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ORIGINAL ARTICLE
Year : 2013  |  Volume : 1  |  Issue : 3  |  Page : 37-44

Evaluation of the effect of intravitreal ranibizumab on choroidal thickness in eyes treated for diabetic macular edema


Department of Ophthalmology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Date of Web Publication1-Nov-2014

Correspondence Address:
Ahmed Mahmoud Abdel Hadi
Lecturer of Ophthalmology, faculty of Medicine, Alexandria University 24 FawzyMoaz Street, Safwa 5, Entrance 2, Alexandria
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2347-5617.143447

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  Abstract 

Purpose: To evaluate the effect of intravitreal Ranibizumab on central choroidal thickness (CCT) in eyes treated for diabetic macular edema (DME). Materials and Methods: This prospective non-randomized interventional cohort study included 20 eyes of 20 diabetic patients, recruited between March 2013 and March 2014. Eyes with DME (thickness from 290 to 600 μm) underwent intravitreal injection of Ranibizumab (three consecutive injections, 1 month apart). Prior to injection, all patients had a complete ophthalmic examination, including manifest refraction, slit-lamp bio-microscopy, intraocular pressure measurement, and a detailed fundus examination. Prior to injection and 1 month from the third injection, the central macular thickness and CCT were assessed again by SD-OCT. After each injection, patients were followed to diagnose and treat any complications from injections. Results: Twenty eyes of 20 diabetic retinopathy (DR) patients, 9 females and 11 males with a mean age of 49.7 ± 4.1 years, were included. The pre-injection mean CCT was 234.35 ± 38.36 μm. In the NPDR group, it was 238.2 ± 41.36 μm; and in the PDR group, it was 228.5 ± 35.26 μm. This was not significantly different (P = 0.851). After injections, the mean CCT in all patients, in the NPRD group and in the PDR group showed a decrease to 215.5 ± 39.08, 224.9 ± 40.72 and 201.31 ± 34.02 μm, respectively (P = 0.362). There was a statistically significant difference between the pre-injection and the post-injection CCT (P < 0.001). The improvement in the CCT after treatment was not significantly correlated with the pre-injection CCT or the pre-injection CMT (P = 0.346, P = 0.096 respectively). No significant correlation was found between post-injection CCT and CMT in all patients (P = 0.436) or in the different groups separately (P = 0.191, P = 0.817, respectively). No injection-related complication was observed in either group. Conclusion: Intravitreal injection of Ranibizumab was effective in significantly decreasing the CCT as well as the CMT after three consecutive injections, 1 month apart regardless of the level of DR. Whether the number of injections can influence the amount of this reduction or not should be evaluated in future studies. No correlation was found between the reduction in CMT and that of the CCT after intravitreal injection with 0.5 mg of Ranibizumab.

Keywords: Central choroidal thickness, diabetes mellitus, diabetic macular edema, diabetic retinopathy, intravitreal Ranibizumab, optical coherence tomography


How to cite this article:
Hadi AM. Evaluation of the effect of intravitreal ranibizumab on choroidal thickness in eyes treated for diabetic macular edema . Egypt Retina J 2013;1:37-44

How to cite this URL:
Hadi AM. Evaluation of the effect of intravitreal ranibizumab on choroidal thickness in eyes treated for diabetic macular edema . Egypt Retina J [serial online] 2013 [cited 2022 Jan 18];1:37-44. Available from: https://www.egyptretinaj.com/text.asp?2013/1/3/37/143447


  Introduction Top


Diabetic macular edema (DME) is the major cause of visual loss in patients with DR. The incidence of DME after 10 years of follow-up has been reported to be 20.1% in type 1 diabetes, 25.4% in type 2 insulin-dependent diabetes, and 13.9% in type 2 non-insulin-dependent diabetes. [1] The development of macular edema and proliferative diabetic retinopathy (PDR) are major causes of visual impairment.[2]

Several studies of eyes with DR suggested that abnormality of the choroidal vasculature in diabetes may play a role in the pathogenesis of DR. [3],[4] A histopathologic study showed vascular abnormalities in the choroidal layer in patients with diabetes, namely choriocapillaris obstruction, vascular degeneration, choroidal aneurysms, and choroidal neovascularization. [5],[6]

To date, there are few studies on choroidal angiopathy in diabetes. This is because of the difficulty of imaging the choroid in vivo. Indiocyanine green angiography reveals both hyper- and hypofluorescent spots in diabetic eyes although the significance is unknown. [7],[8] These hypofluorescent spots have been proposed to be secondary to the presence of choroidal neovascularization and intra-choroidal microvasculature abnormalities [4],[5],[7] also they might be ischemic changes of the choroidal vessels and represent either a dye filling delay or a defect of the choriocapillaris. [9]

