Thursday 27 September 2012

Combined inner limiting membrane peeling and intravitreal triamcinolone acetonide in diffuse diabetic macular oedema By Pankaj Dhaka,MD ; Atul Kumar,MD; R V Azad,MD; Y R Sharma,MD.

Editor                                  
Dr Sudhir Singh
 
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Dr Arun Kshetrapal
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Dr Mayank Agrawal
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Dr Sunil Gupta
Dr Suresh Kumar Pandey
Dr Swati Tomar
Dr Virendra Agrawal
 


Combined inner limiting membrane peeling and intravitreal triamcinolone acetonide in diffuse diabetic macular oedema 
Pankaj Dhaka,MD ; Atul Kumar,MD;  R V Azad,MD; Y R Sharma,MD.
Corresponding Author
Dr.Pankaj Dhaka
                                                                                 M.N Hospital and Research Centre,Bikaner
                                                                                Pin-334001, Phone no. 0151 -2230347, 9314806609
                                                                                 E- mail ID- pankajdhaka79@gmail.
Article Code RJO20110114
Purpose: To evaluate the comparative effect on regression of diabetic diffuse macular edema using combination of surgical ILM peeling and intravitreal triamcinolone acetonide versus intravitreal triamcinolone acetonide (4 mg/0.1 ml) alone versus frequency double Nd:YAG focal/grid photocoagulation (532 nm).
Design: Prospective, comparative case series.
Participants:  Thirty eyes of diabetic patients with diffuse diabetic macular oedema were studied dividing into three groups on the basis of randomization. The study was conducted at Dr. R. P. Centre for Ophthalmic Sciences, AIIMS, New Delhi .
Methods: Three groups were made. In group one,Parsplana vitrectomy with trypan blue (0.2%) assisted ILM peeling was done along with intravitreal triamcinolone acetonide (2 mg/0.1 ml) injection at the end of surgery. In group two, Intravitreal triamcinolone acetonide (4 mg/0.1 ml) is injected in patients with diffuse diabetic macular oedema under topical anaesthesia, and in group three, Focal/grid laser photocoagulation with double frequency Nd: YAG-532 nm was done in patients with diffuse diabetic macular oedema.
Results:  The results showed that in patients who had undergone ILM peeling + IVTA has statistically significant improvement in vision and in patients who had undergone IVTA injection has improvement in vision but it is not statistically significant. But in patients who had undergone focal/grid laser photocoagulation had shown a statistically significant drop in visual acuity. The maximum reduction in central macular thickness after 3 months follow up is patients who had undergone ILM peeling + IVTA followed by patients who had undergone IVTA injection. In patients who were treated with laser photocoagulation the decrease in central macular thickness is less as compared to other groups.
Mean contrast sensitivity before laser was 0.825 which was reduced to 0.825 at 6 weeks follow up and remained same (0.825) after 3 months. These results suggest that in group II patients who were treated by IVTA injection, there is no change in contrast sensitivity but in patients treated with ILM peeling + IVTA and laser photocoagulation, there is decrease in contrast sensitivity and more decrease was in patients treated with laser photocoagulation.
Conclusions: In patients treated with inner limiting membrane peeling + intravitreal triamcinolone acetonide, there is a statistically significant decrease in central macular thickness with statistically significant improvement in visual acuity. In patients treated with intravitreal triamcinolone acetonide, there is a statistically significant decrease in central macular thickness with a statistically non significant improvement in visual acuity. In patients treated with focal/grid laser photocoagulation, there is a statistically significant decrease in central macular thickness with a statistically significant decrease in visual acuity and statistically significant decrease in contrast sensitivity. There is a decrease in contrast sensitivity in patients treated with inner limiting membrane peeling + intravitreal triamcinolone acetonide which is statistically not significant.
INTRODUCTION
Diabetic macular oedema is an important cause of visual impairment in patients with diabetic retinopathy. According to a recent WHO report, India has 31.7 million diabetic subjects and the number is expected to increase to a staggering 79.4 million by the year 2030.1The Wisconsin epidemiologic study of diabetic retinopathy estimated that after 15 years of known diabetes, the prevalence of diabetic macular oedema is ~ 20% in patients with type 1 diabetes, 25% in patients with type 2 diabetes who are taking insulin and 14% in patients with type 2 diabetes who do not take insulin.2Diabetic macular oedema because of the frequency with which it is seen, is a condition that has considerable public health importance. Currently the only demonstrated means to reduce the risk of vision loss from diabetic macular oedema are intensive glycaemic control, as demonstrated by diabetes control and complications trial (DCCT)3 and the U.K. prospective diabetes study4 and laser photocoagulation as demonstrated by early treatment diabetic retinopathy study.5
In the ETDRS, laser photocoagulation of eyes with diabetic macular oedema   reduced the risk of moderate visual loss by ~ 50% (from 24 to 12%, 3 years after initiation of treatment).5 These results show that for some patients, laser photocoagulation is effective but that 12% of treated eyes developed moderate visual loss in spite of treatment furthermore, ~ 40% of treated eyes that had retinal oedema involving the center of macula at baseline still had oedema involving the center at 12 months, as did 25% of treated eyes at 36 months.
Diabetic macular oedema is of two types:           a)Focal – Focal macular oedema derives from individual or small clusters of micro aneurysms that histopathologically leak in more limited extent. b)Diffuse – Diffuse macular oedema derives from extensively damaged capillaries, micro aneurysms and arterioles in a generally dilated capillary bed.
Diffuse diabetic macular oedema is defined as retinal thickening of two or more disc areas and involving some portion of the foveal avascular zone (FAZ) with or without cystoid macular oedema.. ETDRS defines diabetic macular oedema as -(a)Clinically significant macular oedema (CSME) and (b)Non clinically significant macular oedema.
CSME is defined as -          Thickening of retina at or within 500 micron of the center of macula,hard exudates at or within 500 micron of the center of macula, if associated with thickening of adjacent retina and a zone or zones of retinal thickening at least one disc area or larger, any part of which is within one disc diameter of center of macula.
Diffuse diabetic macular oedema does not response to grid laser photocoagulation in nearly 25% of cases.6The frequency of an unsatisfactory outcome following laser photocoagulation in some eyes with diabetic macular oedema has prompted interest in other treatments. One treatment is intravitreal steroids injection.Triamcinolone acetonide has traditionally been used as a periocular injection of the treatment of macular oedema secondary to inflammation or following intraocular surgery.7,8 To achieve a higher intraocular concentration of corticosteroid to treat retinal disease, the intravitreal injection of triamcinolone acetonide was first proposed in 1970, in an animal model, as a pharmacological adjunct to prevent the formation of proliferative vitreoretinopathy in order to improve outcomes following retinal detachment surgery.9
Intravitreal triamcinolone acetonide was first proposed in 1999 as a treatment for diabetic macular oedema because of the safety profile demonstrated in animal models, prior clinical experience with other retinal diseases and the rationale of attenuating the VEGF-mediated retinal capillary permeability that is presumed to contribute to diabetic macular oedema. The use of intravitreal triamcinolone acetonide is now widespread.
Martidis et al10 reported results using intravitreal triamcinolone acetonide injection in 16 eyes with macular oedema due to diabetic retinopathy. They conclude that the intravitreal injection of triamcinolone effectively reduces macular thickening due to diffuse diabetic macular oedema.
Jonas et al11 described results of intravitreal triamcinolone acetonide injection in 26 eyes with diabetic macular oedema. The study concluded that intravitreal triamcinolone injection is beneficial for improving visual acuity in patients of diffuse diabetic macular oedema.Pascale Massin et al12 in these study has also shown reduction of macular oedema in patients of diabetic retinopathy. The commonly used dose of 4 mg / 0.1 mg of triamcinolone is principally being used because of convenience. At a short dose of 40 mg/ml, triamcinolone is easily aliquoted to a 4 mg/0.1 ml dose. A volume of 0.1 ml is readily tolerated when injected into vitreous cavity, other than the convenience of this dose, there are no data that support the use of 4 mg over any other alternative dose.

