Comparative Study between Intravitreal Ranibizumab Injection and Subthreshold Micropulsed Diode Laser (DSM) in Management of Diabetic Macular Edema

INTRODUCTION

Diabetic Retinopathy (DR) is a common and specific microvascular complications of diabetes which affects 17–54% of people with diabetes aged between 49–60 years.^1,2

Diabetic macular edoema (DME) is one of the most common causes of visual loss in today's society. ³ It affects about 10% of diabetic individuals and 29% of those who have had the condition for more than 20 years.⁴

Laser photocoagulation (focal, grid, or diode micropulse) vitrectomy, intravitreal injection of Ranibizumab, or triamcinolone acetonide have all been studied as treatment options for DME. The efficacy of these treatments was examined using best-corrected visual acuity (BCVA) and macular thickness determined using optical coherence tomography (OCT). There is a link between (BCVA) and OCT-measured macular thickness, however the relevance of this link is debatable.⁵

Although conventional laser therapy is the gold standard for slowing the progression of DR, it can sometimes exacerbate macular edoema. Short-pulse laser therapy, which was recently developed, is faster, produces less heat, and is less painful to the

eyes than traditional laser therapy. Furthermore, compared to the traditional pulse duration, short-pulse laser (diode laser micropulse) treatment causes less inflammation, fewer up-regulation of inflammatory cytokines following pan-retinal photocoagulation (PRP), and less macular thickening in patients with DR.⁶

Intravitreal injections of Ranibizumab have recently been shown to be useful in the treatment of DME, with good visual results. ⁷

Ranibizumab (Lucentis^®, Genentech, Inc., South San Francisco, CA) is a recombinant humanized monoclonal antibody Fab fragment that binds and inhibits all isoforms of VEGF-A. Two pilot studies of ranibizumab demonstrated some efficacy in the treatment of DME. ⁸

According to the above data, this study was designed to compare the efficacy of intravitreal ranibizumab injections versus subthreshold micropulsed diode laser (DSM) in  treatment of diabetic macular edoema.

PATIENTS AND METHODS

Patient selection:

This was a prospective, comparative and interventional study that was performed in the departments of ophthalmology at Al Azhar University hospitals between September 2018 and January 2021.

This study involved 50 eyes with DME divided into two groups:Group I: Included (25) eyes where intravitreal ranibizumab injection (0.3mg in 0.05ml) was done. Group II:     Included (25) eyes where subthreshold micropulsed diode laser was done.

Inclusion criteria: Type 2 diabetis mellitus, HA1C less than 10, Phakic patient and pseudophakic patient with past history of cataract extraction since three months or more, Clinically and angiographically diagnosed as DME and have central foveal thickness (CFT) between 250um and 400um on  (OCT).

Exclusion criteria: Prior photocoagulation of the macula with a focal/grid laser, Previous ocular surgery, Pan-retinal photocoagulation, Diabetic papillopathy, Active intraocular inflammation, Drop of vision as a result of other causes, Past history of vitrectomy and past history of intravitreal injection of anti-VEGF or steroid.

Methods:

History Taking:  Age and sex, Diabetic history regarding the type and duration of diabetes.

Ophthalmological examination:

All the patients received complete ophthalmic examinations before injection and laser, incorporating distance (BCVA): Regarding the measurement of visual acuity before and after therapy by using decimal Snellen charts, Intraocular pressure (IOP) by usingGoldmann applanation tonometer. Examination of the anterior segment,including the presence of lens opacities and the presence of iris neovascularization, Posterior segment examination: using slit lamp and + 90 D and + 78 D lens to asses the vitreous for opacities or epiretinal membrane, The retina was assessed for any coexistent diseases, the stage of DR and the periphery of the retina was also examined carefully for any retinal holes or tears using the indirect ophthalmoscope.

Informed consent: The patients signed consent for intervention including: Advantages, disadvantages and the risks of possible complications.

