chen et al 2006 (16)
OL, P
LAT vs TRAVO
12
73
62/38
2
No
No
Chew et al 2006 (14)
DB, P
LAT vs TRAVO
12
319
33/67
5
Yes
Yes
Chen et al 2007 (9)
OL, P
LAT vs BIMAT
12
82
57/43
3
No
No
How et al 2009 (13)
SB, C
LAT vs BIMAT
6
59
31/69
3
Yes
No
BIMAT = bimatoprost; C = crossover; DB = double-blind; DORZ = dorzolamide; P = parallel; SB = single-blind; OL = open-label; LAT = latanoprost; TIM = timolol;
TRAVO = travoprost.
Li et al
21
Fig. 2 - Forest graph of latanoprost
versus other medications: reduction in intraocular pressure (IOP)
(CI = confidence interval; SMD =
standardized mean difference). First
column: number of patients (N),
mean IOP reduction, and standard
deviation (SD) with the latanoprost
group. Second column: number
of patients, mean IOP reduction,
and SD with the control group. In
the plot, the vertical lines signify
means, the horizontal lines signify
95% CI, the center of the diamond
signifies mean, and the 2 terminals
of the diamond signify 95% CI.
versus timolol: reduction in intraocular pressure (CI = confidence
interval; SMD = standardized mean
difference). N = number of total patients. In the plot, the vertical lines
signify means, the horizontal lines
signify 95% CI, the center of the
diamond signifies mean, and the
2 terminals of the diamond signify
95% CI.
proportion of withdrawals owing to lack of efficiency with
timolol than with latanoprost (4.1% vs 1.2%, p = 0.043).
Begg rank correlation test (p = 0.806) and Egger linear
regression test (p = 0.445) did not suggest any publication
bias there. We performed a sensitivity analysis by removing
the study of poorer quality. When we eliminated the study by
Sihota et al (7) from the analysis, the overall result was similar
(SMD = 0.58, 95% CI 0.39 to 0.78).
In contrast, the difference in IOP reduction among
latanoprost and travoprost or bimatoprost was significant,
with latanoprost displaying a lower effect on IOP control
compared to the other prostaglandin analogues (SMD =
-0.19, 95% CI -0.35 to -0.02, p = 0.026) (9, 13, 14, 16). The
difference was more remarkable when more patients
were included in the analysis (Fig. 4). Heterogeneity was
not found among the included trials (χ2 = 1.74, p = 0.628,
I2 = 0.0%). We did not assess potential publication bias
by funnel plot because there were no sufficient studies.
Exclusion of the trial by Chen et al (16) in a sensitivity analysis made little difference to the overall pooled effect size
(SMD = -0.22, 95% CI -0.39 to -0.04).
Tolerability
Overall treatment-emergent ocular adverse events were
summarized (Tab. II). As for conjunctival hyperemia, latanoprost led to a higher proportion than timolol (RR = 2.36,
95% CI 1.27 to 4.37, p = 0.007) (Fig. 5) (6, 7, 12, 15, 17).
22
versus travoprost and bimatoprost:
reduction in intraocular pressure
(CI = confidence interval; SMD =
standardized mean difference). N =
number of total patients. In the plot,
the vertical lines signify means, the
horizontal lines signify 95% CI, the
center of the diamond signifies
mean, and the 2 terminals of the
diamond signify 95% CI.
TABLE II - Summary of ocular adverse events, n (%)
Adverse events
Latanoprost
(n = 561)
Timolol
(n = 254)
Travoprost
(n = 193)
Bimatoprost
(n = 99)
Timolol/dorzolamide
(n = 17)
p Value
Conjunctival hyperemia
69 (12.3)
12 (4.7)
63 (32.6)
28 (28.3)
1 (5.9)
<0.001a
Discomfort (itching, eye
irritation, eye pain)
74 (13.2)
19 (7.5)
28 (14.5)
22 (22.2)
3 (17.6)
0.004a
Blurred vision
33 (5.9)
18 (7.1)
0
7 (7.1)
0
0.854
Keratopathy
10 (1.8)
9 (3.5)
0
0
1 (5.9)
0.201
Foreign body sensation
4 (0.7)
2 (0.8)
0
0
0
1.000
190 (33.9)
60 (23.6)
91 (47.2)
57 (57.6)
5 (29.4)
Total
a
p<0.05.