Role of parsplana vitrectomy and internal limiting membrane peeling in diffuse diabetic macular oedema.
Previous studies have reported favorable anatomic and functional results after vitrectomy and removal of the posterior hyaloid and tractional forces associated with a thickened and taut premacular hyaloid in patients with diabetic macular oedema.13,14,15The surgical procedure consisted of removal of the posterior hyaloid, including peeling of epiretinal fibrocellular proliferations. The inner limiting membrane (ILM) was not approached. In macular hole surgery, the role of removal of the ILM is controversial. A number of vitreoretinal surgeons have reported better success rates with peeling of the ILM.16,17 Although this theory is unproven tangential traction also play a role in the formation and progression of diffuse diabetic macular oedema associated with advanced vitreoretinal interface disease.
Grandorfer et al18 investigated impact of parsplana vitrectomy with ILM peeling in eyes with otherwise refractory diffuse diabetic macular oedema and concluded that, vitrectomy including removal of the ILM leads to expedited resolution of diffuse diabetic macular oedema and improvement of visual acuity.Kumagai et al19 also concluded that the period required for absorption of macular oedema in eyes with ILM peeling was shorter in type II DM. ILM peeling accelerates the absorption of oedema in more severe diabetic macular oedema, but they could not find any improvement of visual acuity.
Mateo C, et al20 from Spain also reported that PPV with ILM peeling could be an effective procedure in the management of non tractional diabetic macular oedema, which is reflected in a reduction of macular thickness and an improvement or stabilization in visual acuity.
OCT versus biomicroscopy in the detection of CSME
The sensitivity of biomicroscopy and OCT in the diagnosis of macular thickening and CSME has been compared by Hee MR, et al.21 The two methods are equally effective in the detection of advanced cases with definite thickening or wide cystic changes. However, shallow changes in retinal thickening of less than 100 microns are invisible at slit lamp and easily observed at OCT.21
OCT therefore seems to be more sensitive in the early diagnosis of DME and in the detection of small changes in retinal thickness after treatment. Moreover, the presence of shallow retinal detachments or fine epiretinal membranes or a partially detached posterior hyaloid are only observed by OCT.22
For our study we used optical coherence tomographer, model-3000 by Carl Zeiss ophthalmic systems, including which have 18 acquisition protocols and 18 analysis protocols. In this study we used fast macular scan as acquisition protocol and retinal thickness single eye (line scan) for analysis purpose.

