DR.DIVYA AGARWAL

Dr. ATUL KUMAR, Dr.TOSHIT VARSHNEY, DR.LOHITH RAMBARKI

Semi Finals

Abstract

Purpose: To evaluate modified approach in treating submacular bleed in PCV cases using intraoperative optical coherence tomography (miOCT) and Ngenuity (Heads up display).

Methods: 10 eyes of 10 patients underwent 23-gauge PPV, then iOCT guided submacular injection of cocktail of rTPA (12.5 μg/0.1 mL), bevacizumab (2.5 mg/0.1 mL), and air (0.3 mL). Patients lay propped up postoperatively.

Results: Complete displacement of bleed from macula and resolution was seen in all cases within 7 weeks. Baseline BCVA 1.64 ± 0.4 logMAR units showed significant improvement to 1.13 ± 0.46 logMAR units at 1 month (p<0.006) and 0.82 ± 0.46 logMAR units at 6 month follow-up (p<0.0005). There was no other intraoperative or postoperative complication.

Conclusion: Favorable outcomes were achieved due to effective displacement of bleed and simultaneous treatment of underlying pathology. iOCT aids in precise delivery of drug, avoiding any inadvertent injection into areas of pigment epithelial detachment.

Full Text

 

ABSTRACT:

Purpose: To evaluate the surgical outcomes of a modified approach in the management of submacular hemorrhage secondary to polypoidal choroidal vasculopathy (PCV) using microscope integrated intraoperative optical coherence tomography (miOCT).

Study Design: Retrospective case-series

Methods: 10 eyes of 10 patients underwent 23-gauge vitrectomy, followed by miOCT guided submacular injection of recombinant tissue plasminogen activator (12.5 μg/0.1 mL), Bevacizumab (2.5 mg/0.1 mL), and air (0.3 mL). Written informed consent was obtained in each case. Propped-up positioning was advised in postoperative period. Patients were evaluated for changes in best corrected visual acuity (BCVA), time taken for the displacement of submacular bleed, recurrence of bleed and occurrence of any intraoperative or postoperative complications. All cases were followed up for 6 months after the initial surgery.

Results: Complete displacement of hemorrhage from macula and resolution of bleed was achieved in all cases. The average time taken was 7.6 ± 6.6 weeks (2- 24 weeks). Mean BCVA at baseline was 1.64 ± 0.4 logMAR units (1- 2.1 logMAR units), which showed significant improvement to 1.13 ± 0.46 logMAR units (0.5- 1.8 logMAR units) at 1 month (p=0.0061) and 0.82 ± 0.46 logMAR units (0.5- 1.7 logMAR units) at 6 month follow-up visit (p=0.0005).

Conclusion: Favorable outcomes were achieved due to effective displacement of hemorrhage and simultaneous treatment of the underlying pathology. miOCT guidance aids in precise delivery of the drug into the subretinal space.

Introduction

Submacular hemorrhage refers to the accumulation of blood between the retinal pigment epithelium and neurosensory retina and/or under the RPE. It occurs mostly secondary to various conditions like neovascular age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), myopia, trauma, presumed ocular histoplasmosis syndrome, angioid streaks, etc.^1–3 The prognosis can be poor in cases of old, thick submacular hemorrhage which may extend beyond vascular arcades.⁴

PCV is a variant of neovascular AMD.Recurrent submacular hemorrhages are common in PCV. As compared to AMD, PCV has a more stable and favorable course if managed appropriately.⁵

Various techniques have been described in the literature for the management of vision-threatening submacular hemorrhage but the surgical management of submacular hemorrhage in cases of PCV needs to be extensively studied.^6–9 With the advent of miOCT, real time imaging is available intraoperatively, resulting in better clinical judgments.¹⁰

In this study, we have tried to find out the efficacy of pneumatic displacement of subretinal blood by adopting a modified technique of pars plana vitrectomy followed by miOCT guided subretinal injection of recombinant tissue plasminogen activator (r-tPA) (12.5 μg/0.1 mL) and Bevacizumab (2.5 mg/0.1 mL), along with 0.3 mL of air.  Favorable outcomes have been previously reported by us in cases of submacular hemorrhage secondary to neovascular AMD, using the above technique.¹¹

Materials and Methods:

A retrospective chart review of patients presenting with submacular hemorrhage attributable to PCV was done. All those cases which underwent 23 gauge (G) pars plana vitrectomy followed by miOCT guided subretinal injection of r-tPA, Bevacizumab and air, were included in the study. Selection bias was avoided by recruiting all consecutive patients. Written informed consent was obtained from all  patients. The study adhered to the tenets of the Declaration of Helsinki.