For intravitreal injection: All injections were done in the operating rooms under complete aseptic conditions, the conjunctiva was anaesthetized first by 0.4 % oxybuprocaine eye drops (Benox).

Standard sterilization using Povidone-Iodine 5% (Betadine®) by lid swabbing and instillation in the conjunctival sac was done. A sharp 30-G needle was used to inject a volume of 0.05ml containing 0.3mg of Ranibizumab (Lucentis®, Genentech, Inc., South San Francisco, CA) into the vitreous cavity in phakic and pseudophakic eyes at distances of 4 and 3.5 mm from the limbus respectively.

Aqueous humour was extracted as needed by paracentesis incision with a 30-G needle to avoid a rise in IOP.

For subthreshold micropulsed diode laser: Using the micropulse mode of the Iridex OcuLightTM Tri-Mode SLx 810 nm laser. In this research, 23 patients were treated with a (DSM)

810 nm by using a (× 1.05 magnification) Mainster focal grid contact lens The following treatment parameters were employed in all cases: Exposure time was 200 milliseconds, the spot size was 200 millimetres, the power was 400 milliwatts, and the duty cycle was 5%. Micropulse technology's on and off cycles are referred to as duty cycle. The laser was turned on for 10 milliseconds and then turned off for 190 milliseconds. To guarantee that the surrounding tissues have enough time to cool before the inner retina is exposed to heat injury.

All patients will be followed up as follows:  Visual acuity testing (BCVA),  Full slit lamp examination, Intraocular pressure (IOP) measurement, Fundus examination, (OCT), at one month, three months and six months intervals.

Statistical analysis

The statistical program for social sciences, version 23.0, was used to analyse the data (SPSS Inc., Chicago, Illinois, USA). When the distribution was parametric, the quantitative values were provided as mean, standard deviation, and ranges (normal).

The tests that were carried out were as follows: Independent-samples The t-test of significance was used to compare two means., and the Mann Whitney U test was used for two-group comparisons in non-parametric data. When the predicted count in any cell was less than 5, the Chi-square test and Fisher's exact test were used instead of the Chi-square test to compare groups with qualitative data.

RESULTS

Table 1: Comparison between studied groups according to baseline characteristics.

shows There is no statistically significant difference between the two groups., with p-value (p >0.05 NS).

Regarding BCVA:

 At the base line: the mean BCVA in group (I) was 0.21 with SD 0.13 ranging from 0.1 to 0.5

 whereas in group (II) it was 0.26 with SD 0.12 ranging from 0.1 to 0.5 without statistically

significant difference between the two groups ( p-value 0.198).

 At one month : the mean BCVA was 0.29 with SD ±0.17 ranging from 0.1 to 0.7 in group (I) with statistically significant difference from the base line and was 0.28 with SD ±0.16 ranging from 0.1 to 0.6 in group (II) with  no statistically significant difference from the base line.

     At three months : the mean BCVA was 0.28 with SD ±0.17 ranging from 0.1 to 0.6 in group (I) with statistically significant difference from the base line and was 0.29 with SD ±0.15 ranging from 0.08 to 0.6 in group (II) with no statistically significant difference from the base line.

  At six months : the mean BCVA was 0.25 with SD ±0.17 ranging from 0.083 to 0.6 in group (I) with statistically non significant difference from the base line and was 0.30 with SD ±0.14 ranging from 0.08 to 0.6 in group (II) with no statistically significant difference from the base line and between the two groups, there is no statistically significant difference as shown in (table 2).

Table 2 : Comparison between studied groups according to BCVA.This table shows statistically significant difference between baseline with after 1m and after 3m in group I, with p-value (p<0.05); while in group II there is no statistically significant difference with baseline, with p-value (p>0.05 NS) and statistically non significant difference between both groups, with p-value (p >0.05 NS).

p-value >0.05 NS; *p-value

Changes in the BCVA between baseline and over the period :

In group (I) the mean difference in BCVA (±SD) was 0.08(±0.18) with change (38.10%) , 0.07(±0.13) with change (33.33%), and 0.04 (±0.07)with change (19.05%) at 1, 3 , and 6, months, respectively. While In group (II), the mean difference in BCVA (±SD) was 0.02(±0.05) with change(7.70%) , 0.03(±0.06) with change (11.54%), and 0.04 (±0.09)with change (15.38%) at 1, 3 , and 6, months, respectively and no statistically significant difference exists between the two groups as shown in (table 3).

