Surgical management of diabetic retinopathy.

Surgery for late complications of proliferative diabetic retinopathy remains the cornerstone of management even in patients who have received optimal laser photocoagulation and medical therapy. With improvisation in the surgical techniques and development of micro-incision surgical techniques for vitrectomy, the indications for surgical intervention are expanding to include diabetic macular edema with a greater number of patients undergoing early intervention. This review describes the current indications, surgical techniques, adjunctive anti-vascular endothelial growth factor therapy, surgical outcomes, and postoperative complications of pars plana vitrectomy for proliferative diabetic retinopathy and macular edema.

INTRODUCTION

Diabetic retinopathy is one of the leading causes of blindness in the working population. The prevalence of diabetic retinopathy increases with duration of diabetes and nearly all patients with Type 1 and more than 60% with Type 2 diabetes develop some signs of retinopathy after 20 years duration.[1] Diabetic retinopathy is primarily a microvascular complication and is characterized by progressive retinal ischemia resulting in the development of non-proliferative diabetic retinopathy (NPDR) or proliferation of new blood vessels in the late phase leading to development of proliferative diabetic retinopathy (PDR) that progresses to develop contractile epiretinal fibrocellular membranes.[23] The new vessels grow along the posterior hyaloid using it as a scaffold and contraction of the fibrocellular membranes causes progressive traction on new vessels resulting in vitreous or pre-retinal hemorrhage, tractional, or combined retinal detachment (CRD).[45]

The patients may first present in the advanced stage of disease with retinal detachment that is not amenable to medical management. In addition, despite medical management including laser photocoagulation, tight systemic control of blood glucose, lipids, cholesterol, blood pressure, and intravitreal injections of steroids and anti-vascular endothelial growth factor (VEGF) drugs,[67891011] nearly 5% of patients show continued progression of retinopathy and require surgical intervention. Additionally, patients with tractional diabetic macular edema require pars plana vitrectomy (PPV).[8] Vitrectomy for complications of diabetic retinopathy was first performed in 1970 in an eye with diabetic vitreous hemorrhage.[1]

This article reviews the current indication, outcomes, techniques, and complications of PPV in diabetic retinopathy .

INDICATIONS AND OUTCOMES FOR PARS PLANA VITRECTOMY IN DIABETIC RETINOPATHY

Vitreous hemorrhage

Vitreous hemorrhage is the most common complication of PDR that causes decreased visual acuity and also interferes with panretinal photocoagulation. Earlier studies suggested PPV and endolaser photocoagulation for vitreous hemorrhage that was persistent and non-clearing for more than 3 months.[121314] However, the Diabetic Retinopathy Vitrectomy Study (DRVS) has shown a clear benefit from earlier surgery in patients with Type 1 diabetes, as delay in the surgery may lead to development of aggressive fibrovascular proliferation with increased risk of tractional/CRD.[151617] The DRVS results indicate that 25% of patients undergoing early PPV regained visual acuity of 20/40 or better compared to 15% of patients who underwent conventional treatment.[17] Since the publication of the DRVS report, this is a trend toward earlier and lower threshold for vitrectomy for diabetic vitreous hemorrhage. With improved surgical techniques the results of PPV for non-resolving vitreous hemorrhage have improved compared to DRVS with a recent study indicating 87% of patients showing improvement by at least 3 ETDRS lines at 12 months.[18] Currently, the general paradigm is to manage patients conservatively for about 1 month from the date of presentation for severe vitreous hemorrhage with no signs of spontaneous clearing in type 1 diabetes while patients with type 2 diabetes are usually given a longer time for spontaneous clearing of vitreous hemorrhage.[5] Other factors influencing the decision to perform PPV include degree of improvement or progression of anterior segment neovascularization, previous panretinal photocoagulation, the visual acuity, and the preference or needs of the patient.[1920] Simple vitreous hemorrhage clears spontaneously through the zonules via aqueous outflow. The presence of red blood cells in the anterior chamber indicates the patency of this outflow channel. The presence of anterior chamber neovascularization or longstanding vitreous hemorrhage with vitreous base fibrosis blocks this pathway for spontaneous drainage and thus are indications for early vitrectomy.[21]

Tractional retinal detachment

The fibrovascular proliferation of tissue contracts and pulls the underlying retina due to vitreoretinal adhesions resulting in the development of tractional retinal detachment (TRD). The TRD generally begins over the arcades and progresses slowly to involve the fovea and requires PPV. Sometimes TRD is peripheral and spares the fovea. Such cases without vitreous hemorrhage may be left untreated if there is no immediate threat to fovea. However, it is important to monitor these patients for any foveal involvement as this progressive disease may involve the fovea over time, warranting PPV. Surgical outcomes are better in patients with recently reduced vision and poorer in patients with longstanding macular heterotopia.[2223]