The risk factors associated with diabetic choroidopathy include the presence of severe DR, poor glycemic control, and the nature of the treatment regimen. [4] Changes in choroidal blood flow in diabetes have also been studied; pulsatile ocular blood flow is increased in non-proliferative retinopathy (NPDR) and decreased in treated PDR. [10]

The adequate visualization of the choroid using optical coherence tomography (OCT) has not been possible until recently, owing to its posterior location and the presence of pigmented cells that attenuate the incident light. Recent reports showed successful examination and measurement of choroidal thickness (CT) in normal and pathologic states using the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany) and Cirrus HD-OCT (Carl Zeiss MeditecInc, Dublin, CA) spectral-domain OCT instruments. [11],[12],[13]

A study by Spaide [14] suggests that DR patients have a reduced subfoveal CT when compared with normal healthy controls. Considering the previous results, we evaluated the effect of the new DR treatments on CT, namely intravitreal Ranibizumab, which is being increasingly used in DME. [15]


  Materials and Methods Top


This prospective non-randomized interventional cohort study included 20 eyes of 20 diabetic patients, presenting between March 2013 and March 2014. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The research protocol was approved by the Ophthalmology Department, Alexandria University Institutional Review Boards and Ethics Committees. Explanation about the nature of the study was given to the subjects in clear, understandable words. All patients provided a written informed consent.

Patients were included in the study regardless of the type of leakage on fluorescein angiography (FA) and independent of their visual acuity. We included cases with DME with a central retinal thickness ranging from 290 to 600 μm as determined by OCT. As for the metabolic control of the included patients, all patients had HbA1c in the range of 6-7.5, which was identified by the treating physician as a sign of fair to good control of diabetes. All patients suffered from type 2 diabetes mellitus. Their ages ranged between 45 and 55 years. Exclusion criteria included eyes with previously treated DR, refractive error higher than ±3 diopters, and other retinal diseases (except DR),

e.g.: drusen, AMD, or retinal vein occlusion. Eyes with a history ocular hypertension or glaucoma (treated or untreated), ocular trauma or inflammation, or a history of any type of intraocular surgery (except cataract surgery) were also excluded. In addition, eyes were excluded when the fellow eye had a condition that were reported to have abnormal CT, such as central serous retinopathy, AMD. [13],[14]

Prior to injection, all patients had a complete ophthalmic examination, including manifest refraction, slit-lamp bio-microscopy, intraocular pressure measurement, and a detailed fundus examination. In the initial visit, all patients underwent spectral domain OCT (SD-OCT)-Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany. The chosen protocol was a high-resolution volume protocol, composed by 25 horizontal lines, 40 averaged B-scans (frames) each, covering an area of 30°X30° centered on the fovea. To improve choroidal visualization, images were acquired using the enhanced depth imaging (EDI) protocol, in which the OCT device is placed closer to the eye, such that an inverted image is obtained. The EDI function available in SD-OCT inverts the image again, enabling a correct visualization of the scan.

To measure central choroidal thickness (CCT), the vertical distance was measured manually at the fovea using the caliper tool in the OCT Heidelberg Eye Explorer software, from the hyper-reflective line of Bruch's membrane to the hyper-reflective line of the chorio-scleral interface. This was repeated at 250 microns nasal and temporal from the foveal center and again at 500 micron nasal and temporal from the foveal center. All these measurements were averaged obtaining what we designate as CCT. The central macular thickness (CMT), inside the 1-mm diameter circle centered to the fovea, was obtained automatically from SD-OCT.

Eyes with DME underwent intravitreal injection of (0.5 mg in 0.05 ml) Ranibizumab (three consecutive injections, 1 month apart).

After each injection, patients were followed to diagnose and treat any complications from the injections. One month after the third injection, the CMT and CCT were assessed again by SD-OCT.

Statistical analysis

Only one eye per subject was treated. Data were expressed as means ± standard deviation. Spearman rank correlation coefficient was used to evaluate the correlation between the CCT and CMT. A 5 level of significance was adopted. All data were collected on an MS-Excel 2010 spreadsheet (Microsoft Corporation, Redmond, WA, USA) and analyzed using SPSS 20.0 for Windows (SPSS Inc., Chicago, IL, USA).