10 eyes of 10 patients suffering from submacular hemorrhage secondary to PCV were included in the study. The baseline evaluation included acquisition of demographic details, best corrected visual acuity (BCVA), history of presenting symptoms, details of previous treatment and history related to systemic illness. All cases underwent a thorough ocular and systemic examination. Ocular examination involved detailed anterior and posterior segment evaluation. The maximum area of hemorrhage was noted in disc diameter (DD). All the cases were subjected to investigations like fundus photography, swept source optical coherence tomography (SS-OCT) and Indocyanine green angiography (ICGA). Due to its longer wavelength, ICGA had the advantage of deeper penetration of rays in areas of hemorrhage, resulting in better imaging. A clinical diagnosis of PCV was made in all those cases in which SS-OCT showed presence of thumb like pigment epithelial detachments (PED), double layer sign or tomographic notch sign. The cases in which ICGA showed presence of polyps with a halo of hypofluorescence around the nodule were also included.(Figure 1) Postoperatively, the diagnosis of PCV was confirmed with the help of SS-OCT and ICGA.

Before starting the surgery, a solution of r-tPA (Boehringer Ingelheim Pharma GmbH & Co, KG, Germany) having a concentration of 1 mg/mL was made by dissolving 20 mg r-tPA in 20 mL of sterile water. Further dilutions were done to achieve a final concentration of 12.5 μg/0.1 mL. 0.3 mL of sterile air was loaded in a 1 mL sterile tuberculin syringe. 0.1 mL Bevacizumab (2.5 mg) {Avastin; Genentech, South San Francisco, California} was then loaded in the syringe. Finally, 0.1 mL of reconstituted r-tPA (12.5 μg/0.1 mL) was drawn. Thus, the total volume of cocktail was 0.5 mL.

Under sterile setting and regional anaesthesia, a standard 3 port 23 G pars plana vitrectomy was performed. Posterior vitreous detachment was induced in all cases. miOCT was used to confirm the site of involvement and to look for any pigment epithelial detachment (PED). The final site of injection was determined using miOCT to avoid any inadvertent injection into PED. The cocktail was then injected subretinally after creating a self-sealing retinotomy using 41 G needle attached to tuberculin syringe. Thus, a small localized bullous retinal detachment was created extending a little beyond the hemorrhage. Air fluid exchange was performed followed by injection of 20% SF6 gas to provide short term tamponade. Propped up position was advised for 3-5 days in the postoperative period.

All cases were followed-up regularly until 6 months after the surgery. Details regarding BCVA, displacement of hemorrhage and any postoperative complication was recorded at each follow-up visit. Detailed anterior, posterior segment examination, color fundus photography and SS-OCT were done at each visit. Cases were subjected to ICGA on a pro re nata basis. In this study, the findings at postoperative 1 month and 6-month visits were analyzed.

Statistical analysis was done using SPSS version 21 software. The continuous data were evaluated using paired t-test. The categorical data were analyzed using Pearson chi square test and Fisher’s exact test. A p-value ≤0.05 was deemed statistically significant.

Results:

Out of 10 patients, 6 patients were male and 4 were female. The mean age of the patients was 67.5 ± 12 years (range, 51-83 years). The average duration of symptoms was 8.8 ± 5.7 days (range, 2- 21 days). The centre of fovea was involved by submacular hemorrhage in all cases on SS-OCT. 4 cases (40%) had hemorrhage extending to vascular arcades.