The results of PPV for TRD have improved following the advent of better surgical techniques. For example, up to 75% of patients had improved vision with or without silicone oil tamponade.[23] However, visual prognosis is influenced by a number of factors including the patient age, location and extent of the TRD, and the duration of macular heterotopia. Older age, anterior segment neovascularization, longstanding macular heterotopia have been associated with poorer visual outcomes.[2324]

Combined tractional and rhegmatogenous retinal detachment

TRD has a fibrovascular component that might contract causing retinal breaks. The development of retinal breaks converts a TRD into a CRD. The retinal break exposes the retinal pigment epithelial cells that cause proliferative vitreoretinopathy with development of tightly adherent membranes on the retinal surface. These pre-retinal membranes contract, adding a component of tangential traction. The visual acuity following PPV for CRD may improve in up to 70% of eyes.[25] These membranes are difficult to dissect from the underlying retina that is mobile and may require bimanual dissection, viscodissection, and silicone oil tamponade.[262728] The outcome of surgery will depend upon the location and extent of the retinal detachment with eyes having good preoperative visual acuity having good prognosis whereas eyes with macular heterotopia have worse outcomes.[25262728]

Pre-macular hemorrhage

Dense pre-macular hemorrhage is a complication of PDR. O’Henley and Canny[29] reviewed 9 patients with dense pre-macular hemorrhage; of the 5 patients who received early PPV within 4 weeks of the onset of hemorrhage, all achieved a visual acuity of 6/12 and better, while those who did not receive PPV within 4 weeks, all developed late macular traction with visual acuity no better than 6/30.

Diabetic macular edema

Diabetic macular edema that is caused by vitreomacular traction or taut posterior hyaloid membrane is an indication for PPV to remove the tractional component contributing towards macular edema.[30] The role of PPV for macular edema without macular traction is controversial. Few studies suggested the improvement of recalcitrant diabetic macular edema refractory to repeated laser photocoagulation treatments with no evidence of macular traction following PPV.[3031] However, other studies provide little evidence in terms of improvement in macular thickness and visual acuity in patients who had an attached posterior hyaloid with no clinical evidence of macular traction or taut posterior hyaloid.[3233] These studies indicate that visual acuity improvement may be compromised by the potential consequences of PPV including progression of cataract, glaucoma, and postoperative vitreous hemorrhage. Persistent DME after PPV with removal of posterior hyaloid may be caused by a taut internal limiting membrane (ILM) and has been reported to respond to PPV and ILM removal.[34] The indications for PPV in diabetic macular edema are summarized in Table 1.

Table 1

Indications for PPV in diabetic macular edema

More recently, ILM peeling is being performed along with PPV and again the reports have conflicting results. Though some studies indicated a better visual outcome for diffuse diabetic macular edema following PPV with ILM peeling,[33343536] others reported little benefit in terms of visual gain during short-term follow up.[373839] For example, quite a few studies have reported good long-term outcomes of PPV with ILM peeling in reducing diffuse diabetic macular edema and improving the visual acuity.[404142] The mechanism of resolution of macular edema in the non-tractional variety is believed to be due to changes in blood flow to the macula following PPV and ILM peeling.[43]

However, a recent study published the results of PPV with or without ILM peeling and reported that PPV and posterior vitreous detachment with or without ILM peeling does not improve vision in patients with diabetic cystoid macular edema and no traction.[44]

TECHNIQUES OF PPV IN DIABETIC RETINOPATHY

PPV for vitreous hemorrhage includes three port core vitrectomy first followed by identification of the posterior hyaloid face (PHF). If there is significant retrohyloidal bleed, an opening is created in the PHF and retrohyloidal blood is aspirated to gain a good view of the underlying retina.[45] Though straightforward, PPV for vitreous hemorrhage may be complicated with intraocular fibrin formation that provides a scaffold for fibrovascular proliferation, and also interferes with clearance of recurrent bleeds through the anterior chamber. Adequate pre-surgery panretinal photocoagulation and good metabolic control are useful in reducing intraoperative fibrin formation.[5] Often, fibrovascular membranes are present on the retinal surface. These membranes are vascularized and bleed intraoperatively and thus cannot be simply peeled from the retinal surface as it results in bleeding and retinal tears.[45464748] The following techniques are useful in dissecting the surface membranes.

