|Year : 2019 | Volume
| Issue : 1 | Page : 9-15
Timing of phacoemulsification in relation to intravitreal ranibizumab injection in diabetic patients type 2 with cataract and mild center involved macular edema
Nehal M Samy El Gendy, Dina El-Fayoumi
Department of Ophthalmology, Kasr Al Ainy Medical School, Cairo University, Giza, Egypt
|Date of Web Publication||14-Aug-2019|
Dr. Nehal M Samy El Gendy
43 Gameat El Dewal El Arabia Street, El Mohandeseen District, 12416 Giza
Source of Support: None, Conflict of Interest: None
Purpose: To compare preoperative ranibizumab (RBZ) 0.5 mg/0.05 ml three-injection protocol to postoperative protocol in cases with center involved macular edema (CiME), undergoing phacoemulsification. Patients and Methods: Cases with non-ischemic clinically significant diabetic macular edema (CSDME) were randomized into two groups. Both groups received three intravitreal RBZ injections on monthly basis. Group 1, received the first two injection 2 months before phacoemulsification and the third one was injected intraoperative by the end of surgey. Group 2 received the first injection intraoperatively followed by 2 other injections, 1 and 2 months postoperatively. Central subfield thickness (CST) was measured using spectral-domain optical coherence tomography (RTvue-100), 1 month after third injection for both groups. Results: The mean postoperative corrected distance visual acuity (CDVA) at 3 months postoperatively was significantly improved (P = 0.005) in Group 1 than in Group 2. The postoperative CST 1 month after the third injection for Group 1 was 252.5 μm ± 16 versus 270.1 μm ± 24.4 for Group 2, which was statistically significant (P = 0.02). Percentage of reduction in central foveal thickness (CFT) was 15.4% and 8%, Groups 1 and 2, respectively. The ellipsoid zone integrity showed Interruption in Group 1 in 19.4% of eyes, which was lower than in Group 2 (28%), however this was not statistically significant (P = 0.4). None of our cases developed epiretinal membranes in either groups. In Group 2 only, four cases developed subretinal fluid (SRF), and one case had cystoid changes. None of the cases developed SRF or de novo cystoid changes, till the last follow-up visit, in Group 1. Conclusion: Using RBZ repeated intravitreal injections protocol prior to phacoemulsification improved significantly CDVA and reduced the CST, than when injected postoperatively. In addition, the number of postoperative intravitreal injections that might be needed was significantly reduced when it is used preoperatively.
Keywords: Central foveal thickness, clinically significant diabetic macular edema, intravitreal, macular edema, phacoemulsification, ranibizumab
|How to cite this article:|
Samy El Gendy NM, El-Fayoumi D. Timing of phacoemulsification in relation to intravitreal ranibizumab injection in diabetic patients type 2 with cataract and mild center involved macular edema. Egypt Retina J 2019;6:9-15
|How to cite this URL:|
Samy El Gendy NM, El-Fayoumi D. Timing of phacoemulsification in relation to intravitreal ranibizumab injection in diabetic patients type 2 with cataract and mild center involved macular edema. Egypt Retina J [serial online] 2019 [cited 2019 Nov 15];6:9-15. Available from: http://www.egyptretinaj.com/text.asp?2019/6/1/9/264520
| Introduction|| |
Diabetic macular edema (DME) and cataract are considered the main causes of decreased vision in patients with diabetic retinopathy (DR). In addition to this, diabetes mellitus (DM) has been linked to increased risk of postoperative ME. Some studies calculated the incidence of ME on optical coherence tomography (OCT) to be 22% in patients with diabetes undergoing cataract surgery., However, Shah and Chen suggested that there was no clear evidence that phacoemulsification surgery could cause progression of DME, especially in patients with low-risk or absent DR or in those with controlled retinal disease.