Mean preoperative BCVA was 1.64 ± 0.4 logMAR units (range, 1-2.1 logMAR units). Displacement of bleed was noticed in all eyes on the first postoperative day. Complete displacement of hemorrhage from macula and resolution of bleed was achieved in all cases. Figure 2, 3 represent successful outcome in the operated cases. The average time taken was 7.6 ± 6.6 weeks (range, 2-24 weeks). Mean postoperative BCVAs of 1.13 ± 0.46 logMAR units (range, 0.5-1.8 logMAR units) and 0.82 ± 0.46 logMAR units (range, 0.5-1.7 logMAR units) were achieved at 1 month and 6 month visits, respectively. There was a statistically significant improvement in visual acuity from preoperative BCVA of 1.64 ± 0.4 logMAR units to 1.13 ± 0.46 logMAR units at 1-month follow-up (p=0.0061). Similarly, visual acuity continued to improve up to 0.82 ± 0.46 logMAR units at 6 months follow-up visit (p=0.0005). No intraoperative or postoperative complication was noted after the surgery. Only one case had a rebleed which was managed conservatively with repeat Intravitreal anti-VEGF injection leading to improvement in vision with final BCVA of 0.8 logMAR units at 6-month follow-up.

Discussion:

PCV is characterized by the presence of slow-growing, complex neovascularization that has a branching vascular network (BVN) with aneurysmal dilations at the outer border of the network. It is highly prevalent in Asian races.⁵ One of the usual presentations of PCV is recurrent submacular hemorrhage which can have variable prognosis depending upon volume (horizontal extent and thickness) and duration of the hemorrhage.

Various techniques have been described in the literature which focus on the pneumatic displacement of bleed with intra-vitreal gas alone or in combination with adjuncts like intravitreal r- tPA or anti-VEGF agent.^6,7 Lin et al. studied 20 cases with PCV and submacular hemorrhage who received either intravitreal injection of tPA and gas or subretinal tissue plasminogen activator (tPA) with vitrectomy. Better results were obtained in the vitrectomy arm.¹²

Haupert et al. first described the technique of subretinal tPA along with pneumatic displacement in cases of subretinal bleed due to neovascular AMD.¹³ Main drawback was sequential management of the underlying pathology rather than simultaneous management, which is pertinent. Hence, modifications were made and published by Martel and Mahmoud et al. in cases of choroidal neovascular membrane (CNVM), where they performed 23 G vitrectomy along with injection of subretinal tPA (12.5 μg/0.1mL) with bevacizumab and air.¹⁴ Prone positioning was advised. They treated the CNVM simultaneously by halting its progression.

The above studies encouraged us to modify the technique. Using a 41 G translocation needle, a bullous neurosensory detachment was created by directly injecting a cocktail of subretinal tPA, Bevacizumab and air and intravitreal 20% SF6. Direct injection of tPA helped in liquefaction of clot as studies have shown that displacement of clotted blood without prior dissolution causes damage to photoreceptor cells. To prevent rebleed, injection bevacizumab was also injected subretinally in the dose of 2.5mg/0.1mL. Treumer et al. showed the efficacy of vitrectomy with subretinal application of tPA and bevacizumab in cases of subretinal bleed due to CNVM.¹⁵ Although the intravitreal injection of Bevacizumab does produce an effect but the direct injection into the subretinal space ensures direct drug delivery over the pathological lesion. Thus, direct high dose injection was used in our study. Subretinal air (0.3mL) along with intravitreal gas (20% SF6) injection helped in pneumatic displacement by acting subretinally and from the vitreous side. Absorption of even sub RPE bleed is rapid due to pressure effect. Propped-up positioning helps in faster inferior displacement of bleed as compared to prone position.

Identification of appropriate site for needle penetration can be challenging. miOCT guidance can help in visualisation of retinal microarchitecture and proper localisation of needle/ cannula. PIONEER study has shown positive results in this aspect.¹⁰

In the present study, complete displacement of bleed was achieved in all cases with no major intraoperative or postoperative complications. Early presentation within 1-2 weeks of the onset of symptoms helped in achieving favorable visual outcomes. Rebleeds and breakthrough hemorrhages are common in PCV. One patient developed rebleed and was managed successfully with intravitreal injection of anti-VEGF agent (Aflibercept) as it reduced the permeability of abnormal choroidal vessels and polyps.⁸ Thus, all the patients experienced significant visual improvement due to timely intervention and effective clot displacement. The use of 41G translocation needle reduces the chance of rhegmatogenous retinal detachment and miOCT guidance further helps in precise delivery of drugs, making it a safe procedure. Similar results were obtained by us in cases of neovascular AMD, reiterating the efficacy of the above technique.¹¹

The study has its limitations due to the limited sample size and the retrospective nature of the study. Further prospective studies like randomized control clinical trials (RCT) can help in establishing the efficacy and safety of this technique.