Segmentation

It is used to release circumferential traction with the help of vertical cutting scissors or vitreous cutter. These membranes are segmented into small segments that can be left as remnants center on neovascular pegs.[45464748]

Delamination

This technique involves removal of fibrovascular membranes from the surface of retina. Horizontal scissors are used to find the correct plane between the posterior hyaloid and the retina where en bloc delamination can be performed to remove the fibrovascular tissue from the retinal surface.[45464748] It is helpful to keep the posterior hyaloid partially intact that facilitates dissection of epiretinal membranes by elevating the epiretinal membranes due to antero-posterior traction. The dissection maybe performed with a vitreous cutter in cases where there are multiple isolated adhesions with adequate space between retina and vitreous.[45] In cases where these membranes are firmly attached to the underlying retina, the dissection maybe performed using long curved scissors, MPC scissors, picks, and/or forceps.[45464748] Bimanual dissection or illuminated forceps may be used to facilitate dissection. Using perfluorocarbon may aid in dissection of firmly adherent membranes.[49] Many of these eyes require long-term silicone oil tamponade for anatomical and functional stability.[5051] Due to improved instrumentation, currently, smaller gauge transconjuctival PPV is being favored compared to 20 gauge PPV with faster recovery in patients with PDR [Figures 1–4].[51525354] Issa et al.[55] compared the results of 20 and 23 gauge transconjunctival vitrectomy for PDR. In their[55] retrospective review of two series of patients who had undergone primary PPV for PDR and a control group that had undergone 20 gauge vitrectomy, they reported a significant reduction in the incidence of peripheral sclerotomy-related retinal breaks with 23-gauge (5%) versus 20-gauge (16%) vitrectomy.

Figure 1

Color fundus photograph of the right eye showing fibrovascular proliferation extending from nasal half of the optic disc to the fovea causing macular pucker. The patient underwent 23-gauge transconjuctival pars plana vitrectomy

Figure 4

Same eye as in Figure 3, 2 months postoperatively, showing a flat retina. The best corrected visual acuity improved from 20/200 to 20/40 postoperatively

Same eye as in Figure 1, 3 months later showing release of traction over the fovea with normal foveal contour

Figure 3

Color photograph of the left eye showing tractional retinal detachment. The patient underwent 23-gauge transconjunctival pars plana vitrectomy

Endolaser

Endolaser photocoagulation during PPV is performed routinely in all patients undergoing PPV for PDR to minimize postoperative hemorrhage. It is important to examine the retinal periphery for any retinal breaks that warrant laser photocoagulation/cryotherapy and internal tamponade.

Sima and Zoran[56] prospectively evaluated 174 patients undergoing vitrectomy for diabetic retinopathy and reported retinal breaks in 39% of cases. Though the majority of these breaks were posterior and seen during membrane dissection, 17% were seen at the entry site.[56] In another study,[57] the overall incidence of iatrogenic breaks was reported to be 29% in patients undergoing 20-gauge vitrectomies for diabetic retinopathy. The most common cause of iatrogenic breaks was dissection of fibrovascular membranes with posterior vitreous detachment creation, and shaving of peripheral vitreous associated with retinal breaks formation in only in 8% of cases and retinal dialysis in 2% of cases.[57] Oral retinal dialysis was also associated with increased incidence of postoperative hemorrhage.

ROLE OF PREOPERATIVE INTRAVITREAL BEVACIZUMAB

Intraoperative bleeding from the fibrovascular membranes is the major intraoperative complication in PPV for TRD and CRD. Pretreatment with intravitreal anti- VEGF, 3-4 days prior to surgery helps in reducing intraoperative bleeding, thus facilitating fibrovascular membrane peeling. It is also reported to reduce postoperative vitreous hemorrhage.[575859606162] Preoperative bevacizumab led to improved visual outcome that was maintained at 6-months with reduced occurrence of postoperative vitreous hemorrhage.[6263] Ushida et al.[64] reported safety of intravitreal bevacizumab in 23 patients, and evaluated its effect on the visual function in PDR eyes, and reported that average visual acuity improved postoperatively from 20/250 to 20/70 with no change in visual fields and ERGs. A recent study however reported a higher incidence of early postoperative vitreous hemorrhage (27%) than in a control group (7%).[65] However, the rate of vitreous hemorrhage after 4 weeks was not different between groups.[65] Jirawison and Ittipunkul[66] reported that intravitreal injection of 1.25 mg of bevacizumab at the end of diabetic vitrectomy was associated with lowest incidence of early postoperative vitreous hemorrhage with significant visual recovery at the end of 6 months.