To lower the possible risk of ME worsening after phacoemulsification, preexisting DME is often treated prior to surgery. After publication of the Early Treatment DR Study (ETDRS), laser photocoagulation became the standard line of treatment for clinically significant DME (CSDME). CSME is defined as thickening of the retina at or within 500 microns of the center of the macula, hard exudates at or within 500 microns of the center of the macula, if associated with thickening of adjacent retina, or a zone or zones of retinal thickening 1 disc area or larger of which any part is within 1 disc diameter of the center of the macula.
Afterward, The Diabetic Retinopathy Clinical Research Network reported improved visual acuity outcomes noticed in patients with center involved DME who were treated with intravitreal ranibizumab (RBZ) with either immediate or deferred laser, compared to patients treated with prompt laser alone.
Debates remain regarding treatment of the cohort of eyes with central-involved DME. Whether eyes with central-involved DME and good vision do better with anti-vascular endothelial growth factor (VEGF) therapy initially, or focal/grid laser treatment or observation initially followed by anti-VEGF only if vision worsens, is still not known. Results from DRCR.net Protocol I suggest that anti-VEGF therapy will be effective at reducing retinal thickening, but it is uncertain whether this will translate into a value in visual acuity outcomes that outweighs the risks associated upon multiple injections. In cases with cataract the challenge is even more, as visual acuity reduction cannot be ruled out to be related to macular edema or not. It is also unknown how long eyes with central-involved DME and good vision maintain vision of >20/25 without intervention, especially if the eye is exposed to cataract surgery.
In a study conducted by Patel et al., they reported that VEGF levels in the aqueous humor increased as early as the first day following phacoemulsification and normalized by 1 month in patients with diabetes. Since then, several studies had been conducted using different anti-VEGF agents such as pegaptanib sodium, bevacizumab, and RBZ., A detailed analysis of phase 3 clinical trials had generated evidence-based guidelines for using RBZ for the treatment of DME. RBZ, a human monoclonal antibody that is known to inhibit all VEGF-A isoforms.
Prophylaxis of DME after cataract surgery with intravitreal RBZ in patients with DR has been shown in previous studies, although, owing to the short half-life, the effect is transient and could show individual changes.,
In our study, RBZ was injected before phacoemulsification in one group and after in the second group of patients with mild center involved macular edema (CiME), and studied the macular thickness and morphology by OCT preoperative as well as after the third injection. We aimed to compare the efficacy of preoperative versus postoperative intravitreal RBZ injections for early CiME in patients who has to do cataract surgery.
| Patients and Methods|| |
This study was conducted in accordance with the Declaration of Helsinki. Protocol was revised and approved by our Ophthalmology ethical committee. All the patients provided an informed consent. A prospective, randomized, comparative, interventional study was conducted on patients with nonischemic CiME and cataract performed by the same surgeon (N. E) in the period from June 2015 to June 2017.
Cases with non-ischemic CiME with cataract indicated for surgery were recruited from retina clinic and randomized into two groups (Randomization was envelope based, through sealed envelopes). Ischemia was diagnosed by fundus fluorescein angiography (FFA) as enlarged or irregular foveal avascular zone. Group 1, the first dose of intravitreal injection of RBZ 0.5 mg/0.05 ml, started 2 months pre-cataract surgery, second dose was injected 1 month before cataract surgery and third dose during cataract surgery session.
Group 2, received intravitreal RBZ 0.5 mg/0.05 ml injection, starting first dose intraoperative by the end of phacoemulsification. Then received the 2 other injections 1 and 2 months following the surgery. SD-OCT RTvue machine (model RT100, optovue, Inc., Fremont, CA, USA) scans were done at baseline and then 1 month after last injection and three months post-cataract surgery (with total of at least two scans for Group 2 and three scans for Group 1). Patients then were injected (Pro Re Nata) till central foveal thickness (CFT) was ≤250 μm (Protocol 1) or no reduction in CFT after last injection. FFA was done once at the beginning of the study to exclude ischemic cases.
