Juniper Publishers-Journal of Ophthalmology
Abstract
Purpose: To determine
intravitreal bevacizumab (IVB) effect on ocular development by comparing
refractive and biometric outcomes of intravitreal bevacizumab (IVB) and
laser photocoagulation for treatment of retinopathy of prematurity
(ROP).
Methods: A prospective
nonrandomized interventional comparative study was conducted in a
referral hospital for ROP management. All patients who received either
single IVB or diode laser photocoagulation were enrolled. Cycloplegic
refraction and biometry was performed before treatment and at the
corrected age of 9 months.
Results: The IVB group
included 17 patients (28 eyes; gestational age (GA): 28.54 ±2.2 weeks)
and the laser group included 17 patients (34 eyes; GA: 28.53 ± 1.6 w).
GA, BW and corrected age at the end of follow-up was statistically
similar between the two groups. Eyes in IVB group had significantly
longer axial lengths and thinner lenses at final visit (p=.037 and
p=.002).
Conclusions: Following IVB
treatment of ROP, eye development in general and crystalline lens in
particular are less affected compared to laser treatment. This supports
the idea that anterior segment arrest which was first described for
laser therapy of ROP occurs minimally with IVB if at all.
Keywords: Retinopathy of
Prematurity; Intravitreal Bevacizumab; Diode Laser photocoagulation;
Refraction; Biometry
Abbreviations: IVB: Intravitreal Bevacizumab; ROP:
Retinopathy of Prematurity; GA: Gestational Age; ETROP: Early Treatment
of ROP study; VEGF: Vascular Endothelial Growth Factor; AL= Axial
Length; ACD= Anterior Camber Depth; LT= Lens Thickness; V= Vitreous
Cavity
Introduction
Retinopathy of prematurity (ROP) is a
vasoproliferative disease of preterm neonates which may result in severe
complications if left untreated in high risk patients. In 2001 Early
Treatment of ROP study (ETROP) showed significant benefit of laser
photocoagulation in eyes with type 1 prethreshold ROP [1]. Since then,
laser photocoagulation of the avascular retina using either
transpupillary or transscleral approach is the standard of care for type
1 ROP [2-6]. In recent years, the use of anti-vascular endothelial
growth factor (VEGF) agents mainly bevacizumab, has been increasingly
popularized for the treatment of various ocular neovascular diseases
including ROP [7-11] Promising results have been reported for IVB
injection in ROP especially in patients with severe or aggressive
posterior ROP [12].
Previous studies have shown that ROP patients show
significant myopia (55.2 to 80.04% in age group under 3 years old) after
laser photocoagulation [13-15]. It is well established that myopia
associated with prematurity and conventionally treated (cryo- or laser
therapy) ROP is not fully explainable by axial length changes. In fact,
it may be a result of a disruption of emmetropization called anterior
segment arrest consisting of corneal steepening, anterior chamber depth
reduction, and lens thickening [16-19]. Recently, a few studies have
reported less myopia after intravitreal bevacizumab (IVB) injection in
ROP patients in comparison to laser photocoagulation or combination
treatments [20-25]. Geloneck et al. [25] speculated that IVB
minimally disrupts anterior segment development, hence less myopia.
However biometric effects of anti-VEGF agents on ocular growth have not
been fully evaluated in a pre- and post-treatment model. Current study
was conducted to compare the refractive errors and biometric indices
before and after single IVB injection and conventional laser therapy for
ROP.
Methods
In this prospective comparative study, from March to
September 2013, all premature infants who were scheduled to undergo
either diode laser photocoagulation or IVB injection for the treatment
of type 1 ROP in Rassoul Akram Hospital, Iran, Tehran were eligible for
this study. Informed consent was obtained from the parents of all
infants enrolled in the study, fully describing the treatment modalities
and ultrasonography technique. Iran University Eye Research Center
Ethics Committee approved the study. Screening and management of all
patients were performed by retinal specialists (MMP and AS) in
accordance to the guidelines of the American Association for Pediatric
Ophthalmology and Strabismus [26] and the revised guidelines of the
International Committee for the Classification of Retinopathy of
Prematurity [27]. For prethreshold disease in zone I or posterior zone
II, an intravitreous injection of 0.625 mg bevacizumab (Avastin;
Genentech Inc, San Francisco, California, USA) was performed [10].