Success with preoperative intravitreal bevacizumab has also reported in eyes that require silicone oil tamponade although it may carry a higher incidence of subretinal bleeding.[67] Intravitreal bevacizumab primarily affects the blood vessels and also regulates the vascular microenvironment by causing the contraction of blood vessels, increasing pericyte ratio, and transforming growth factor-beta expression in fibrovascular membranes; thus making them easier to peel.[68]

Intra- and Post-operative complications

Corneal edema: Patients with diabetes are reported to have an abnormal basement membrane that causes reduced epithelial adherence resulting in intraoperative corneal edema.[697071] Use of viscoelastic and corneal lubrication reduces the need for corneal debridement.[71]

Iatrogenic retinal breaks: Posterior retinal breaks usually occur adjacent to vitreoretinal adhesions during dissection and are commonly seen in eyes where membranes are fibrous while the retina is thin and atrophic.[7273] Kamura et al.[57] evaluated iatrogenic retinal breaks in 760 eyes of 609 patients who underwent PPV for PDR and found an overall incidence of 29%. They reported a poorer outcome with iatrogenic retinal breaks during fibrovascular membrane dissection than peripheral retinal breaks or oral dialysis.[57] In the absence of retinal break, the tractional retinal detachment can be successfully managed without any tamponade.[74]

Intraoperative bleeding and intraocular fibrin formation: Intraoperative hemorrhage and fibrin formation are potentially serious complications of vitrectomy in diabetic eyes. However, preoperative bevacizumab has reduced this complication (see above). Significant fibrin in the postoperative period may require injection of recombinant tissue plasminogen activator (tPA).[7576]

Elevated Intraocular pressure: The incidence of postoperative intraocular pressure (IOP) of 30mm Hg or more has been reported in up to 35% of eyes following PPV.[77] Eyes with diabetic retinopathy are quite susceptible to visual loss from elevated IOP due to underlying retinal ischemia and require close monitoring.

Cataract: Intraoperative lenticular opacities can be reduced by supplementation of glucose in the infusion fluid.[7078] Visually significant cataract occurs in 17-37% of eyes undergoing vitrectomy for diabetic retinopathy.[7980]

Rubeosis and neovascular glaucoma: The reported incidence of iris neovascularization following diabetic vitrectomy in the earlier studies is 8-26% in phakic eyes and 31-55% in aphakic eyes and neovascular glaucoma in 4-13% of phakic eyes and 11-35% of aphakic eyes.[818283] However, these studies were published prior to the development of endolaser and the current rate of rubeosis and neovascular glaucoma is lower.[8485] Treatment includes topical steroids, cycloplegics and intravitreal bevacizumab.[86] A recent study has reported benefit of intrasilicone injection of bevacizumab in the treatment of patients with iris neovascularization after vitrectomy for advanced PDR with silicone oil tamponade.[87]

Postoperative vitreous hemorrhage: Postoperative vitreous hemorrhage following PPV for PDR has been reported in 12%-63% of cases and may occur within the first few weeks or even months later.[888990] Park et al.[91] reported comparable rates of postoperative bleed following 23 gauge (17%) versus 20-gauge (26%) vitrectomy.[91] Khuthaila et al.[92] reported that 32% of eyes develop vitreous hemorrhage following 23-gauge PPV for diabetic retinopathy and was associated with inadequate laser photocoagulation, phakia, and younger age.[92] Yang et al.[93] have reported the use of C3F8 gas tamponade was effective in preventing recurrent vitreous hemorrhage. One must consider that postoperative bleeding may be due to fibrovascular proliferation at the sclerotomy site.[9495] Yeh et al.[94] have reported prophylactic cryotherapy treatment of the sclerotomy sites to prevent postoperative hemorrhage. However, Entezari et al.[95] did not find this useful in reducing the postoperative hemorrhage. The current evidence regarding the role of perioperative intravitreal bevacizumab preventing early postoperative hemorrhage is contradictory.[96979899] Jirawion and Ittipunkul[66] reported the lowest incidence of early postoperative vitreous hemorrhage in eyes that received intravitreal bevacizumab injection at the end of diabetic vitrectomy.

Anterior hyaloidal fibrovascular proliferation (AHFVP): This complication has been reported to occur in nearly 13% of cases, especially in young patients with long standing diabetes and extensive retinal ischemia.[100101] Fibrovascular proliferation at the sclerotomy site can produce a similar picture.[102103104] This usually causes vitreous hemorrhage 3-12 weeks after vitrectomy and is reported to be due to increased VEGF levels in the postoperative period.[105] Additional panretinal photocoagulation, cryotherapy of sclerotomy sites, and surgical intervention are usually necessary.

