Intravitreal Injection of Ranibizumab in Macular Edema Secondary to Retinal Vein Occlusion

Aim: This study aimed to evaluate the safety and efficacy of intravitreal Ranibizumab 0.5mg in the treatment of macular edema secondary to retinal vein occlusion. Patients & Methods: This was a prospective interventional analytical study included 39 eyes of 39 patients with retinal vein occlusion. Ophthalmic examination included assessment of visual acuity, measurement of intraocular pressure, and fundus examination. All patients were scanned using Swept source optical coherence tomography (3D DRI OCT Triton [plus], Topcon Corporation, Tokyo, Japan) to assess central macular thickness. The changes of visual acuity, IOP, and central macular thickness were assessed. Data were analyzed via Kolmogorov-Smirnov test and Wilcoxon signed rank. Results: The mean age was 56.56 ± 9.6, 48.7% were male and 51.3% were females. Hypertension was detected in 69.2%, and hyperlipidemia in 2.6%. The mean best corrected visual acuity was 1.5 logMAR, 1.00 logMAR,1.00 logMAR, preoperative, fourth month, six months postoperative, respectively, (p<0.001). The mean central macular thickness was 675 µ, 306 u, 264 u, preoperative, fourth month, six months postoperative, respectively, (p< 0.001). The OP was 16.5 mmHg, 16.9 mmHg, 17.1 mmHg, preoperative, fourth month, six months postoperative, respectively, (p=0.423). There were no observed significant ocular adverse events such as ocular inflammation, sterile and infectious endophthalmitis, or sustained increase in intraocular pressure with the use of intravitreal ranizumab injections. Conclusion: as monotherapy have shown promising results with BCVA improvement and a decrease of central macular thickness in patients with macular edema secondary to retinal vein occlusion.


Introduction
Retinal vein occlusion (RVO) is the most common retinal vascular disease after diabetic retinopathy [1]. Depending on the area of retinal venous drainage effectively occluded it is broadly classified as either central retinal vein occlusion (CRVO), hemispheric retinal vein occlusion , or branch retinal vein occlusion (BRVO) [2]. Although the exact etiology of RVO remains elusive, it is likely to follow a thrombotic event. In CRVO this may occur in the central retinal vein (CRV) at the lamina cribrosa or at a variable distance in its journey within the optic nerve posterior to the lamina cribrosa [2]. Hypoxia-induced expression of vascular endothelial growth factor (VEGF) is thought to be a trigger for macular edema.
High intravitreal levels of VEGF have been found in patients with retinal vein occlusion [3]. Upregulation of VEGF is associated with breakdown of the blood-retina barrier with increased vascular permeability resulting in retinal edema, stimulation of endothelial cell growth, and neovascularization [4,5]. Macular edema leads to vision loss in many patients with either central or branch retinal vein occlusions (CRVO or BRVO). BRVO is the more common of the two presentations, accounting for approximately 80% of RVO [6].

Study Population
This was a prospective interventional analytical study conducted at Mansoura ophthalmic center, Mansoura university. The study protocol approved by medical research ethics committee, faculty of medicine, Mansoura University (code number: MS/16.02.108).
Informed consent was obtained from each participant in the study after assuring confidentiality.

Inclusion criteria
Included patients older than 18, both gender, patients with clinically significant macular edema secondary to retinal vein occlusion and central macular thickness (CMT) was > 250 um by optical coherence tomography.

Exclusion Criteria
Included patients with macular scar, macular hole, uveitis, neovascular glaucoma, age related macular degeneration, diabetic macular edema, patients had undergone treatment for macular edema secondary to retinal vein occlusion triamcinolone and vitrectomy. Also, patient has relevant malignant systemic disease, and media opacity that does not permit optical coherence tomography acquisition with good signal strength were excluded.

Ocular Examination
All subjects underwent an ophthalmic examination including assessment of visual acuity using Snellen chart at 6 meter distance and converted to log MAR, anterior segment evaluation using slit lamp biomicroscope (Haag Streit BP 900) (Haag-Streit, Koeniz, Switzerland), refraction using auto-refractometer (Topcon , KR-800), intraocular pressure (IOP) measurement using Goldman applanation tonometry, Fundus examination using slit lamp bio microscopy using non-contact Volk lens +78 D or +90 D, Ocular coherence tomography imaging for CMT (central macular thickness). The steps of scanning were done as follows, Mydriatic ( tropicamide 1%) eye drop used to achieve a pupil dilatation to assure maximal OCT signal and analysis in patients prior to OCT examination. The patient's chin was positioned in the chin rest. The patient was asked to fixate on a target point inside the instrument the phase is completed by a camera, located inside the instrument that displays the fundus and scan beam. After the patient scanning was finished, analysis protocol was used to obtain circular maps on the macula.

The steps of OCT imaging were done as follows:
• Mydriatic eye drops Swixolate (Cyclopentolate Hydrochloride 10mg/ml CHEMIPHARM) eye drops three times within 30 minutes were used to achieve as much pupil dilatation as we can to assure maximal OCT signal and analysis in patient's eyes prior to OCT examination.
• The patient's chin was positioned in the chin rest.
• The patient was asked to fixate on a target point inside the instrument the phase is completed by a camera, located inside the instrument that displays the fundus and scan beam.
• After the patient scanning was finished, analysis protocol was used to obtain circular maps on the fovea ( Figure 1).