Heterogeneity did not appear among the eligible studies
(χ2 = 2.48, p = 0.479, I2 = 0.0%). On the contrary, latanoprost
caused a significantly lower incidence of conjunctival hyperemia than travoprost or bimatoprost (RR = 0.42, 95% CI 0.30
to 0.59, p<0.001) (Fig. 6) (9, 13, 14, 16). We did not observe
heterogeneity (χ2 = 3.62, p = 0.306, I2 = 17%).
In addition, there was no statistically significantly difference
between latanoprost and timolol with regard to the incidence
of all ocular side effects except for conjunctival hyperemia
(RR = 1.13, 95% CI 0.90 to 1.43, p = 0.299) (Fig. 7) (6, 7, 12, 15,
17). There was no heterogeneity in our calculation (χ2 = 3.32,
p = 0.345, I2 = 9.7%). Compared to the other 2 prostaglandin
analogues, fewer ocular adverse events (excluding conjunctival
hyperemia) were reported in latanoprost group (RR = 0.61, 95%
CI 0.48 to 0.78, p<0.001) (Fig. 8) (9, 13, 14, 16). The test did
not suggest any heterogeneity (χ2 = 0.85, p = 0.837, I2 = 0.0%).
No serious treatment-related systemic adverse events were
reported in the included trials.
Discussion
This meta-analysis of 10 RCTs involving 1096 patients
indicates a significant IOP-lowering effect of the prostaglandin analogs in the treatment of CACG. Our results showed
that 0.005% latanoprost once daily was significantly more
effective in reducing IOP than 0.5% timolol, but the other
2 prostaglandin analogues (0.004% travoprost, 0.03% bimatoprost) provided greater IOP control than latanoprost in
patients diagnosed with CACG.
There were some important strengths to our study.
Because of insufficient statistical power in each study, our
analysis of 10 trials containing a large number of patients
Li et al
23
versus timolol in conjunctival hyperemia (CI = confidence interval; RR =
relative risk). First column: number
of events and number of patients in
the latanoprost group. Second column: number of events and number
of patients in the control group. In
the graph, the vertical lines signify
RRs, the horizontal lines signify 95%
CI, the center of the diamond signifies RRs, and the 2 terminals of the
versus travoprost and bimatoprost
in conjunctival hyperemia (CI = confidence interval; RR = relative risk).
First column: number of events and
number of patients in the latanoprost group. Second column: number of events and number of patients in the control group. In the
graph, the vertical lines signify RRs,
the horizontal lines signify 95% CI,
the center of the diamond signifies
RRs, and the 2 terminals of the diamond signify 95% CI.
versus timolol in other ocular side
effects (excluding conjunctival hyperemia) (CI = confidence interval;
RR = relative risk). First column:
number of events and number of
patients in the latanoprost group.
Second column: number of events
and number of patients in the control group. In the graph, the vertical
lines signify RRs, the horizontal lines
signify 95% CI, the center of the diamond signifies RRs, and the 2 terminals of the diamond signify 95% CI.
24
versus travoprost and bimatoprost
in other ocular side effects (excluding conjunctival hyperemia) (CI
= confidence interval; RR = relative risk). First column: number of
events and number of patients in
the latanoprost group. Second column: number of events and number
of patients in the control group. In
the graph, the vertical lines signify
RRs, the horizontal lines signify 95%
CI, the center of the diamond signifies RRs, and the 2 terminals of the
increased the power to provide more reliable assessments.
Meanwhile, all primary studies used a RCT design, which
largely reduced the likelihood of confounders. The 10 studies
did not differ in medical concentration, time of application,
or frequency of dosing. Moreover, Goldmann applanation tonometry was used to measure IOP in all the studies. In addition, there were 4 multicenter studies included in our analysis, performed among several countries. These factors make
the results from this analysis more convincing.