References:

1. Ozkaya A, Erdogan G, Tarakcioglu HN. Submacular hemorrhage secondary to age-related macular degeneration managed with vitrectomy, subretinal injection of tissue plasminogen activator, hemorrhage displacement with liquid perfluorocarbon, gas tamponade, and face-down positioning. Saudi J Ophthalmol. 2018;32(4):269–74.
2. Doi S, Kimura S, Morizane Y, Shiode Y, Hosokawa M, Hirano M, et al. Successful displacement of a traumatic submacular hemorrhage in a 13-year-old boy treated by vitrectomy, subretinal injection of tissue plasminogen activator and intravitreal air tamponade: a case report. BMC Ophthalmol [Internet]. 2015 Aug 7 [cited 2019 May 5];15. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527187/
3. Chang K-J, Cheng C-K, Peng C-H. Clinical characteristics and visual outcome of macular hemorrhage in pathological myopia with or without choroidal neovascularization. Taiwan J Ophthalmol. 2016;6(3):136–40.
4. Bennett SR, Folk JC, Blodi CF, Klugman M. Factors prognostic of visual outcome in patients with subretinal hemorrhage. Am J Ophthalmol. 1990 Jan 15;109(1):33–7.
5. Kumar A, Kumawat D, Sundar M D, Gagrani M, Gupta B, Roop P, et al. Polypoidal choroidal vasculopathy: a comprehensive clinical update. Ther Adv Ophthalmol. 2019 Feb 27
6. Nayak S, Padhi TR, Basu S, Das T. Pneumatic displacement and intra-vitreal bevacizumab in management of sub-retinal and sub-retinal pigment epithelial hemorrhage at macula in polypoidal choroidal vasculopathy (PCV): rationale and outcome. Semin Ophthalmol. 2015 Jan;30(1):53–5.
7. Chen CY, Hooper C, Chiu D, Chamberlain M, Karia N, Heriot WJ. Management of submacular hemorrhage with intravitreal injection of tissue plasminogen activator and expansile gas. Retina Phila Pa. 2007 Mar;27(3):321–8.
8. Kang HG, Kang H, Byeon SH, Kim SS, Koh HJ, Lee SC, et al. Long-term visual outcomes for treatment of submacular haemorrhage secondary to polypoidal choroidal vasculopathy. Clin Experiment Ophthalmol. 2018 Nov;46(8):916–25.
9. Kimura S, Morizane Y, Hosokawa M, Shiode Y, Kawata T, Doi S, et al. Submacular hemorrhage in polypoidal choroidal vasculopathy treated by vitrectomy and subretinal tissue plasminogen activator. Am J Ophthalmol. 2015 Apr;159(4):683–9.
10. Ehlers JP, Petkovsek DS, Yuan A, Singh RP, Srivastava SK. Intrasurgical assessment of subretinal tPA injection for submacular hemorrhage in the PIONEER study utilizing intraoperative OCT. Ophthalmic Surg Lasers Imaging Retina. 2015 Mar;46(3):327–32.
11. Kumar A, Roy S, Bansal M, Tinwala S, Aron N, Temkar S, et al. Modified Approach in Management of Submacular Hemorrhage Secondary to Wet Age-Related Macular Degeneration. Asia-Pac J Ophthalmol Phila Pa. 2016 Apr;5(2):143–6.
12. Lin T-C, Hwang D-K, Lee F-L, Chen S-J. Visual prognosis of massive submacular hemorrhage in polypoidal choroidal vasculopathy with or without combination treatment. J Chin Med Assoc JCMA. 2016 Mar;79(3):159–65.
13. Haupert CL, McCuen BW, Jaffe GJ, Steuer ER, Cox TA, Toth CA, et al. Pars plana vitrectomy, subretinal injection of tissue plasminogen activator, and fluid-gas exchange for displacement of thick submacular hemorrhage in age-related macular degeneration. Am J Ophthalmol. 2001 Feb;131(2):208–15.
14. Martel JN, Mahmoud TH. Subretinal pneumatic displacement of subretinal hemorrhage. JAMA Ophthalmol. 2013 Dec;131(12):1632–5.
15.  Treumer F, Klatt C, Roider J, Hillenkamp J. Subretinal coapplication of recombinant tissue plasminogen activator and bevacizumab for neovascular age-related macular degeneration with submacular haemorrhage. Br J Ophthalmol. 2010 Jan;94(1):48–53.