AT the end of the study, there were 13 eyes (52%) have the same BCVA , 10 eyes (40%) have increase in BCVA  and 2 eyes (8%) have decrease in BCVA in group (I) , while there were 8 eyes (32%) have the same BCVA , 14 eyes (56%) have increase in BCVA  and 3 eyes (12%) have decrease in BCVA in group (II) and no statistically significant difference exists between the two groups as shown in (table 4).

Table 3: Comparison between studied groups according to change in BCVA between baseline and over the period (there was no statistically significant difference between both groups, with p-value (p >0.05 NS).

Table 4: Comparison between studied groups according to BCVA after 6months.which shows that between the two groups, there was no statistically significant difference. with p-value (p>0.05 NS).

Regarding CMT:

At the base line: the mean CMT was 347.84 µm with SD ±34.95 µm ranging from 269 to 390 µm  in group (I) andwas 333.04  µm with SD ±37.85 µm ranging from264 to 391 µm in group (II) with no statistically significant difference between both

groups with ( p-value 0.157).

At one month : the the mean CMT was 292.48 µm with SD ±39.63 µm ranging from 210 to 358 µm in group (I)with statistically significant difference from the base  line and was 324.44 µm with SD ±39.45 µm ranging from 260 to 390 µm in group  (II) with no statistically significant difference from the base line and also between the

two groups, there is a statistically significant difference. with ( p-value 0.006).

 At three months : the the mean CMT was 310.96 µm with SD ±46.18 µm ranging from 210 to 372µm in group (I) with statistically significant difference from the base line and was 308.24 µm with SD ±44.20 µm ranging from 245 to 395 µm in group (II) with statistically significant difference from the base line and between the two groups, there was no statistically significant difference.

At six months : the the mean CMT was 322.48 µm with SD ±53.36 µm ranging from 213 to 397µm in group (I) with statistically significant difference from the base line and was 305.48 µm with SD ±48.70 µm ranging from 240 to 400 µm in group (II) with statistically significant difference from the base line and between the two groups, there was no statistically significant difference as shown in (table 5).

Table 5: Comparison between studied groups according to CMT which shows statistically significant difference between groups according to CMT after 1 months, with p-value (p

Reduction in CMT:

 The mean reduction in CMT as compared to baseline (±SD) was -55.36(±45.40), -36.88(±32.09), and -25.36(±23.08) µm at 1, 3, and 6 months respectively in group (I) and -8.6 (±7.05), -24.8 (±21.58), and  -27.56 (±25.08) at 1, 3, and 6 months, respectively in group (II) as shown (table 6).

Percentage of reduction in CMT:

The mean percentage of reduction in CMT was -15.92%, -10.60%, and -7.29% at 1,3,6 Months respectively in group (I) and was -2.58%, -7.45%, -8.28% at 1,3 and 6 Months respectively in group (II) as shown (table 6).

There was no statistically significant difference in the percentage of reduction of CST between the two studied groups except at 1 months as shown in table (6).

Table 6: Comparison between studied groups according to change in CMT between baseline and over the period which shows statistically significant difference after 1months, with p-value (p

CASE PRESENTATION

Fig. 1: Case 5 group I (upper left image) OCT baseline 386µm, (upper right image) OCT 1st month 315 µm, (lower left image) OCT 3rd month 339 µm, (lower right image) OCT 6th month 372 µm.

Fig. 2: case 1 group II (upper left image) OCT baseline 350µm, (upper right image) OCT 1st month 338 µm, (lower left image) OCT 3rd month 320 µm, (lower right image) OCT 6th month 304 µm