MATERIALS AND METHODS

 Patient selection
The study was conducted at Dr. R. P. Centre for Ophthalmic Sciences, AIIMS, New Delhi .Thirty eyes of diabetic patients with diffuse diabetic macular oedema were studied dividing into three groups on the basis of randomization.
Group I: Study group (10 eyes)
Parsplana vitrectomy with trypan blue (0.2%) assisted ILM peeling was done along with intravitreal triamcinolone acetonide (2 mg/0.1 ml) injection at the end of surgery.
The surgical technique will include a standard three port parsplana vitrectomy, complete posterior cortical vitrectomy, followed by careful identification, engagement and removal of posterior cortical vitreous layer. Sterile trypan blue dye (0.2%) is then squirted over macula and kept for 5 minutes. Excess of dye is aspirated from vitreous cavity with a vitrector.
The ILM is pinched with pic forceps and flap grasped with the forceps and a shexis is created by slowly tearing the ILM in a circular motion, concentric with the fovea. ILM peeling is combined with injecting triamcinolone acetonide (2 mg/0.1 ml) intravitreal at the end of surgery.
Group II: Study group (10 eyes)
Intravitreal triamcinolone acetonide (4 mg/0.1 ml) is injected in patients with diffuse diabetic macular oedema under topical anaesthesia.
Group III: Control group (10 eyes)
Focal/grid laser photocoagulation with double frequency Nd: YAG-532 nm was done in patients with diffuse diabetic macular oedema.

 

PATIENTS ELIGIBILITY CRITERIA

Inclusion criteria -Patients having persisting diffuse diabetic macular oedema (with cystoid changes on OCT line scan) inspite of previous focal/grid laser photocoagulation at least 3 months back,patients having type-2 diabetic mellitus,patients having nonproliferative diabetic retinopathy (NPDR) with diffuse diabetic macular oedema ,patients having best corrected visual acuity: Snellen’s < 6/60,media clarity, papillary dilatation and patients cooperation sufficient for adequate fundus photography.Informed consent was taken.

Exclusion criteriapatients having age related macular degeneration (ARMD),patients having vascular occlusive disease affecting macula, patients having optic disc disease like open angle glaucoma, patients with macular oedema due to other cause e.g. pseudophakic macular oedema, patients having any major intraocular surgery done within 3 months, patients having any focal/grid laser photocoagulation done or intravitreal triamcinolone injected within 3 months, patients having uncontrolled DM, patients having chronic renal failure, presence of macular traction (on OCT).