  Results Top


Twenty eyes of 20 DR patients, 9 females and 11 males with a mean age 49.7 ± 4.1 years, were included. Of these patients, 12 eyes (60%) were included in the NPDR group, with a mean age of 50.08 ± 4.5 years. The other eight eyes (40%) were included in the PDR group, with a mean of age 49.1 ± 3.5 years. The difference between the means in the two groups as regards age was not statistically significant (P = 0.604). [Table 1] presents the demographic and clinical characteristics (means for pre-injection CCT, CMT and post CCT, CMT of both groups).
Table 1: Patients' clinical and demographic characteristics, CCT and CMT means pre-and post-injection of Ranibizumab

Click here to view


The mean CCT before injection representing the mean of all the nine CT measurements in the 1-mm diameter circle centered to the fovea [Figure 1] was 234.35 ± 38.36 μm. In the NPDR group, it was 238.2 ± 41.36 μm [Figure 2] and [Figure 3] and in the PDR group, it was 228.5 ± 35.26 μm. The difference between the two groups was not significantly different (P = 0.583).
Figure 1

Click here to view
Figure 2: Color and FA showing right eye with moderate NPDR. Pre-injection CMT: 390 microns and 1 month after the last injection with CMT of 257 microns, we manually calculated the CCT at the central fovea, 250 and 500 microns on either side of the central point, these measurements were averaged to get the CCT before and after injection as shown in the middle (pre-injection) OCT and bottom (post-injection OCT)

Click here to view
Figure 3: Color and FA of the left eye with mild NPDR, as shown from the pre-injection OCT (middle) post-injection (lower), the average CCT dropped with drop of CMT

Click here to view


After injections, the mean CCT in all patients, in the NPRD group and in the PDR group showed a decrease to 215.5 ± 39.08, 224.9 ± 40.72 and 201.31 ± 34.02 μm, respectively. Again the difference between the two groups was not statistically significant (P = 0.362).

There was a statistically significant difference between the pre-injection and the post-injection CCT (paired sample t test; P < 0.001).

The improvement in the CCT after treatment was not significantly correlated with the pre-injection CCT or the pre-injection CMT to that matter, [Figure 5]. (P = 0.346, P = 0.096, respectively).
Figure 4: Fluorescein angiography of the right eye of a patient with severe NPDR. Pre-injection OCT (middle) and thickness map (CMT: 463 microns), post-injection OCT (bottom) and thickness map (CMT =219 microns). It was noted here that the CCT (averaged) increased slightly in spite of marked drop of CMT post-injection

Click here to view
Figure 5: Left graph showing scatter dot between the CCT difference and the pre-injection CMT, while the right side graph showing the relation with the pre-injection CCT. These graphs show linear relationship, however they were not significantly correlated

Click here to view


This means that the improvement in the CCT (Mean ± SD = 18.85 ± 19.24 μm) after injection was not affected by the pre-injection thickness.

The mean CMT before injection in all patients, in the PDR and in the NPDR groups were 375.4 ± 71.9, 359.7 ± 43.7 and 385.8 ± 86.1 μm. The difference in the pre-injection means was not statistically significant (P = 0.385). After injections, the mean CMT in all patients, in the NPDR group and in the PDR group showed a decrease to 290.8 ± 42.6, 311 ± 49.7 and 277.3 ± 32.7 μm, respectively. Again the difference between the two groups was not statistically significant (P = 0.12).

Similarly, the mean pre-injection CMT was significantly different from the post-injection CMT (paired sample t-test; P < 0.001). The improvement of the CMT (Mean ± SD = 84.6± 70.4 μm) after injection was found to be significantly correlated with the pre-injection CMT (Spearman's rho: 0.613, P = 0.004).

No significant correlation was found between post-injection CCT and CMT when considering all patients (P = 0.436). In one case we found the mean CCT decreased after injection in spite of a significant increase in the post-injection CMT [Figure 4].

We then separately performed the same analysis for the NPDR and the PDR groups, again the improvement in CCT and post-injection improvement in CMT did not significantly correlate (P = 0.191, P = 0.817, respectively).

No injection-related complication was observed in any of the two groups during the follow-up period.


  Discussion Top


Diabetes is a metabolic disease affecting the systemic vasculature. Although the principal changes in diabetic eyes occur in the retinal vasculature, additional changes are also observed in the choroidal layer, an important vascular tissue that supplies blood to the outer retina. [16] Until recently, examination of the choroidal layer morphology in vivo has been hindered by the limitations of the first-generation OCT.

In the current study, we found the mean pre-injection CCT in the studied eyes to be 234.35 ± 38.36 μm. This was less than the mean CT measured in non-diabetic patients documented in other studies; it was 283.7 ± 84.1 μm in the work of Ikuno et al. [17]

Similarly, Regatieri et al. reported in 2012 by using the Cirrus high definition (HD)-OCT (Carl Zeiss Meditec, Inc., Dublin, CA), that CT decreases in eyes with DME and in eyes treated with scatter PRP (mean subfoveal CT was 232 ± 15 μm in normal eyes, 169.5 ± 14.7 μm in eyes with DME). [18] The mechanism of choroidal thinning in eyes with early DR remains unknown. Studies reported that thinning of the choroidal layer could be the result of vascular constriction or choriocapillaris loss secondary to hypoxia in association with early diabetic choroidopathy. [19],[20]

