Aims: The aim of the study was to examine the changes in visual acuity, fluorescein angiography (FA) and optical coherence tomography (OCT) macular thickness of subfoveal, and juxtafoveal choroidal neovascularisation (CNV) in highly myopic eyes treated by intravitreal bevacizumab.
Methods: The study was a prospective, non-randomised, multicentre, interventional case series. Twenty-nine highly myopic eyes from 28 patients with subfoveal and juxtafoveal CNV were treated by three monthly intravitreal injections of 1.25 mg bevacizumab. Patients were evaluated for best-corrected visual acuity (BCVA) and OCT at baseline and then monthly for 1 year. FA was performed at baseline, after 3 months, and whenever CNV activity was suspected.
Results: The average age was 50 (SD 15, range 29–82) years. The mean LogMAR BCVA at baseline was 0.55 (SD 0.25, range 0.2–1.0) and 0.38 (SD 0.32, range 0.0–1.2) at 1 year. Sixteen eyes were naïve for treatment and 13 eyes had been previously treated by photodynamic therapy (average 2.5 sessions). Leakage from CNV had ceased in all eyes at month 3. OCT central foveal thickness decreased significantly from 282 (SD 68) μm at baseline to 224 (SD 46) μm at month 12 (p = 0.008, Student t test for paired data). Six eyes needed one re-injection during follow-up at month 4 (one eye), month 6 (four eyes) and month 12 (one eye). Neither ocular nor systemic adverse reactions appeared during follow-up.
Conclusions: The results of this case series suggest that intravitreal bevacizumab seems to be an effective therapeutic procedure to treat subfoveal and juxtafoveal CNV in highly myopic eyes at 1-year follow-up. Further studies are required to verify the efficacy and usefulness of this therapy compared with established treatments for this condition.
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High myopia affects approximately 2% of the global population. Myopic maculopathy is the main cause of vision loss among highly myopic patients, and is the leading aetiology for subfoveal choroidal neovascularisation (CNV) among patients <50 years of age.1
Different therapeutic approaches have been attempted to treat myopic CNV, including argon laser photocoagulation,2 3 surgical removal and macular translocation,4 5 and photodynamic therapy (PDT) with verteporfin.6–8 The frequent need to repeat PDT sessions and the limited improvement in visual acuity after PDT monotherapy led to combination treatment with intravitreal triamcinolone and PDT. This combined therapy reduces the number of PDT sessions needed, although it is associated with a high risk of glaucoma and cataracts, and does not seem to improve final visual acuity.9 10
New anti-angiogenic drugs have been used off-label to treat subfoveal CNV secondary to high myopia, although results at 1-year follow-up have not been reported.11–18 The purpose of this pilot study was to evaluate the visual outcome 1 year after intravitreal bevacizumab to treat subfoveal and juxtafoveal CNV in highly myopic eyes.
MATERIALS AND METHODS
A multicentre, prospective, non-randomised, interventional case series was performed. Twenty-nine eyes from 28 highly myopic patients with active subfoveal and juxtafoveal classic CNV were treated by three monthly intravitreal injections of 1.25 mg bevacizumab and followed for 1 year. Patients being treated by PDT were started on intravitreal bevacizumab if they were losing visual acuity or the CNV did not respond to PDT.
Snellen best corrected visual acuity (BCVA) was determined by certified optometrists using standard ETDRS charts at 4 m (Lighthouse, New York, USA). A complete ocular examination, BCVA and optical coherence tomography (OCT) were performed at the first visit and then monthly during follow-up. Fluorescein angiography was performed at the initial visit, at month 3 and whenever CNV activity was suspected during follow-up.
Patients were informed about the off-label condition of this therapy, and women of child-bearing age were also informed about the possible risks to the fetus; these patients agreed to use two forms of contraception (barrier and hormonal methods) throughout the 3 months of injections and during the following 3 months. At each visit the patients were specifically asked for the appearance of systemic side effects (medication changes, high blood pressure as measured by their general practitioner, signs of cerebrovascular accidents, myocardial infarctions or ischaemia) and ocular side effects (pain, floaters, reduced visual acuity).
The average age of the patients was 50 (SD 15 years, range 29–82) years. Five patients were male and 23 were female. Average spherical equivalent was −13.6 (SE 4.3, range −6.0 to −22.0) D. Thirteen eyes had undergone previous unsuccessful PDT to treat myopic CNV: one patient eight times, two patients four times, five patients twice and five patients once (one of the these associated with intravitreal triamcinolone). The last PDT session had been performed 3 months prior to the first injection of bevacizumab in all cases.
Follow-up was at least 1 year for 27 eyes; two cases were lost to follow-up (one at month 9 and one at month 12).
The changes in LogMAR BCVA, number of letters read and OCT central foveal thickness (CFT) are shown in tables 1 and 2.
LogMAR BCVA was 0.30 or better in 15/27 eyes at 1 year. Ten of 27 eyes with more than 1-year follow-up gained two or more ETDRS lines (ten or more letters) and three eyes lost two or more ETDRS lines (one eye lost two lines, one eye lost three lines and one eye lost four lines)
Leakage from CNV had ceased in all eyes at month 3. One patient <50 years of age (one eye) needed one re-injection at month 4. Five patients (five eyes) aged ⩾50 years required to be re-treated: four cases at month 6 and one case at month 12.
Neither ocular nor systemic side effects appeared during follow-up.