Cases with significant (nuclear grade 2 or more, cortical or posterior subcapsular) cataract indicated for surgery, yet allowing proper visualization for spectral-domain OCT (SD-OCT) scanning were included. Age between 50 and 60 years old with type 2 DM. Cases with controlled blood sugar level only were included (hemoglobin A1c [HbA1c] <8). Patients with normal lipid profile only were included. Cases with central subfield thickness (CST) 275 μ in women, and 290 μ in men were include d. Mild cases were only included with max CST of 350 μm. This is rather an early treatment study for mild cases of macular edema. Severe cases with cataract allowing proper OCT scanning may be an indication of preoperative 3 injections. We did not want to expose cases with high edema to surgery before stabilization of retinal condition.
The following were excluded – Ischemic maculopathy (based on FFA), proliferative DR, corneal opacity, glaucoma and uveitis. Age related macular degenerations and cases with previous macular treatment were also excluded. Cases with scans showing epiretinal membrane (ERM) or subretinal fluid (SRF) preinjection were excluded. This was done for better comparability between the two groups and as mentioned before we only included mild cases. ERM may be an indication of surgery and may create bias according to its mechanical effect, extent, thickness and duration.
Spectral-domain macular optical coherence tomography scanning
Spectral-domain OCT (SD-OCT) imaging of the macula with the RTvue-100 SD-OCT (algorithm version 22.214.171.124) (Optovue, Inc., Fremont, CA, USA). Each scan is 7 mm long on the horizontal axis. Each B-scan is made of 385 A scans (one A-scan every 0.018 mm). The software determines automatically inner retinal surface. Presence of ERM, SRF and subfoveal ellipsoid zone (EZ) were evaluated. Macular map 5 mm (MM5): CSFT defined as average retinal thickness of 1 mm of central scanned area, using macular cube (MM5) in which 5 mm × 5 mm grid centered on fixation, grid spacing was 0.25 mm in inner 3 mm × 3 mm area and 0.5 mm in outer area. Seventeen horizontal then 17 vertical line scans centered at fovea.
Patients' demographic data, including age and sex were recorded. Complete ophthalmological examination was done. This included: corrected distance visual acuity (CDVA) in LogMAR, slit-lamp examination, intraocular pressures (IOP) applanation measurement, and dilated fundus examination using binocular indirect slit-lamp biomicroscopy.
All cases were done under local anesthesia. Patients' eyes were prepped and sterilized, 2.4 mm microkeratome clear corneal incision was done. Two corneal stab wounds were done using 20 gauge MVR blades. Capsulorhexis was done followed by hydro-dissection and divide and conquer phacoemulsification of the nucleus. After irrigation aspiration removal of cortical matter, foldable single piece intraocular lense (IOL) was implanted in the bag.
All cases received topical antibiotics and steroids that were tapered gradually over 4 weeks postoperative period. No nonsteroidal anti-inflammatory eye drops were prescribed.
Eyes were sterilized and prepped as usual. Phakic cases were injected 4 mm from the limbus, while pseudophakic cases were injected 3 mm from the limbus. All patients received intravitreal RBZ 0.5 mg/0.05 ml.
Postinjection treatment included combined steroid/antibiotic eye drops for 5 days.
Data management and analysis were performed using SPSS version 16 (Statistical Package for the Social Sciences, SPSS Inc., Chicago, IL, USA). Numerical data were summarized using means and standard deviations. Categorical data were expressed as frequency and percentage. Comparisons between groups with respect to numeric variables were done by the Student's t-test. The Chi-square was used to compare between the groups with respect to categorical data. All P values are two-sided. P <0.05 were considered significant.
| Results|| |
The study included 35 eyes of 29 patients in Group 1 and 35 eyes of 30 patients in Group 2. Six cases had one eye in either group. Only 26 cases (31 eyes) in Group 1 and 27 cases (32 eyes) in Group 2 completed the study and were included in statistical analysis. Mean patients' age ranged from 50 to 60 years old. Demographic data are summarized in [Table 1].