Infants with prethreshold disease in anterior zone II, received
transscleral diode laser photocoagulation of avascular retina [28].
Patients who did not respond to primary monotherapy and needed further
intervention were excluded. Also, eyes with media opacity including
cataract, corneal opacity and vitreous hemorrhage, and those with other
ocular diseases including glaucoma, and congenital vitreoretinal
diseases were excluded.
Refractive errors and biometry indices were obtained
under cycloplegic condition approximately 30 minutes after instillation
of topical Tropicamide (Mydrax; Sina Darou, Tehran, Iran), 3 times with
an interval of 5 minutes. Measurements were performed immediately before
treatment, and at the age of 9 month.
Handheld retinoscopy was performed by two of the
three expert examiners (RA, JK and MSS), masked to the planed treatment.
If their results disagreed by more than 0.5 Diopters (D), refractions
were repeated and the discrepancy was resolved. Spherical equivalent
(SE) ≤ − 0.5 and ≤ − 5.00 D was considered as myopia and high myopia,
respectively [29, 30].
Biometry was performed in supine position with the
lid speculum in situ via A-scan contact mode ultrasonography
(OcuScanRxP; Alcon Lab, Dallas, TX, USA). Measured indices included
axial length (AL), anterior chamber depth (ACD), lens thickness (LT),
and vitreous cavity length (V). All scans were performed by a single
investigator (JK). After instillation of topical Tetracaine 0.5%
(Anestocaine; Sina Darou, Tehran, Iran), 10 subsequent scans were
recorded in Auto-save mode. Scans were repeated until standard deviation
of less than 0.1 was achieved. Care was taken to apply minimum pressure
on the cornea during ultrasonography.
Data analysis was done using SPSS software (version
16, SPSS, Inc., Chicago, IL, USA). T tests (paired t test when
applicable) and Chi square test were used for analysis of continuous and
categorical variables, respectively. P values less than 0.05 were
considered statistically significant.
Results
A total of 34 neonates including 17 patients (28
eyes) in the IVB group and 17 patients (34 eyes) in the laser groups
were studied. Table 1 shows demographics of the patients. Birth age,
birth weight, follow up duration and corrected age at the end of
follow-up were similar between the two groups; however, patients in IVB
group received therapy significantly earlier (p< 0.001). All patients
in the study responded to treatment in terms of resolution of ROP, no
recurrence of ROP and no detachment/hemorrhage after treatment.
Results of refractive error measurements are
summarized in Table 2. At baseline examination, a marginally significant
difference was found in the mean SE between the 2 groups (-3.37 ± 4.68
Diopters [D] in the IVB group and -1.5± 3.97 D in the laser group, p:
0.08) and prevalence of myopia was significantly higher in IVB group
(71.04% vs. 35.55%; P= 0.004). At final exam, refractive error in the
IVB group and laser therapy group was -1.02 ± 2.96 D vs. -0.12 ± 2.28 D
(P = 0. 18) and the rate of myopia in IVB group decreased to 50%, while
no significant change was observed in the laser group (38.24%, P=0.36).
Finally the absolute change in SE was not significantly different
between the 2 groups (P=0.3).
Table 3 shows the biometric measurements. At
baseline, no significant difference was found between the two groups in
any of the biometric measurements. At final exam, eyes in the IVB group
had significantly higher AL and V measurements and shallower ACD and
shorter LT measurements compared to the laser group (p=.037, p=.017,
p=.002 and p=.002). The biometric changes after treatment were
significantly different between the two groups in AL, LT and V
measurements (P=0.002, P=0.007 and P< 0.000).