Treatment protocol
Ranibizumab (0.5mg, 0.05mL) was injected intravitreally under complete sterile conditions via the pars plana once monthly for 3 months.

Treatment procedure
Intravitreal injections were carried out, under aseptic conditions at mansoura ophthalmic center operating theater.

Preoperative preparation
Prophylactic topical antibiotic (Vigamox ED Q.I.D) on the day before the operative day. Pupil dilatation: One hour before surgery the pupil was dilated with cyclopentolate Hcl 1% every 10 minutes for half an hour preoperatively.

Follow Up
Follow-up was one day and one week after injection and then every month for six months.

Outcomes
Outcomes included BCVA (functional response) and central foveal thickness (anatomical response),IOP and complications.

Statistical analysis
Data were analyzed with Statistical Package for the Social Sciences (SPSS) software package version 24.0 (Armonk, NY.IBM Cor).The normality of data was first tested with one-sample Kolmogorov-Smirnov test. Qualitative data were described using number and percent. Parametric data (normally distributed data) were described as mean (SD), non-parametric (non-normally distributed data) were described as median. Wilcoxon signed rank (for non-parametric data) was used to compare change within the same group pre and postoperative injection. P Level is considered statistically significant <0.05.

Result
Thirty-nine ( 5). Correlation coefficients and P values for 6 th month postoperative BCVA and independent variables was calculated. Variables that had 6 th month best corrected visual acuity is significantly correlated with preoperative and 4 th month BCVA. Also significantly correlated to the 6 th month central macular thickness (Table 5).

Ocular side effects
There were no observed significant ocular adverse events such as ocular inflammation, sterile and infectious endophthalmitis, The breakdown of the BRB mediated by VEGF [9] and that intraocular levels of VEGF in the eyes with RVO are elevated [10].
The response to different anti-vascular endothelial growth factor treatments is not the same among patients despite they receive the same regimen [11]. Why some patients respond positively to treatment while the others do not is still a mystery. Studies have investigated and reported on factors such as age [12] smoking [13], and Genetic factors [14,15]. This was a prospective interventional study concentrated on short term visual and anatomical improvement after three loading doses of intravitreal with a mean BCVA improvement as well as a decrease of central macular thickness [16]. Identifying predictive factors for good and poor visual outcomes with anti-VEGF therapy allows for more accurate prediction of prognosis based on the patient's baseline characteristics [17]. In the present study, after three loading doses, mean best corrected visual acuity improved from log MAR 1.5 to 1.00 (p < 0.001). This is in agreement with studies [18][19][20][21][22][23]. There was significant reduction in central macular thickness from 675µ at baseline to 306 µ at first month follow up (p < 0.001) and to 264 µ at third month follow up (p=0.77) .This is an agreement with studies [18][19][20][21][22][23]. The present study found that ranibizumab is effective in improvement central macular thickness and best corrected visual acuity of the patients and the main improvement is statistically patients were sustained in the months following the 6-month treatment period [21]. Pielen et al. [18] found that BCVA was reported from the baseline to follow-up at month 6 the results revealed that treatment with IVR 0.5 mg significantly improved BCVA, compared with non-anti-VEGF (P < 0.001) at six months. CMT is considered to be a strong prognostic measure for ME levels. At six months, CMT was significantly decreased (P < 0.001) and this also agrees with the present study. Campochiaro et al. [10] found that at the primary endpoint in patients with macular edema due to RVO, the median change in visual acuity from baseline was 10 letters in 18 in the 0.5mg dose group. One patient in the 0.5mg dose group showed a reduction in VA of three letters at the primary endpoint, but all other patients showed improved vision. They also found that there was no correlation between the amount of improvement in VA and patient age as found in the current study. Wolf-Schnurrbusch et al. [20] revealed that the response to ranibizumab at four weeks after the first anti-VEGF injection, mean BCVA ranged from 20 to 86 letters (mean, 53 ± 17 letters).These results tunes with our results which explain that the main response of ranibizumab at one month after injection. Puche et al. [19] made the patients received a mean of Pielen et al. [18]  showing functional and anatomical improvement after intravitreal ranibizumab for 6 months and 12 months in many studies as [21][22][23][24]. In the present study presence of systemic risk factor or the age had no statistically significant correlation with patient response to the treatment .That was also found in many studies as in [18,22]. In the current study no, significant ocular adverse effects occurred such as endophthalmitis, cataract ,retinal detachment and increase IOP, or systemic arterial thromboembolic events. This is consistent with Spaide et al. 2009 [24]. The BRAVO study assessed the safety and efficacy profile of Lucentis® in a total of 397 patients with macular edema following BRVO showed sustained vision improvement during the six-month study, with an effect seen as early as seven days and a benefit nearly maintained throughout the 12 months of follow-up [16]. BRIGHTER and CRYSTAL studies reported that a rapid and statistically significant decrease from baseline in central macular thickness was observed at one month and maintained up to month 24. The effect of ranibizumab treatment was similar irrespective of the presence of retinal ischemia. In BRIGHTER, patients with ischemia present (N=46) or absent (N=133) and treated with ranibizumab monotherapy , at Month 24. In CRYSTAL, patients with ischemia present (N=53) or absent (N=300) and treated with ranibizumab monotherapy . The long-term safety profile of ranibizumab observed in the 24-month studies is consistent with the known Lucentis safety profile [25,26].