Corrected distance visual acuity
Mean preoperative CDVA was 0.8 ± 0.14 logMAR (6/24, 5/60) in Group 1, and 0.8 ± 0.12 logMAR (6/24, 6/60) in Group 2 (P = 0.64).
CFT thickness Group 1: Mean 298.5 ± 21.2, Group 2: 293.6 ± 16.9 (P = 0.3). There was no statistical difference at baseline.
Ellipsoid zone integrity
Interruption detected in 35.5% of eyes in Group 1, compared to 45.5% in Group 2, which was not statistically significant (P = 0.7)
All cases went uneventful surgery in both groups. No vital dyes were needed in any case. Foldable IOL was injected in the bag in all cases. All cases were done by the same surgeon (N. E).
Corrected distance visual acuity
Mean postoperative CDVA was 0.57 ± 0.2 logMAR (6/9.5, 6/60) in Group 1, and 0.71 ± 0.19 logMAR (6/12, 5/60) in Group 2 (P = 0.005).
Central subfield thickness thickness
Group 1: 252.5 ± 16.7 μm, group 2: 270.1 ± 24.4, the difference was statistically significant (P = 0.02). Percentage reduction in CSFT was 15.4% and 8%, Group 1 and 2 respectively. Three months post-phacoemulsification CSFT for Group 1 was 254.6 ± 20.5 μm the difference compared to Group 2 was still statistically significant (P = 0.01)
Ellipsoid zone integrity
Interruption in Group 1 was 19.4% of eyes, which was lower than in Group 2 (28%), however this was statistically not significant (P = 0.4).
none of the cases developed ERM in either groups.
Subretinal fluid and cystoid changes
Four cases developed SRF and one case had de novo cystoid changes in Group 2 only [Figure 1] and [Figure 2]. No cases developed SRF or de novo cystoid changes, till the last follow up visit, in Group 1.
|Figure 1: Changes in central subfield thickness at baseline (before first injection) and 3 months postinjection (1 month after the third injection) for both groups and 3 months post cataract surgery for both groups|
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|Figure 2: (a) Preoperative (above) and three months (below) postoperative spectral-domain optical coherence tomography horizontal scans of a patient in group 2, showing de novo cystoid changes. (b) Preoperative (above) and postoperative (below) scans of another patient from group 2 showing development of subretinal fluid|
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Average number of total injections (including the initial 3 injections) – For Group 1: 3.5 ± 0.7 injections, compared to Group 2, 3.9 ± 0.99 injections. The difference was statistically significant (P = 0.02).
Postoperative complications – one case in Group 2 developed post phacoemulsification inflammatory membrane that was controlled by medical treatment. No cases in either groups developed IOP spikes.
Average follow up duration: Last follow up visit was 10.19 ± 2.5 (6–16) months for Group 1, compared to10.15 ± 2.3 (7–14) months for Group 2. Group 1 cases did not need further injections within the first 3 months after the last injection.
Percentage of cases with dry retina (CST ≤ 250 μm) was 67.7% in Group 1 and 28.1% for Group 2. The final CST in the six cases with one eye in each group was as follows: Group 1 eyes had 243 ± 15 μm versus group 2 eyes with 286.6 ± 38.3 μm, the difference was statistically significant P = 0.03.
| Discussion|| |
The development of macular edema results from the breakdown of inner blood–retina barrier with subsequent release of endogenous permeability factors by an ischemic retina.,, DME is characterized by intraretinal and subretinal accumulation of fluid which is caused mainly from retinal vascular leakage., RBZ had been proven to play an important role in the treatment of DME. Ongoing studies are now focused on adjusting the recommended treatment regimen to determine the most effective treatment dose, frequency, and duration to optimize visual outcomes and safety.