PARS PLANA VITRECTOMY FOR DIABETIC MACULAR EDEMA

In 1988, Nasrallah et al.[106] reported the possible role of vitreous traction in causing macular edema. A few years later, Lewis et al.[107] reported a group of patients with recalcitrant diabetic macular edema who had a taut, thickened posterior hyaloid and hypothesized the tangential tractional forces were responsible for macular edema. Diabetic macular edema caused by the traction from a taut posterior hyaloid, vitreomacular traction, or epiretinal membranes has been reported to improve following PPV resulting in visual improvement and resolution of macular edema.[107108109110] The Diabetic Retinopathy Clinical Research Network reported improvement of visual acuity in 28% to 49% of eyes undergoing vitrectomy for vitreomacular traction, whereas 13% to 31% of eyes experienced a decrease in visual acuity.[111] Furthermore, removal of epiretinal membranes was associated with better visual outcome.[112] There are reports of improvement in macular edema in eyes with no evidence of vitreomacular traction. One study reported a significant improvement in visual acuity in patients with diabetic macular edema non-responsive to grid laser photocoagulation.[113] However, other studies reported a reduction of macular volume without much improvement in visual acuity.[114115] The mechanism of action of vitrectomy remains unclear in these eyes. It is postulated that diabetic eyes have cytokines that may promote vascular permeability and vitrectomy with or without ILM peeling that removes the vitreous reservoir by facilitating the diffusion of these agents. Furthermore, PPV improves oxygenation, which further improves the integrity of inner blood retinal barrier.

Ocular factors including preoperative visual acuity and foveal average retinal thickness were reported to influence the final visual outcome, and no history of diabetes treatment until diabetic retinopathy and high glycosylated hemoglobin were associated with poorer outcome.[116] Preoperative integrity of the external limiting membrane was found to be associated with good postoperative visual outcome.[117] Murakami et al.[118] performed segmentation analysis of retinal thickness after vitrectomy in diabetic macular edema and found that outer retinal thickness of the temporal subfield was associated with disruption of the junction between the inner and outer segments (ellipsoid zone) at the fovea and was associated with poor visual outcome. In addition, Yoshikawa et al.[119] have recently reported that the papillofoveal distance was shortened and the temporal retina thinner in eyes that underwent ILM peeling to treat diabetic macular edema.

PHARMACOLOGICAL VITREOLYSIS

The anatomical and functional success of PPV depends on the complete separation of posterior hyaloid from the retinal surface. Studies have shown that residual cortical vitreous tends to be left behind despite meticulous peeling of posterior hyaloid[120] and the process of surgical separation itself may cause structural damage to the underlying retina.[121] An attempt to peel the ILM for better cortical cleanup also increases the risk of complications including nerve fiber layer damage associated with paracentral scotomas.[122] The term pharmacologic vitreolysis indicates the role of pharmacologic agents to modify the molecular structure of the vitreous that induces vitreoretinal separation. Plasmin, a serine protease is known to degrade laminin, fibronectin[123124125] and generate increased levels of matrix metalloproteinases, elastase resulting in weakening of vitreoretinal insertion and liquefaction of the vitreous.[126127] Autologous plasmin enzyme (APE) has been reported to cause a nonsignificant increase in spontaneous posterior vitreous detachment in eyes with tractional diabetic macular edema[128129130] and advanced PDR.[131] Azzolini et al.[129] reported higher visual acuities at the end of one year in patients with DME who had received intravitreal APE compared with those who had not received.

Microplasmin is a commercially available recombinant molecule that is currently preferred over plasmin for PVD induction. Microplasmin intravitreal injection (MIVI) was a clinical trial designed to assess efficacy at various doses and exposures of microplasmin in enzyme-assisted vitrectomy for the treatment of vitreomacular adhesion related pathologies including tractional DME. Only less than 50% of eyes in any cohort developed spontaneous PVD.[132] The results were dose and exposure dependent. The results of MIVI-II (TG-MV-002) which is a phase II sham-controlled non-vitrectomy study in patients with tractional DME are still being gathered.

CONCLUSION

The role of pars plana vitrectomy is unquestionable for managing complications of proliferative diabetic retinopathy including those that were previously considered blinding. With newer improved techniques and pharmacologic interventions and including minimally invasive vitreoretinal surgery, and intravitreal bevacizumab, early vitrectomy is favored due to better visual outcomes. There is also growing evidence favoring vitrectomy for diabetic macular edema refractory to laser and medical therapy. Pharmacological vitreolysis seems promising and results of more clinical trials in diabetic retinopathy are awaited.