On the other hand, Kim et al. demonstrate that CT increases with the presence of DME, especially in eyes with serous retinal detachment. Eyes with DME had a mean sub foveal CT of 311.6 6 99.7 μm, and in those without DME, the mean sub foveal CT was 274.4 6 79.8 μm. This may reflect the concurrent progression of diabetic choroidopathy. The mechanism of choroidal thickening in eyes with advanced stages of retinopathy is unknown. [21]

The current study found no difference in the pre-injection CCT between the PDR and the NPDR eyes (P = 0.583), this is contrary to what Kim et al. found in their work in which they demonstrate that CT is closely correlated with the stage of DR, and with the degree or type of DME. Subfoveal CT increased with increasing severity of DR (from no DR to proliferative DR). [22]

Regarding the effect of the Ranibizumab injection on CCT, there was a statistically significant difference between the post-injection CCT and the pre-injection CCT in either group (P < 0.001). But the improvement in the CCT after treatment was not significantly correlated with the pre-injection CCT or the pre-injection CMT (P = 0.346, P = 0.096, respectively).

This means that Ranibizumab was effective in decreasing the CCT in eyes with DME, nevertheless, this improvement (Mean ± SD = 18.85 ± 19.24 μm) after injection was not affected by the pre-injection choroidal or macular thickness.

The role of vascular endothelial growth factor (VEGF) is clearly demonstrated in the work of Savage et al., who utilized a computerized pneumotonometer to investigate pulsatile ocular blood flow as a reflection of choroidal circulation in eyes with DR. Compared with non-diabetic controls, choroidal blood flow increased in severe NPDR and PDR and decreased in treated DR. These findings might reflect an increased production of VEGF or other cytokines mediating choroidal vasodilation and elevation in choroidal blood flow, which subsequently increase the thickness of the choroidal vascular layer, especially in patients with severe NPDR or PDR. Considering these facts, down regulation of VEGF might down size the CT. [10]

Down regulation of VEGF can be achieved by several means. Choroidal blood flow was demonstrated to markedly decrease after laser PRP, possibly due to the down regulation of VEGF. [22] It is thought that the choroidal layer becomes significantly thinner after PRP due to decreased blood flow and subsequent ischemic atrophic change.

Explaining the role of VEGF, several studies found it to be secreted from the RPE into the choroidal vasculature serving a trophic role. VEGF receptors have been identified both in choriocapillaris and in larger blood choroidal vessels. [23] Studies suggest that the choroid is highly dependent on VEGF, [24] namely for the survival of endothelial cells and for normal vascular angiogenesis. Its blood flow increases by a mechanism of nitric oxide production. [25]

Research performed in animal models with intravitreal administration of Ranibizumab(IVR) [26] and Bevacizumab (IVB) [27] showed that these agents can penetrate all retinal layers and reach the choroid, where they can accumulate and block VEGF. After anti-VEGF administration, normal rat choriocapillaris have reduced fenestration compared with controls, and repeated injections can result in irreversible dysfunction. [28] In primates, IVB seems to induce thrombotic microangiopathy in the choriocapillaris and to alter the blood flow in choroidal vessels. [29] In humans, there are one study evaluating the potential effect of the anti-VEGF agents on CT. In this study, the comparison of CT revealed that eyes treated with anti-VEGF injections had a significant reduction of CCT (P = 0.002). [30]

In the current work, the mean pre-injection CMT was significantly different from the post-injection CMT, moreover the improvement of the CMT was found to be significantly correlated with the pre-injection CMT, i.e. the more the CMT before injection, more the decrease in the CMT after injection. The efficacy of Ranibizumab in decreasing the central thickness in eyes with DME is clearly demonstrated in the review by Frampton. [31]

In the current study, we tried to find a correlation between the CMT and the CCT after injection, but such a correlation was not found in all patients as well as in each of the studied groups separately.

A study by Sizmaz, testing the retinal and CT changes after single anti-VEGF injection in neovascular age-related macular degeneration, found that both Ranibizumab and Bevacizumab provided a significant decrease in CMT; however, the agents caused no significant change in CT. In this study they didn't correlate the improvement in CMT to the CT before applying treatment. [32]

In conclusion , intravitreal injection of Ranibizumab was effective in significantly decreasing the CCT as well as the CMT after three consecutive injections, 1 month apart regardless of the level of DR. Whether the number of injections can influence the amount of this reduction or not should be evaluated in future studies. No correlation was found between the reduction in CMT and that of the CCT after intravitreal injection with 0.5 mg of Ranibizumab. We recommend that research on the potential long-term effects of Ranibizumab on the eye structures, especially in the choroid, should be carried out considering its crucial importance for photoreceptors survival.

 
  References Top

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