In bivariate correlation analysis, SE change in the
laser group correlated significantly to axial and vitreous cavity length
changes (p=0.005 and p=0.006). No significant correlation between SE
and biometric changes were found in IVB group.
In multivariate analysis, no significant association
was found between SE changes and the treatment modality (p=0.46), AL
changes (p=0.56), ACD changes (p=0.49), LT changes (p=0.08), V changes
(p=0.49), GA (p=0.56) and BW (p=0.74).
Discussion
Although there are few reports of more hyperopic
changes following laser treatment of ROP [31] most recent studies
comparing IVB and laser monotherapy or combination therapies show a
myopic preponderance in laser therapy (Table 4).
Whether the observed myopic shift is attributable to
the allocated treatment or the severity of the disease has been a matter
of controversy, however, the follow up of the BEAT- ROP clinical trial
[10,25] the only large randomized prospective study in the field,
demonstrated that the higher degree and frequency of myopia in laser
treated eyes (compared to the eyes who received IVB) did occur in spite
of no significant difference in myopia severity.
In a process called emmetropization a relatively wide
distribution of refractive error in full term newborns, gets narrower
toward hyperopia in the first few years of life [30,32]. In this
process, vitreous cavity length elongation is balanced by reduction of
corneal curvature (from 51 to 44 D), crystalline lens power (by getting
thinner) [33]. Myopia associated with prematurity and conventionally
(cryo- or laser therapy) treated ROP is not fully explained by axial
length, but it is a result of an emmetropization disruption called
anterior segment arrest consisting of corneal steepening, anterior
chamber depth reduction, and lens thickening [16-19]. Although Geloneck et al.
[25] speculated that IVB minimally disrupts anterior segment
development; effect of anti-VEGF agents on ocular growth is not fully
evaluated.
In the present study despite the initially higher
prevalence of myopia among IVB group (71%) in comparison to laser
therapy group (35.55%) before treatment, the frequency decreased to 50%
at the age of 9 month in IVB group while no significant change was
observed in laser therapy group (38.2%). On the other side, biometry
results demonstrated that although the eyes in IVB group were initially
marginally smaller than those in the laser group, they finally had
significantly larger size. At a concordant trend lens thickness in IVB
group significantly decreased leading to less frequency of myopia in
this group. Such a significant reduction in lens thickness was not
observed in the laser group. These observations support the idea that
the crystalline lens development (the expected lens thinning) continues
following IVB treatment of ROP while it is arrested by laser therapy.
This is in consistence with a previous study which suggests that high
myopia associated with ROP is primarily a reflection of inappropriately
higher lens thickness and power [34]. To the best of our knowledge, it
is for the first time that a study reports the refractive and biometric
indices of eyes before and after undergoing treatment for ROP.
It has been proposed that anterior segment growth may
be slowed by decreased levels of local growth factors as a result of
delayed migration of vessels to oraserrata (in premature neonates)
alongside photoreceptors maturation arrest [35,36]. It is also known
that laser therapy stops retinal vessel development, while vessels
continue to develop beyond neovascular ridges upto the oraserrata after
IVB injection [10].This may partly explain the pathophysiology of the
so-called anterior segment arrest following the laser therapy; however,
further experimental investigation is needed.
The present study has several limitations. Although
randomization would avoid analytical concerns inherent to the
non-randomized design, investigators believed it would be unethical to
randomize ROP patients, regardless of their stage of the disease, to the
two treatment group. In the current ROP protocol applied in this
reference hospital, ROPs in zone I and posterior zone II are treated
with IVB and ROPs in anterior zone II are offered the laser treatment.
Additionally enrolled infants in the present study have notably higher
birth weight and gestational age compared to some studies which may also
contribute to the smaller degree of myopia observed in the pretreatment
examination in this study compared to other reports. Finally for the
investigators a relatively short follow-up was considered an acceptable
trade-off for the prospective design. Despite these limitations, current
study is the first to report pre- and post-treatment biometric and
refractive indices of eyes treated for ROP and its results further
support the theory that IVB does not halt anterior segment development
in ROP patients as laser therapy does.
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