Some prior studies performed in glaucoma subjects with
POAG and normal-tension glaucoma reported similar findings
to ours. A multicenter clinical trial by Walters et al (33) showed
that bimatoprost had a greater ability to lower IOP than latanoprost in POAG. Sato et al (34) reported that Japanese patients
whose IOP was poorly controlled by using latanoprost achieved
significant IOP lowering after switching to bimatoprost in normal-tension glaucoma. Meanwhile, an included study of our
research indicated that travoprost offered equal or greater
IOP lowering than latanoprost (14). Although the difference
associated with the prostaglandin analogs was statistically
significant in our findings, more research is needed to evaluate these medications in patients with CACG because of the
small sample size. Another 2 studies also demonstrated that
prostaglandin analogs could reduce IOP greatly in patients
with CACG (travoprost vs pilocarpine, bimatoprost vs timolol)
(10, 11). With regard to timolol, our conclusion was comparable to the previous review (19). Furthermore, fail-safe n =
74 in our subgroup study. So we needed 74 additional studies
having a zero effect not included in this study to nullify the
significant IOP-lowering effect of latanoprost as compared
with timolol.
The mechanism of action of prostaglandin analogs in CACG
is unclear. They are believed to lower IOP though promoting
uveoscleral outflow of aqueous humor (35, 36). Kook et al (37)
confirmed that 0.005% latanoprost could achieve a significant
reduction in IOP among patients with CACG with 360 degrees
of PAS. They elucidated that efficacy of latanoprost might
result from its action on available trabecular meshwork, which
enhanced the total outflow facility in glaucomatous eyes. In
addition, Aung and colleagues (30) documented that the extent of PAS or the degree of angle narrowing was not related
to the reduction of IOP in PACG by latanoprost. They speculated that the latanoprost has access to ciliary body via the still
open part of anterior chamber angle or by the way of posterior
chamber, iris root, and sclera. There is still much to learn about
the mechanism of action of prostaglandin analogs in PACG
eyes.
In this study, we observed a lower percentage of conjunctival hyperemia and other ocular adverse events in latanoprost vs the other prostaglandin analogs treatment group.
However, the incidence of conjunctival hyperemia was significantly higher with latanoprost than with timolol. In general,
these effects were mild and transient. Timolol has been the
mainstream medicine for CACG (38). Nevertheless, timolol
is contraindicated in patients with cardiovascular or pulmonary disorders (39). Our results displayed a higher proportion
of withdrawals owing to lack of efficiency with timolol than
with latanoprost. Therefore, these results support the idea
that latanoprost use would lead to improved compliance and
persistence.
There are some limitations of this meta-analysis. First,
publication bias cannot be excluded in the subgroup analysis
because of small number of trials. Thus we did not conduct
statistical tests to detect publication bias in a stratified analysis. Second, as the duration of follow-up is short (2-12 weeks),
the long-term IOP-lowering effect of prostaglandin analogs in
CACG is unknown. It is also important to observe the effect
of these medications on PAS progression. Reports on iris pigmentation or development of darker and longer eyelashes
are few. More clinical trials will be necessary to carry on longterm follow-up visits in different degree of CACG. Finally, the
results of our analysis were mainly based on data from the
Asian population; additional investigations in other countries
are needed to generalize the findings.
Li et al
In summary, this meta-analysis suggests that latanoprost
as monotherapy is more effective than timolol, but travoprost
and bimatoprost were found to be marginally better in their
IOP-lowering effects as compared with latanoprost in patients
with CACG. Patients with travoprost or bimatoprost use experienced a higher proportion of ocular adverse events. Prostaglandin analogs have the advantage of once-daily dosing,
and can be well-tolerated locally and systemically in patients
with CACG, which contributes to favorable compliance and
persistence. Hence, they may be a good choice for medical
treatment in patients with CACG. Future multicenter controlled trials are needed to assess prostaglandin analogs used
in treatment of CACG.
Disclosures
Conflict of interest: None of the authors has conflict of interest with
this submission.
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