WORKUP AND STUDY PARAMETERS

After the patients were selected based on the inclusion/exclusion criteria, work up was done as follows:

General examination -Demographic data, presenting complaints, history of presenting complaints, detailed blood chemistry study done which includes Hb1AC levels, serum urea, serum creatinine, fasting blood sugar levels, postprandial blood sugar levels, systemic examination.

 

Ocular examination- Snellen’s best corrected visual acuity (BCVA), ETDRS best corrected visual acuity ,Contrast sensitivity (Pelli Robson chart), + 90D slit lamp biomicroscopy, Fundus fluorescein angiography (FFA), Colour fundus photography, Macular thickness measured by OCT.

FOLLOW UP

Follow up of patient was done at 1 week, 6 week and 3 months postoperatively. At each follow up, the above study parameters were recorded and repeated. Also, fluorescein angiography and OCT was done at 6 weeks and 3 months.

 

STATISTICAL ANALYSIS

Data were recorded on a predesigned Performa and managed on an excel spread sheet. All the entries were checked for any possible keyboard error. Data obtained was statistically analyzed by student t test. Friedman’s test was used for intra group comparison. For inter group comparison chi-square test was used. In this study, p value of < 0.05 has been taken as statistically significant.

OBSERVATIONS AND RESULTS
For the purpose of study, total 30 patients were taken, 10 each in three groups.
1.         DEMOGRAPHIC PROFILE -In our study the mean age in group I in 59.1 years and standard deviation 6.790 and out of 10 patients, 5 patients were females (50%).In group II patients the mean age is 59.6 years and standard deviation in 8.003 and 3 out of 10 patients were females (30%). In group III patients the mean age is 58.4 years and standard deviation is 7.351 and 2 out of 10 patients were females (20%).In all 30 patients in our study, 33% were females and 67% males with p value of 0.01.
2.         VISUAL ACUITY- (a)Group I: 3 patients showed significant visual improvement (Snellen’s BCVA) by 1 line, p value – 0.049, and the remaining 7 patients showed no improvement.(b)Group II: 2 patients showed visual improvement (Snellen’s BCVA) by 1 line, p value – 0.1353, not significant. The remaining 8 patients showed no improvement in vision.(c)Group III: 2 patients showed a decrease in vision (Snellen’s BCVA) by 2 lines and 1 patient showed a decrease in vision by 1 line (Snellen’s BCVA), p value – 0.049, statistically it is a significant decrease in vision.
3.         CENTRAL MACULAR THICKNESS
(a)          Group I: All 10 patients showed as statistically significant decrease in central macular thickness (p value – 0.0003).
(b)          Group II: All 10 patients showed a statistically significant decrease in central macular thickness (p value – 0.0001).
(c)          Group III: All 10 patients showed a significant decrease in central macular thickness (p value – 0.0003).
Comparison of mean CMT values of all the 3 groups.
 4.CONTRAST SENSITIVITY
(a)          Group I: 3 patients showed a decrease in contrast sensitivity and the remaining 7 patients did not show any change in contrast sensitivity. The decrease is not statistically significant (P value – 0.061).
(b)          Group II: Patients in this group did not show any change in contrast sensitivity (p value – 1.0)
(c)          Group III: 3 patients showed a decrease in contrast sensitivity which is statistically significant decrease (p value – 0.049).
Comparison of mean of contrast sensitivity values of all the three groups.