The spontaneous visual outcome of myopic CNV is poor according to the reported series. Yoshida et al have reported a natural history of visual acuity loss from 70% of the eyes with 20/200 or better at the onset of CNV, to 55% at 3 years and 11% at 5 years. Active treatments should be recommended to prevent long-term visual impairment.19
The results of PDT do not seem to be satisfactory, as has been reported previously by our group, with 28% of the patients <55 years and 54% of those ⩾55 years losing two or more lines by the end of the first year of treatment.7
The presence of high levels of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor is suspected to be involved in the development of myopic CNV.20 Anti-angiogenic therapies, such as intravitreous triamcinolone,9 10 21 22 intravitreous bevacizumab11–18 and intravitreous ranibizumab, have been used to treat subfoveal myopic CNV.23
Short-term reports have been made on intravitreal bevacizumab for CNV associated with high myopia.12 15 17 More recently, results at 6 months follow-up have been published.14 16 24 Chan et al performed three monthly intravitreal injections of bevacizumab followed by further monthly injections in those cases where CNV had not stopped leaking. Ninety per cent of the eyes showed angiographic closure by month 3 with an average gain of 13 letters by month 6.14 In our series 11/16 eyes with more than 3 months follow-up and 2/4 eyes with more than 6 months follow-up achieved BCVA equal or better than 20/40 with the same schedule of treatment. Nine of 16 eyes with more than 3 months follow-up gained more than two ETDRS lines.24 These poorer results may be related to the previous PDT performed in 11/26 eyes, which is known to induce retinal pigment epithelium (RPE) and choriocapillaris atrophy.25
Marked differences were detected between patients who were treatment-naïve and those who had received prior PDT (table 1) and different age groups (table 2). However, we are not able to draw any conclusion from this, since the number of patients in each group was small. In our series, three patients (two of them were >50 years old and had undergone two and four unsuccessful PDT sessions, respectively) had marked vision loss (11, 17 and 20 letters), which was attributed to progression of macular atrophy secondary to high myopia. In a previous report we did not find differences between treatment-naïve eyes and those previously treated by PDT at 6 months follow-up.24 However, in the present series PDT seems to be a predictor for poor results since only 2/13 eyes with previous PDT gained two or more ETDRS lines vs 8/16 eyes without previous PDT.
Patients <50 years of age showed a better visual outcome but no significant improvement in CFT, whereas patients ⩾50 years showed improvement in CFT but no gain in BCVA.
Adverse effects associated with intravitreal bevacizumab in myopic eyes have not been reported so far. Lynch and Cheng reviewed 7113 bevacizumab injections to treat different conditions, reporting <0.21% adverse events.26
The use of intravitreal anti-angiogenic drugs to treat myopic CNV involves some specific risks in addition to those inherent to any intravitreous injection. First, the presence of degenerative lesions and peripheral vitreoretinal adhesions may increase the chance of retinal tears or detachments associated with the procedure, as occurs in other surgical procedures such as phacoemulsification and refractive surgery.27 28 However, the frequency of retinal detachment after intravitreous bevacizumab seems to be very low. One case of retinal detachment has been reported following intravitreal bevacizumab in a myopic patient.29 Wu et al have recently reported one rhegmatogenous retinal detachment in a series formed by 4303 intravitreal injections of bevacizumab on 1310 eyes, for conditions such as proliferative diabetic retinopathy and CNV of several aetiologies, after 1 year follow-up (frequency 0.02%).30 In addition, the use of anti-angiogenic drugs among younger patients, many of them women of child-bearing age, increases the concern about teratogenic effects. No form of contraception or combination of contraception would prevent a pregnancy in 100% of cases in a woman of child-bearing age who is sexually active. This point should be made clear to every woman who is receiving bevacizumab, as well as the advantages and side effects of other therapeutic procedures to treat myopic CNV.
On the other hand, the advantages of this therapy compared with intravitreous triamcinolone associated with PDT are lower risk of cataracts and glaucoma, as well as less atrophic changes on the macular RPE.
The number of intravitreal injections needed to achieve CNV closure in highly myopic eyes is not known. The results from the prospective OCT study with Lucentis for Neovascular AMD (PrONTO) clinical trial on exudative age-related macular degeneration (AMD) suggest that less frequent injections adjusted by OCT follow-up may be enough.31 However, accurate determinations of CNV activity are difficult to obtain due to the poor quality of OCT examinations in highly myopic eyes and the fact that myopic neovascularisation is usually not associated with frank subretinal fluid.14 We performed three consecutive bevacizumab injections in order to achieve complete CNV inactivation and prevent early recurrences, following a schedule that has been previously reported in other series.14 24
Another unknown issue is the need to adjust the dose of intravitreal bevacizumab in myopic eyes. The vitreous volume of the highly myopic eye may be up to twofold greater than that of an emmetropic eye, implying that the final intravitreous concentration of the injected drug may be much lower than that usually achieved in normal eyes.
Intravitreal bevacizumab seems to be a useful procedure to treat CNV associated with high myopia, as a first line therapy. Special care should be taken with highly myopic patients with peripheral retinal degenerations predisposing to retinal tears and detachments, as well as with women of child-bearing age.
Randomised clinical trials comparing this therapy with PDT, and longer follow-up studies, are needed to evaluate the efficacy of this therapy and the safest injection regimen. Presently, two randomised clinical trials to evaluate the efficacy and safety of intravitreal bevacizumab to treat non-AMD CNV and including myopic CNV (NCT00407719 and NCT00370786) are registered in the ClinicalTrials.gov registry.
Funding: This study was supported in part by a grant of the Spanish Ministry of Health, Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa en Salud “Patología ocular del envejecimiento, calidad visual y calidad de vida” (RD07/0062).
Competing interests: None declared.
Ethics approval: Approval for this treatment was obtained from the National Ministry of Health. Individualised approval from the National Ministry of Health was obtained prior to the procedure. This study was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki.
Patient consent: Obtained. Patients were informed about the off-label situation of this therapy and women of child-bearing age were also informed about the possible risks of pregnancy and in utero exposure.
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