In our study, visual outcome and CFT were assessed after the combination of phacoemulsification surgery and intravitreal RBZ in diabetic patients with cataract and clinically significant macular edema. We compared two regimens of intravitreal injections. Depending on RBZ as a monotherapy. The number of injections was 3 injections, on monthly basis. In Group 1, the patients started to receive the injections 2 months prior to surgery with the third injection was taken during the phacoemulsification. The second group received also, three injections starting the first injection intraoperative and continued other 2 injections 1 month and 2 months following the surgery.
It is known that significant cataract may impede the treatment and even diagnosis of CSDME.,
Previous studies suggested that diabetic patients with macular edema at the time of cataract surgery usually have poorer visual outcomes, caused by the progression of both retinopathy and maculopathy.,
The effect of phacoemulsification on the progression of DR was studied by Chung et al. and showed progression of retinopathy significantly more in the operated eye to which they related to preoperative CSME and poor renal function.
In general, short-time phacoemulsification surgery using a small self-sealed corneal incisions without iris trauma, and in-the-bag implantation of IOLs, usually don't cause DR to progress. A number of other patient factors such as older age, female sex, duration of DM, poor glycemic control with HbA1c at the time of surgery and moderate to severe retinopathy have been found associated with poor prognosis after cataract surgery in diabetic patients.,,
In our study phacoemulsification and in-the-bag intraocular lens implantation with a self-sealing corneal tunnel was the standard technique. The mean patients' age was 56.3.7 ± 2.3 years (50–60), with 11 females (35.5%), in Group 1, while in Group 2, it was 55.7 ± 3.1 years (50–60), with 14 females (43.75%). There was no statistically significant difference between the two groups with regard to age (P = 0.4) and sex (P = 0.57), the patients were in good glycaemic control.
The ETDRS showed a significant benefit of focal macular laser photocoagulation for eyes with CSDME. In an effort to improve anatomic and visual outcomes in the treatment of DME with grid laser photocoagulation, researchers have thought of other treatment options like intravitreal injection of corticosteroids.,
Previous studies used triamcinolone before cataract surgery both as a separate procedure and intraoperative. These studies demonstrated improvements in the visual acuity and ME.,,,, But giving intravitreal triamcinolone (IVTA) before surgery as a separate procedure had several complications such as the potential for progression of lens opacities which may impede laser photocoagulation in CSDME.
Combining cataract surgery with IVTA rather than giving triamcinolone before surgery as a separate procedure avoided the risk for progression of lens opacities as well as IOP elevation associated with intraocular steroids which could have further interfered with retinopathy assessment. Also combining the two procedures reduces the patient's potential risk of endophthalmitis from two separate intraocular episodes to one, while at the same time offering improved patient convenience.,
Results from different studies indicate that cataract surgery with injection of IVTA may be performed safely with significant improvement in BCVA postoperatively.,, But Ahmadabadi et al. showed that its injection after phacoemulsification had no effect on visual acuity.
The use of Anti-VEGF drugs was proven to have a role in treating coexisting DME in cataract patients undergoing surgery. Patel et al. measured VEGF levels in 7 diabetic patients following phacoemulsification. They found a 10-fold increase at postoperative day 1, and by the end of first month, VEGF levels showed a significant reduction (2.5-fold). Krohne et al. found that the half-life of RBZ in human aqueous humor was 7.19 days and Muether et al. reported a therapeutic effect lasting 33.7 ± 5.1 days for intraocular RBZ.,
Chen et al. reported significant visual improvement and FT reduction after intraoperative bevacizumab injection in 15 patients. Akinci et al. found similar results, but they added grid laser photocoagulation at the first postoperative month. Contradictory to these results, Cheema et al. did not notice any significant improvement in FT and VA during their 6 months of follow-up. Though widely used all over the world, bevacizumab is still an off-label drug for the treatment of DME.
The effect of RBZ on DME in patients undergoing cataract surgery has been shown in a small number of studies. None of these studies compared the preoperative repeated (3 injections) protocol to postoperative injections. Hence in our study we chose to use RBZ as an anti-VEGF and giving it three times due to its short duration of action and to compare its effect on the CFT and visual acuity when given before the cataract surgery to the result of it being given after the surgery.