 
DISCUSSION
The results of our study has shown that there is statistically significant visual improvement in patients who had undergone ILM peeling + intravitreal triamcinolone but in patients in which intravitreal triamcinolone was injected (Group II patients), the visual recovery is not statistically significant. In 3 months follow up the central macular thickness was reduced maximally in group I patients followed by group II patients.It seems that ILM peeling has additive role in decreasing central macular thickness over intravitreal triamcinolone. Studies have shown the close relationship between the vitreous, especially the posterior hyaloid and diabetic macular oedema. Hikichi et al23demonstrated that vitreomacular separation may promote the spontaneous resolution of diabetic macular oedema.
Nasarallah et al24 showed that diabetic eyes with macular oedema have a lower rate of PVD than those without macular oedema, and speculated on a possible role of the vitreous in the pathogenesis of diabetic macular oedema.
Lewis et al13 found that vitrectomy with removal of the thickened, taut premacular posterior hyaloid resulted in reduced macular oedema and improved visual acuity. Tachi and Nobuchika further noted that removal of loose posterior hyaloid also had a significant effect on the reduction of macular oedema. The vitreous may behave as a reservoir of inflammatory substances and its cortex may be a source of tangential traction on the retinal vessels.
Structural changes of the vitreous gel, such as liquification and posterior vitreous detachment are associated with aging and the development of diabetic retinopathy. Stitt et al25 recently reported significantly increased evels of advanced glycation end products in the vitreous of patients with diabetes, forming increased irreversible cross linking of vitreous collagen. Moreover, the ILM thickens with age, and an increase in the bilaminated pattern of fibronectin deposits has been observed. Little is known about the molecular structure of the vitreoretinal interface in the eyes of patients with diabetes, but it seems unlikely that changes of the vitreous in these eyes would be limited exclusively to the vitreous gel. More likely, these changes may affect the vitreoretinal interface including the ILM.
The ILM is known to play an important role as a scaffold for proliferating astrocytes. Its removal not only may result in an almost complete release of tractiona forces, but also may inhibit. The reproliferation of fibrous astrocytes on the retinal surface. Moreover, the removal of the basal lamina of muller cells theoretically may lead to changes in the protoplasmic skeleton of the retina and thereby enable more rapid resolution of diffuse macular oedema.
The rationale for the use of triamcinolone acetonide to treat diabetic macular oedema follows from the observation that the increase in retinal capillary permeability that results in a macular oedema may be caused by a breakdown of the blood retinal barrier mediated in part by VEGF, a 45-kD a glycoprotein.
Antonetti et al26 demonstrated that VEGF may regulate vessel what could be the reason of such decrease in contrast sensitivity after ILM peeling?
The structural boundary between the retina and the vitreous consists of the ILM, which is adherent to the collagenous cortex of the vitreous on its one side, and to the muller (glial) cells end feet on the other.
This latter adhesion is strong enough to cause tearing between the end feet and the rest of muller cells if the ILM is peeled.28 Removal of the end feet may cause changes in physiological features of muller cells even if membranes eventually seal and the cells survive.28
Because the muller cells are known to be sites of an intense exchange of waste products of active retinal neurons with the vitreous body acting as a buffering sink, any loss of muller cell end feet or even of their normal interaction with the vitreous, should interfere with retinal function.29 Unfortunately, it is difficult to assess whether ILM peeling causes impairment of the human retina.
Permeability by increasing the phosphorylation of tight junction proteins such as occluding and zonula occluding.1 This model provides, at the molecular level, a potential mechanism for VEGF-mediated vascular permeability in the eye. With anti-inflammatory properties, triamcinolone acetonide have been demonstrated to inhibit the expression of the VEGF gene.27 In a study by Nauck et al,27 the platelet-derived growth factor induced expression of the VEGF gene was inhibited by corticosteroids in a dose dependent manner. Nauck et al27 also demonstrated that corticosteroids down regulate the induction of VEGF by the proinflammatory mediator platelet-derived growth factor and platelet-activating factor, in a time and dose dependent manner.
Increased diffusion by modulation of calcium channels could also account for the efficacy of the corticosteroids in reducing macular oedema.
In our study, the results are showing that these in statistically nonsignificant decrease in contrast sensitivity in group I patients and no change in contrast sensitivity in group II patients in 3 months follow up. Electron microscopic studies of excised membranes showed a varying degree of adherent cellular structures of presumed glial origin.
The damage to muller cells during surgery and obvious surgical trauma may be the cause of reduction in contrast sensitivity as seen in our study in group I patients.
Our study clearly indicates the beneficial role of ILM peeling + IVTA in reduction of macular oedema in improvement of visual acuity as compared to conventional focal/grid laser photocoagulation.
 
CONCLUSION
In patients treated with inner limiting membrane peeling + intravitreal triamcinolone acetonide, there is a statistically significant decrease in central macular thickness with statistically significant improvement in visual acuity. In patients treated with intravitreal triamcinolone acetonide, there is a statistically significant decrease in central macular thickness with a statistically non significant improvement in visual acuity. In patients treated with focal/grid laser photocoagulation, there is a statistically significant decrease in central macular thickness with a statistically significant decrease in visual acuity and statistically significant decrease in contrast sensitivity.There is a decrease in contrast sensitivity in patients treated with inner limiting membrane peeling + intravitreal triamcinolone acetonide which is statistically not significant.

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