Rauen et al. used RBZ injected intraoperatively in 11 patients with refractory DME undergoing phacoemulsificetion; however, there was no control group in their study. The authors reported improvement of the CDVA at 4, 8, and 12 weeks following cataract extraction. Six patients required additional macular laser photocoagulation due to increased FT at 4 weeks. No significant difference in FT postoperatively was found which was linked to the refractory nature of the ME.
Chae et al. investigated the effect of intraoperative RBZ following cataract surgery in 76 DR patients not known to have any ME. 39 patients in the phacoemulsification group and 37 patients were controls. There was no significant difference in FT or BCVA postoperatively at 6 months. Only total macular volume significantly differed in RBZ patients.
In our study, the Mean postoperative CDVA at 3 months postoperatively was significantly improved in Group 1 than in Group 2 (P = 0.005). The postoperative CFT thickness 1 month after the third injection Group 1 was 252.5 μm ± 16 versus 270.1 μm ± 24.4 in Group 2. Which was statistically significant (P = 0.02). Percentage reduction in CFT was 15.4% and 8%, Group 1 and 2 respectively. The EZ integrity (EZI) showed Interruption in Group 1 in 19.4% of eyes, which was lower than in Group 2 (28%), however this was statistically not significant (P = 0.4). None of our cases developed ERM in either groups. Four cases developed SRF and de novo cystoid changes in Group 2 only. No cases developed SRF or de novo cystoid changes, till the last follow up visit, in Group 1. This may show the potential role of preoperative regimen as a prophylaxis against postoperative cystoid ME which may worsen CiME.
Group 1 required an average of 3.5 ± 0.7 injections to reach a baseline CFT, whereas to Group 2, 3.9 ± 0.99 injections. The difference was statistically significant (P = 0.02). There were no laser treatments during the follow-up period.
In a study by Yumuşak and Örnek, the authors compared pre-, intra-, and postoperative RBZ injections for DME in patients undergoing cataract surgery. Visual acuity was found to be significantly improved in three injection groups, but the CFT increased in all groups after surgery, although this increase was less marked in patients who were treated with intra-and postoperative RBZ injection. There were no laser treatments during the follow-up period. Intergroup comparisons did not show any significant differences for BCVA and FT.
The authors concluded that Intravitreal RBZ injection did not seem to have a significant effect on postoperative ME following cataract surgery in DR patients. However these results which were contradictory to our results could be explained by that they used a single injection whereas in our study we used repeated injection.
Our study showed that lowering the level of VEGF by 3 repeated injections prior to surgical insult and interference is recommended. This could be applicable also with other intraocular procedures; however, this was beyond the scope of our study. Strict control of intravitreal level of VEGF may be as important as well as blood glucose, blood pressure and cholesterol level control in blood before surgery.
| Conclusion|| |
Macular oedema after cataract surgery in diabetic patients may be the consequence of cataract surgery, existing DR, or both, but it is typically difficult to differentiate between the two causes. Using RBZ repeated intravitreal injections protocol before the cataract surgery significantly results in improvement of CDVA and reduction of the CFT than using it postoperatively. In addition the number of postoperative intravitreal injections that might be needed to reach a baseline FT is significantly reduced when it is used preoperatively.
Our study was limited by the absence of a control group without intravitreal RBZ injection, and the relatively small sample size. Also, we need to test the level of VEGF in these patients. Although we did not encounter any case of endopthalmitits in our study, still repeated injections may carry the risk of infection.
Sample size was a limitation in our study. The study involved cases with mild edema as those cases are more debatable than those with more severe edema, were preoperative treatment could be more advised.
Further studies with longer follow-up periods and larger groups are needed to confirm the efficacy of RBZ as a monotherapy in the treatment of DME in patients undergoing cataract surgery.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]